S-1/A Amendment No.3
Table of Contents

As filed with the Securities and Exchange Commission on June 19, 2018.

Registration No. 333-225178

 

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

Amendment No. 3

to

FORM S-1

REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

 

 

MAGENTA THERAPEUTICS, INC.

(Exact name of Registrant as specified in its charter)

 

 

 

Delaware   2834   81-0724163

(State or other jurisdiction of

incorporation or organization)

 

(Primary Standard Industrial

Classification Code Number)

 

(I.R.S. Employer

Identification Number)

Magenta Therapeutics, Inc.

50 Hampshire Street, Cambridge,

Massachusetts

02139

(857) 242-0170

(Address, including zip code and telephone number, including area code, of registrant’s principal executive offices)

 

 

Jason Gardner

President and Chief Executive Officer

Magenta Therapeutics, Inc.

50 Hampshire Street, Cambridge,

Massachusetts

02139

(857) 242-0170

(Name, address, including zip code, and telephone number, including area code, of agent for service)

 

 

Copies to:

 

Mitchell S. Bloom, Esq.

William D. Collins, Esq.

Goodwin Procter LLP

100 Northern Avenue

Boston, Massachusetts 02210

(617) 570-1000

 

Zoran Zdraveski, Esq.

Chief Legal Officer and Secretary

Magenta Therapeutics, Inc.

50 Hampshire Street

Cambridge, Massachusetts 02139

(857) 242-0170

 

Deanna Kirkpatrick, Esq.

Davis Polk & Wardwell LLP

450 Lexington Avenue

New York, New York 10017

(212) 450-4000

 

 

Approximate date of commencement of proposed sale to public: As soon as practicable after this Registration Statement becomes effective.

If any of the securities being registered on this Form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, check the following box:  ☐

If this Form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, please check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering:  ☐

If this Form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering:  ☐

If this Form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering:  ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

 

Large accelerated filer      Accelerated filer  
Non-accelerated filer   ☒  (Do not check if a smaller reporting company)    Smaller reporting company  
     Emerging growth company  

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 7(a)(2)(B) of the Securities Act.  ☐

 

 

CALCULATION OF REGISTRATION FEE

 

 

Title of Each Class of

Securities to be Registered

 

Amount to be
Registered(1)

 

Proposed

Maximum

Offering Price
Per Share

 

Proposed

Maximum

Aggregate

Offering Price(2)

  Amount of
Registration Fee(3)

Common Stock, par value $0.001 per share

  7,666,667   $16.00   $122,666,672   $15,272

 

 

(1) Estimated solely for the purpose of calculating the registration fee pursuant to Rule 457(a) under the Securities Act of 1933, as amended. Includes 1,000,000 shares that the underwriters have an option to purchase.
(2) Includes the offering price of shares that the underwriters may purchase pursuant to an option to purchase additional shares.
(3) Previously paid.

 

The Registrant hereby amends this Registration Statement on such date or dates as may be necessary to delay its effective date until the Registrant shall file a further amendment which specifically states that this Registration Statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933 or until the Registration Statement shall become effective on such date as the Securities and Exchange Commission, acting pursuant to said Section 8(a), may determine.

 

 

 


Table of Contents

The information in this preliminary prospectus is not complete and may be changed. We may not sell these securities until the registration statement filed with the Securities and Exchange Commission is effective. This preliminary prospectus is not an offer to sell these securities and it is not soliciting an offer to buy these securities in any jurisdiction where the offer or sale is not permitted.

 

Subject to Completion, dated June 19, 2018

PRELIMINARY PROSPECTUS

6,666,667 Shares

 

LOGO

COMMON STOCK

 

 

We are selling 6,666,667 shares of our common stock in this offering. This is our initial public offering and no public market currently exists for our shares. We anticipate that the initial public offering price of our common stock will be between $14.00 and $16.00 per share.

We have applied to list our common stock on The NASDAQ Global Market under the symbol “MGTA.”

We are an “emerging growth company” as that term is used in the Jumpstart Our Business Startups Act of 2012, as amended, and, as such, have elected to comply with certain reduced public company reporting requirements for this prospectus and future filings.

Investing in our common stock involves risks. See “Risk Factors” beginning on page 15.

 

 

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or passed upon the adequacy or accuracy of this prospectus. Any representation to the contrary is a criminal offense.

 

     Per
share
     Total  

Public offering price

   $                   $               

Underwriting discounts and commissions(1)

   $      $  

Proceeds to us before expenses

   $      $  

 

(1) We have agreed to reimburse the underwriters for certain FINRA-related expenses, in addition to underwriting discounts and commissions. See “Underwriting.”

Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to approximately $40.0 million of shares of our common stock in this offering at the initial public offering price. However, because indications of interest are not binding agreements or commitments to purchase, the underwriters may determine to sell more, less or no shares in this offering to such stockholders, and such stockholders could determine to purchase more, less or no shares in this offering.

We have granted the underwriters an option for a period of 30 days from the date of this prospectus to purchase up to 1,000,000 additional shares of our common stock at the public offering price, less the underwriting discount.

The underwriters expect to deliver the shares of common stock to purchasers on                , 2018.

Joint Book-Running Managers

 

J.P. Morgan   Goldman Sachs & Co. LLC                                   Cowen

Co-Manager

Wedbush PacGrow

The date of this prospectus is                , 2018


Table of Contents

TABLE OF CONTENTS

 

     Page  

PROSPECTUS SUMMARY

     1  

THE OFFERING

     11  

SUMMARY FINANCIAL DATA

     13  

RISK FACTORS

     15  

CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

     70  

USE OF PROCEEDS

     72  

DIVIDEND POLICY

     74  

CAPITALIZATION

     75  

DILUTION

     77  

SELECTED FINANCIAL DATA

     80  

MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS

     82  

BUSINESS

     98  

MANAGEMENT

     169  

EXECUTIVE COMPENSATION

     178  

CERTAIN RELATIONSHIPS AND RELATED PARTY TRANSACTIONS

     187  

PRINCIPAL STOCKHOLDERS

     193  

DESCRIPTION OF CAPITAL STOCK

     196  

SHARES ELIGIBLE FOR FUTURE SALE

     202  

MATERIAL U.S. FEDERAL INCOME TAX CONSIDERATIONS FOR NON-U.S. HOLDERS

     204  

UNDERWRITING

     208  

LEGAL MATTERS

     215  

EXPERTS

     215  

WHERE YOU CAN FIND MORE INFORMATION

     215  

INDEX TO FINANCIAL STATEMENTS

     F-1  

We and the underwriters have not authorized anyone to provide any information other than that contained in this prospectus or in any free writing prospectus prepared by or on behalf of us or to which we have referred you. We take no responsibility for, and can provide no assurance as to the reliability of, any other information that others may give you. We and the underwriters are not making an offer to sell these securities in any jurisdiction where the offer or sale is not permitted. You should assume that the information appearing in this prospectus is accurate only as of the date on the front cover of this prospectus. Our business, financial condition, results of operations and prospects may have changed since that date.

This prospectus contains forward-looking statements that are subject to a number of risks and uncertainties, many of which are beyond our control. See “Risk Factors” and “Cautionary Note Regarding Forward-Looking Statements.”

Dealer Prospectus Delivery Obligation

Until                , 2018 (the 25th day after the date of this prospectus), all dealers that effect transactions in these securities, whether or not participating in this offering, may be required to deliver a prospectus. This is in addition to the dealers’ obligation to deliver a prospectus when acting as underwriters and with respect to their unsold allotments or subscriptions.

For investors outside of the United States: We have not, and the underwriters have not, done anything that would permit this offering or possession or distribution of this prospectus in any jurisdiction where action for that purpose is required, other than the United States. Persons outside of the United States who come into possession of this prospectus must inform themselves about, and observe any restrictions relating to, the offering of the shares of common stock and the distribution of this prospectus outside of the United States.

 

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Trademarks and Trade Names

We own or have rights to various trademarks, service marks and trade names that we use in connection with the operation of our business. This prospectus may also contain trademarks, service marks and trade names of third parties, which are the property of their respective owners. Our use or display of third parties’ trademarks, service marks, trade names or products in this prospectus is not intended to, and does not imply a relationship with, or endorsement or sponsorship by us. Solely for convenience, the trademarks, service marks and trade names referred to in this prospectus may appear without the ®, TM or SM symbols, but the omission of such references is not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the right of the applicable owner of these trademarks, service marks and trade names.

 

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PROSPECTUS SUMMARY

Our Business

For more than 50 years, doctors and patients have had difficult conversations about bone marrow transplant: the procedure can save lives and cure patients, however the risks of toxicity and death often deter its use. At Magenta, we believe we can refocus that conversation on the cure and enable many more patients with devastating diseases such as severe autoimmune disorders, including multiple sclerosis; blood cancers, including leukemia; and genetic diseases such as sickle cell disease to benefit from advances in transplant medicine.

We are a clinical-stage biotechnology company developing novel medicines to bring the curative power of bone marrow transplant to more patients.

Transplant is a well-established and often curative medical procedure, and emerging data on stem cell gene therapy, which is bone marrow transplant using gene-modified stem cells, suggest the potential for meaningful benefit with this newer form of transplant. Bone marrow transplant and stem cell gene therapies use the same widely-adopted decades-old transplant process. As it exists today, bone marrow transplant is a large market opportunity, and improvements to the current approaches could extend bone marrow transplant to more patients. The ability to treat patients with a bone marrow transplant is limited by the challenge of obtaining sufficient cells to perform the procedure, the inherent morbidity and mortality of current methods used to prepare patients for transplant, and complications following transplant.

At Magenta, we believe we are uniquely positioned to overcome these challenges and to lead a new era in transplant medicine. Our portfolio of product candidates includes biologics, small molecules and a cell therapy designed to address deficiencies in existing approaches and extend the curative power of bone marrow transplant to more patients across many diseases. Currently, only a fraction of eligible patients with these diseases receive a transplant because the risks and challenges outweigh the potential for a cure. These include diseases where bone marrow transplant is a standard of care (e.g., blood cancers such as acute myelogenous leukemia, myelodysplastic syndromes, multiple myeloma, and non-Hodgkin lymphoma), diseases where transplant is performed but limited in use (e.g., hemoglobinopathies such as sickle cell disease and beta-thalassemia), and autoimmune diseases. Emerging clinical data suggest that bone marrow transplant may represent a breakthrough approach with curative potential for patients with severe autoimmune diseases. For example, recent results from multiple clinical trials show that patients with autoimmune diseases, including multiple sclerosis and scleroderma, can be cured with a transplant. However, based on our epidemiology analyses, currently only approximately 1 to 2% of eligible patients with multiple sclerosis or scleroderma in the United States and Europe receive a bone marrow transplant.

To address the major unmet medical needs in the existing bone marrow transplant process, we are developing a stem cell biology discovery platform and comprehensive portfolio of novel therapeutics. Our programs will improve stem cell dose (expansion), stem cell collection (mobilization), patient preparation for transplant (conditioning), and potential post-transplant complications to address key limitations of the bone marrow transplant process to allow more patients to benefit. Within our expansion program, MGTA-456, our most advanced clinical product candidate, is a cell therapy that has achieved clinical proof of concept in 36 patients with blood cancers and is now being studied in patients with fatal inherited metabolic diseases. MGTA-456 is an expanded cord blood product, and has the potential to allow more patients to have a better chance for a successful stem cell transplant. Within our mobilization program, MGTA-145 is focused on enabling physicians to more easily harvest a greater number of blood stem cells, known as hematopoietic stem cells or HSCs, from patients and donors to improve patient outcomes. Our targeted transplant conditioning programs, which prepare the patient for transplant, are designed to selectively remove stem and/or immune cells from a patient prior to transplant, and to be far less toxic than the decades-old radiation and chemotherapy-based approaches which are still the only available options. Our post-transplant complications program is designed to target the donor immune cells within the patient that cause Graft vs. Host Disease, or GvHD, which can be a fatal complication of transplant.



 

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We intend to become a fully integrated discovery, development and commercial company in the field of transplant medicine. We believe that our product portfolio will offer significant commercial synergies. We are developing our products so that they can each be used individually or in combination with each other. As a result, our portfolio could be utilized in a manner tailored to the patient’s disease, such that a patient may receive more than one Magenta therapy as part of their individual transplant journey.

Background on Bone Marrow Transplant

Bone marrow is the tissue inside bones where HSCs are located. HSCs produce all of the cells in the blood and immune systems, including: T cells and B cells to fight infections; red blood cells to carry oxygen and platelets to control bleeding. The bone marrow is highly active and gives rise to billions of new cells every day. However, abnormal functioning of the system can lead to serious and sometimes fatal blood and immune diseases. The aim of bone marrow transplant, also called HSC transplant or stem cell transplant, is to replace the diseased blood and immune cells with new stem cells that will produce new blood and immune cells, thereby effectively restoring the blood and immune systems to a healthy state.

Bone Marrow Transplant: The Process and Challenges

A bone marrow transplant procedure utilizes a number of integrated steps, which we explain below: stem cell sourcing and collection, patient conditioning and stem cell infusion and engraftment. All transplants are categorized as either autologous or allogeneic, depending on the source of cells for the transplant. In an autologous transplant, used for conditions such as multiple myeloma, non-Hodgkin lymphoma and autoimmune diseases, the patient’s own stem cells are used. This is also the case for stem cell gene therapy. In an allogeneic transplant, used for conditions such as acute leukemia and genetic diseases, patients receive cells from a stem cell donor or umbilical cord blood.

Step 1: Stem Cell Sourcing and Collection

Once the patient and physician agree that bone marrow transplant is the best treatment option, first the source of stem cells must be identified and then the cells are collected. There are three sources of stem cells for transplant: extraction from the bone marrow, mobilization into the peripheral blood and harvesting from umbilical cord blood units. In the case of stem cell gene therapy, once the cells are collected from the patient, they are then modified to either insert a functioning gene or correct a defective gene.

Finding a matched donor and collecting enough stem cells are two significant challenges associated with the first step of bone marrow transplant. It is critical that physicians obtain enough stem cells for the transplant as higher cell doses are closely correlated to better patient outcomes. Although there are more than 25 million registered bone marrow donors worldwide, nearly half of all patients are unable to find a matched donor. Patients without a matched donor require the use of an alternative stem cell source such as unmatched donor or umbilical cord blood, or UCB. Although more than 712,000 units are available in the worldwide cord blood inventory, the number of stem cells in a cord blood unit is low, and fewer than approximately 4% of these units contain enough stem cells for use in adults. Another option, stem cell harvesting, involves multiple invasive bone marrow harvests, or repeated injections, which are often associated with bone pain, nausea, headache and fatigue. It is difficult to predict whether mobilization will be successful, especially in heavily treated blood cancer patients.

Step 2: Conditioning

Once sufficient cells have been obtained, the patient is then conditioned for transplant using systemic, toxic chemotherapy and/or radiation. Depending on the disease and type of transplant, the conditioning treatment is intended to remove or deplete: existing stem cells in the bone marrow, immune cells (T cells and B cells) and/or cancer cells.



 

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Bone marrow transplant conditioning is very burdensome and risky for both pediatric and adult patients. Conditioning treatments today are typically non-targeted and involve systemic, toxic chemotherapy and/or radiation. The current treatments damage the DNA and kill normal, healthy cells in the body, which can lead to severe infections, organ failure, infertility, secondary cancers and even death. Nearly all transplant patients experience complications as a result of current conditioning treatments, and conditioning toxicity is responsible for up to 35% of mortality following allogeneic transplants.

Step 3: Stem Cell Infusion and Engraftment

Once conditioning is complete, the stem cells are infused back into the patient via the bloodstream. The cells travel to and integrate into the bone marrow and begin to make new blood and immune cells, a process referred to as engraftment. Once the bone marrow has made enough blood cells—particularly white blood cells to fight infection—which typically takes several weeks, the patient can be discharged from the hospital.

Some of the common challenges include transplant rejection, delayed engraftment and GvHD. Delayed or failed engraftment can lead to prolonged hospitalization, the need for an additional transplant or death. After engraftment, GvHD can occur. This is when the donor T cells recognize the patient’s cells as foreign and attack the patient’s tissues and organs, particularly the skin, liver and gastrointestinal system. GvHD accounts for approximately 10% of deaths following allogeneic transplant.



 

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Our Current Programs

We are developing a pipeline of small molecules; biologics, including antibody drug conjugates; and a cell therapy, which we believe can meaningfully improve and expand curative bone marrow transplant options for many more patients with autoimmune diseases, blood cancers and genetic diseases. Our portfolio of novel medicines for transplant has the potential to allow more patients with debilitating or life-threatening diseases to access a one-time, transformative bone marrow transplant with better outcomes, less risk of toxicity and mortality. We are developing our product candidates so that they can each be used individually or in combination with each other, such that a patient may receive more than one Magenta therapy as part of their individual transplant journey. In addition to our first set of clinical and preclinical product candidates, we are in the process of identifying several other potential candidates from our discovery programs. The chart below highlights the status of our IND-enabling-stage and clinical-stage product candidates. We anticipate that we will have three distinct clinical programs in multiple indications by 2020 with a series of data read-outs as further described herein.

LOGO

C100, C200, C300: targeted antibody-drug conjugates for conditioning

We are developing a suite of novel antibody-drug conjugates, or ADCs, for transplant conditioning, a step in the transplant process that is still dominated by the use of systemic chemotherapy agents and radiation. We are seeking to replace these non-targeted toxic conditioning agents with our targeted ADCs. These drugs are designed for transplant and specifically deplete only the cell types required to be eliminated in order to perform a successful transplant. Certain ADCs are currently used to treat cancer by directing a toxin to specific cells. Our programs are adapting this clinically validated modality for conditioning patients for bone marrow transplant.



 

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All of our conditioning programs share an ADC platform but differ in the targeted cell types. The C100 program targets HSCs, immune cells and disease-causing cells, the C200 program targets HSCs and disease-causing cells and the C300 program targets only immune cells. This is achieved by tuning the antibodies to specific cellular markers or receptors that are expressed on the particular cell types.

 

LOGO

Our most advanced conditioning program, C200, is designed to specifically deplete HSCs and disease-causing cells. Our lead target for C200 is CD117, also known as c-Kit, which is highly expressed on HSCs and leukemia cells, making it an ideal target for conditioning across a broad range of diseases. This includes blood cancers as well as hemoglobinopathies like sickle cell disease and beta-thalassemia, with potential applicability in both bone marrow transplant and stem cell gene therapy. We are currently studying ADCs targeting CD117 in non-human primates and expect to submit primate data for presentation at a medical meeting in late 2018. We intend to develop CD117-ADCs initially in patients with acute myelogenous leukemia or myelodysplastic syndrome. We are planning to explore CD117-ADCs in other diseases where patients undergo transplant with gene-modified cells, such as sickle cell disease.

The second conditioning program in our portfolio is C100, under which we are developing ADCs that specifically deplete host HSCs, immune cells and disease-causing cells. Within our C100 program, our lead target is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune systems. We are currently in the lead identification stage for this program and intend to identify a development candidate targeting CD45 in 2019. We plan to develop product candidates under our C100 program for use in patients with leukemias and lymphomas, followed by patients with autoimmune diseases such as multiple sclerosis and scleroderma.

Our third ADC-based conditioning program, C300, targets T cells, a type of immune cell. T cell depletion is currently performed with highly toxic, non-specific drugs, such as fludarabine and cyclophosphamide, which can lead to immune deficiency, infections and other complications including secondary autoimmune reactions. We are pursuing targets expressed on the surfaces of T cells with the goal of offering a safer and more optimized targeted conditioning approach through T cell depletion before CAR T therapy for blood cancers, prevention of stem cell rejection prior to allogeneic bone marrow transplant or achievement of immune system reset before autologous bone marrow transplant in autoimmune disease patients.

MGTA-145: CXCR2 agonist for stem cell mobilization

MGTA-145 is a novel stem cell mobilization product candidate intended to achieve mobilization of high numbers of stem cells in a single day to replace granulocyte colony-stimulating factor, or G-CSF, the current standard of care. G-CSF mobilizes stem cells indirectly and comes with limitations that include a prolonged treatment period of up to one week of injections, lack of efficacy in some patients, and significant bone pain. MGTA-145 is a CXCR2 agonist protein that activates neutrophils to release proteases that cause the release of HSCs into the blood. This novel mechanism of action is complementary to that of plerixafor, another



 

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commonly used mobilization agent marketed by Sanofi. The combination of MGTA-145 and plerixafor has been shown to lead to a synergistic, robust and rapid stem cell mobilization in non-human primates. We have initiated IND-enabling studies of MGTA-145 in combination with plerixafor and expect to file an Investigational New Drug Application, or IND, with the U.S. Food and Drug Administration, or FDA, for this product candidate in 2019. We plan to develop MGTA-145 for mobilization first in patients with multiple myeloma and non-Hodgkin lymphoma, followed by healthy donors for allogeneic transplant. We plan to further investigate MGTA-145 in patient populations where G-CSF can exacerbate the disease such as autoimmune diseases, and patient populations where G-CSF is contra-indicated, such as sickle cell disease.

MGTA-456: aryl hydrocarbon receptor (AHR) antagonist-expanded stem cells

Our most advanced product candidate, MGTA-456, is a novel proprietary allogeneic stem cell therapy that was developed based on the mechanisms that control stem cell growth. The goal of MGTA-456 is to extend the use of cord blood transplant to more patients by increasing the number of stem cells in a single cord blood unit to yield a higher stem cell dose. MGTA-456 has the potential to improve overall survival by allowing more patients to have access to better matched cord blood units, which is associated with better outcomes and lower rates of post-transplant complications.

MGTA-456 has achieved human proof-of-concept in Phase I/II trials in a total of 36 patients with blood cancers. Data from the trials showed that all 36 patients treated with MGTA-456 were successfully transplanted and the median time to transplant recovery was accelerated. We are encouraged by these promising results and looking at blood cancer and other conditions where we believe MGTA-456 may show transformative benefit for patients. These include inherited metabolic diseases, or IMDs, a group of diseases where cord blood transplant is a standard of care but up to 20% of patients with inherited metabolic diseases experience transplant failure, resulting in severe complications, including death. We have initiated a Phase II study of MGTA-456 in patients with inherited metabolic diseases and intend to explore other debilitating diseases where we believe MGTA-456 could bring transformative benefit to patients. We expect to report initial data from our Phase II study in late 2018. We also intend to initiate a Phase II study of MGTA-456 in patients with sickle cell disease in early 2019. On April 11, 2018, we received orphan drug designation from the FDA for MGTA-456 for the enhancement of cell engraftment in patients receiving bone marrow transplant.

We are the sponsor of the IND for MGTA-456 in inherited metabolic diseases. The IND was originally filed by Novartis International Pharmaceutical Ltd., or Novartis, on November 6, 2015 and formally transferred to us on July 25, 2017. The IND is active and up to date with reporting requirements, such as annual reports.

We added MGTA-456 to our portfolio through an April 2017 license agreement with Novartis granting us the sole worldwide rights for development and commercialization of cord blood-derived non-gene-edited/-modified HSCs expanded with certain AHR antagonists. See “Business—Licenses and Collaborations” section.

E478: AHR antagonist for expansion of gene-modified stem cells

E478 is our novel and proprietary small molecule AHR antagonist that was developed to increase the number of gene-modified HSCs ex vivo for stem cell based-gene therapy. Gene therapy, or bone marrow transplant with gene-modified or genome-edited cells, is a promising treatment approach for several diseases. However, this approach is significantly limited by the inability to generate a sufficient dose of gene-modified HSCs that retain the ability to engraft in patients as well as the costs and complexity of manufacturing viral vectors for gene modification of cells. These constraints could limit the commercial viability of this approach. We have designed E478 to address these issues by expanding the number of gene-modified HSCs using AHR antagonism, the same clinically validated mechanism used to manufacture MGTA-456. We are developing E478 specifically to partner with gene therapy and genome editing companies. E478 would be integrated into our potential partners’ cell-



 

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based products leading to a newly defined cell therapy. We believe that E478 could represent a key component for unlocking the full value of gene therapy by providing each patient with an optimal dose of gene modified cells for rapid and successful engraftment.

G100: ADC program for prevention of acute GvHD

We are developing G100 as a unique approach to preventing acute GvHD, a major complication and a leading cause of death in allogeneic transplant. GvHD occurs when alloreactive T cells in the donor stem cell graft recognize the patient as foreign and attack their tissues. Current treatments for acute GvHD prevention include the prophylactic use of non-specific immune suppressive agents. These treatments cause an increased risk of infection and poor immune function, and despite the use of these powerful immune suppressive agents, approximately 50 to 80% of allogeneic transplant patients experience acute GvHD, depending on the specific indication. Our G100 program is designed to selectively eliminate only the components of the donor graft that cause acute GvHD, specifically the alloreactive T cells. This ADC therapy is intended to be dosed in vivo at the time of transplant. By specifically targeting the donor alloreactive T cells that arise shortly after transplant, this therapy should spare the remainder of the patient’s immune system to allow immune recovery and protection from infections.

Magenta 2020 Vision

Our goal is to have three clinical programs moving forward in multiple indications by 2020, with a rapidly advancing portfolio and sustainable platform.

 

LOGO

Our Team

We have assembled a group of world leaders and pioneers in the fields of stem cell biology, biotherapeutics and transplant medicine. With this team, we are converting recent scientific breakthroughs into a product engine for transplant therapies. Our Chief Executive Officer, Jason Gardner, brings more than 20 years of experience in stem cell science, drug development and business leadership to Magenta. He has created and led successful industry teams, including the Boston R&D Satellite, Center of Excellence for External Drug Discovery and the Regenerative Medicine Unit at GlaxoSmithKline plc. He also worked on the development of approved



 

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medicines, Tykerb for breast cancer, and Strimvelis, the first stem cell gene therapy. Michael Cooke, our Chief Scientific Officer, has more than 20 years of experience in biotechnology and pharmaceutical companies, where he has been responsible for the discovery and development of a portfolio of products to treat autoimmune disease and immune diseases and improve hematopoietic stem cell transplant, including our most advanced program, MGTA-456. Dr. Cooke is an author on more than 60 peer-reviewed publications. Our Chief Medical Officer, John Davis, joined Magenta from Pfizer Inc., where he was Senior Vice President and Head of Early Clinical Development. Prior to Pfizer, Dr. Davis served as Vice President and Global Therapeutic Area Head of Immunology at Baxalta and as Senior Group Director and Head of the Inflammation and Cardiovascular/Metabolism Group in the Early Clinical Development Group at Genentech, Inc. Dr. Davis spent nearly 10 years on faculty at The University of California San Francisco leading clinical research in autoimmune diseases, where he most recently was Professor of Clinical Medicine until 2015. Christina Isacson, our Chief Business Officer, has more than 13 years of experience in senior business development in biotechnology companies and company creation. Dr. Isacson is responsible for our business and corporate development, and the establishment and management of partnerships. Zoran Zdraveski has served as our Chief Legal Officer since April 2017 and is responsible for all aspects of our legal, intellectual property, and compliance functions. Dr. Zdraveski has more than 16 years of experience in the legal field in the biopharmaceutical industry. Our scientific advisory board is chaired by David Scadden, M.D., Gerald and Darlene Jordan Professor of Medicine at Harvard University and one of the world’s foremost experts in stem cell biology. The other members of our world-class scientific advisory board include John DiPersio, M.D., Ph.D., of Washington University School of Medicine; Robert Negrin, M.D., of Stanford University; Megan Sykes, M.D., of Columbia University, Alan Tyndall, M.D., formerly of University of Basel; and Luigi Naldini, M.D., Ph.D., of San Raffaele-Telethon Institute for Gene Therapy.

Our Core Values

At Magenta, we are working to revolutionize bone marrow transplants by applying equal parts courage, commitment, and excellence:

 

    Courage to make a difference for patients, their families, and their healthcare providers

 

    Commitment to patients, our partners, and one another

 

    Excellence in everything we do

Our Strategy

Our mission and our culture are centered around the goal of enabling more patients with severe or life-threatening diseases to have access to the transformative benefit of a bone marrow transplant. We intend to provide physicians with a tailored, multi-product treatment regimen based on the disease setting and the individual needs of each patient. Our strategic priorities are as follows:

 

    Bring the curative power of bone marrow transplant to all patients who can benefit by advancing an integrated product portfolio.

 

    Build on our deep expertise in stem cell biology to lead a new era in transplant medicine.

 

    Create a fully integrated patient-focused biotechnology company.

 

    Commercialize our therapeutics to bring tailored transplant solutions to physicians and patients.

 

    Leverage our most advanced product candidate, MGTA-456, as a clinical catalyst and commercial beachhead for our portfolio.

 

    Continue to integrate our innovative collaboration with Be The Match with our science, medicine and business approaches.

 

    Strategically collaborate to realize the full potential of our portfolio.


 

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Risks Associated with Our Business

Our ability to implement our business strategy is subject to numerous risks that you should be aware of before making an investment decision. These risks are described more fully in the section entitled “Risk Factors” in this prospectus. These risks include, among others:

 

    we are a clinical-stage company with a limited operating history, have incurred significant losses since our inception, and anticipate that we will continue to incur significant losses for the foreseeable future;

 

    even if this offering is successful, we will need to raise additional funding before we can expect to generate any revenues from product sales;

 

    if we are unable to obtain regulatory approval for MGTA-456 or any other product candidates that we may identify or develop, our business will be substantially harmed;

 

    we are heavily dependent upon the success of MGTA-456, which has just completed a Phase I/II clinical trial and is currently in a separate Phase II clinical trial, and none of our other product candidates are in clinical trials;

 

    results of earlier studies may not be predictive of future clinical trial results, and we may fail to establish an adequate safety or efficacy profile to conduct advanced clinical trials or obtain regulatory approval for MGTA-456 or any other product candidates that we may pursue;

 

    if serious adverse events, undesirable side effects, or unexpected characteristics are identified during the development of any of our product candidates, we may need to delay, abandon or limit our further clinical development of those product candidates;

 

    if we are not able to identify a safe and effective dose for any of our ADCs, we may need to delay, abandon or limit our development of any potential product candidates;

 

    if we are unable to successfully develop our current programs into a comprehensive portfolio of product candidates, or experience significant delays in doing so, we may not realize the full commercial potential of our current and future product candidates;

 

    we are developing E478 specifically to partner with gene therapy and genome editing companies, and if we are unable to find willing collaborators, this may adversely affect the development of E478 and our business;

 

    we expect to continue to rely on third parties to manufacture our clinical product supplies, and we intend to rely on third parties to produce and process our product candidates, if approved;

 

    we are highly dependent on intellectual property licensed from third parties and termination of any of these licenses could result in the loss of significant rights, which would harm our business;

 

    if we are unable to obtain and maintain sufficient intellectual property protection for MGTA-456, our technologies, or any future product candidates, we may not be able to compete effectively in our markets; and

 

    our future success depends in part upon our ability to retain our key employees, consultants and advisors and to attract, retain and motivate other qualified personnel.

Corporate History and Information

We were incorporated under the laws of the State of Delaware on June 17, 2015 under the name HSCTCo Therapeutics, Inc. From our inception until the closing of our Series A preferred stock financing in November 2016, our founding investors, Third Rock Ventures and Atlas Venture, supported our seed-stage activities, which were overseen by our founding investor directors, Alexis A. Borisy and Bruce Booth, D.Phil., and our co-



 

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founders, Jason Gardner, D.Phil., and David T. Scadden, M.D. In February 16, 2016, we changed our name to Magenta Therapeutics, Inc. Our principal executive office is located at 50 Hampshire Street, Cambridge, Massachusetts 02139, and our telephone number is (857) 242-0170. Our website address is www.magentatx.com. We do not incorporate the information on or accessible through our website into this prospectus, and you should not consider any information on, or that can be accessed through, our website as part of this prospectus.

Implications of Being an Emerging Growth Company

We qualify as an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012, as amended, or the JOBS Act. As an emerging growth company, we may take advantage of specified reduced disclosure and other requirements that are otherwise applicable generally to public companies. These provisions include:

 

    two years of audited financial statements in addition to any required unaudited interim financial statements with correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations” disclosure;

 

    reduced disclosure about our executive compensation arrangements;

 

    no non-binding advisory votes on executive compensation or golden parachute arrangements; and

 

    exemption from the auditor attestation requirement in the assessment of our internal control over financial reporting.

We may take advantage of these exemptions for up to five years or such earlier time that we are no longer an emerging growth company. We would cease to be an emerging growth company on the date that is the earliest of (i) the last day of the fiscal year in which we have total annual gross revenues of $1.07 billion or more; (ii) the last day of our fiscal year following the fifth anniversary of the date of the completion of this offering; (iii) the date on which we have issued more than $1.0 billion in nonconvertible debt during the previous three years; or (iv) the last day of the fiscal year in which we are deemed to be a large accelerated filer under the rules of the Securities and Exchange Commission, or SEC, which means the market value of our common stock that is held by non-affiliates exceeds $700 million as of the prior June 30th. We may choose to take advantage of some but not all of these exemptions. We have taken advantage of reduced reporting requirements in this prospectus. Accordingly, the information contained herein may be different from the information you receive from other public companies in which you hold stock. We are in the process of evaluating the benefits of relying on other exemptions and reduced reporting requirements under the JOBS Act. Subject to certain conditions, as an emerging growth company, we may rely on certain of these exemptions, including without limitation, providing an auditor’s attestation report on our system of internal controls over financial reporting pursuant to Section 404(b) of the Sarbanes-Oxley Act.



 

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THE OFFERING

 

Common stock offered by us

6,666,667 shares

 

Common stock to be outstanding after this offering

34,370,267 shares

 

Underwriters’ option

We have granted the underwriters an option to purchase a maximum of 1,000,000 additional shares of common stock from us. The underwriters can exercise this option at any time within 30 days from the date of this prospectus.

 

Use of Proceeds

We estimate that we will receive net proceeds from the sale of shares of our common stock in this offering of approximately $89.8 million, or $103.8 million if the underwriters fully exercise their option to purchase additional shares, assuming an initial public offering price of $15.00 per share, the midpoint of the price range set forth on the cover page of this prospectus, and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. We intend to use the net proceeds from this offering and our existing cash and cash equivalents to fund our conditioning programs and product candidates, the development of MGTA-456, the development of MGTA-145, our mobilization product candidate and the remainder, if any, to fund new and ongoing research and development activities, our new product engine, working capital and other general corporate purposes. See “Use of Proceeds” for additional information.

 

Risk Factors

You should carefully read the “Risk Factors” section of this prospectus beginning on page 15 and other information included in this prospectus for a discussion of factors that you should consider before deciding to invest in our common stock.

 

The NASDAQ Global Market symbol

“MGTA”

 

Directed Share Program

The underwriters have reserved up to 5% of the shares of common stock being offered by this prospectus (excluding the shares of common stock that may be issued upon the underwriters’ exercise of their option to purchase additional common stock) for sale to our directors, officers, employees, business associates and related persons. The number of shares of common stock available for sale to the general public will be reduced to the extent these individuals purchase such reserved shares. Any reserved shares that are not so purchased will be offered by the underwriters to the general public on the same basis as the other shares offered by this prospectus. See “Underwriting—Directed Share Program.”


 

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Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to approximately $40.0 million of shares of our common stock in this offering at the initial public offering price. However, because indications of interest are not binding agreements or commitments to purchase, the underwriters may determine to sell more, less or no shares in this offering to such stockholders, and such stockholders could determine to purchase more, less or no shares in this offering.

The number of shares of common stock to be outstanding after this offering is based on 27,703,600 shares of common stock outstanding as of April 30, 2018, which includes 1,641,351 shares of unvested restricted stock subject to repurchase by us, after giving effect to the automatic conversion of all outstanding shares of our preferred stock and excludes:

 

    1,783,859 shares of common stock issuable upon the exercise of stock options outstanding as of April 30, 2018 under our 2016 Stock Option and Grant Plan, or the 2016 Plan, at a weighted average exercise price of $7.16 per share (which does not include options to purchase an aggregate of 1,464,137 shares of common stock, at an exercise price of $9.49 per share, that were granted subsequent to April 30, 2018);

 

    2,606,273 shares of common stock reserved and available for future issuance under the 2016 Plan, as of April 30, 2018 (which does not account for options to purchase 1,464,137 shares of common stock that were granted subsequent to April 30, 2018). Shares of common stock remaining available for issuance under the 2016 Plan will be made available for issuance under our 2018 Stock Option and Incentive Plan, or the 2018 Plan, upon the effectiveness of the 2018 Plan; and

 

    1,765,162 shares of our common stock reserved for future issuance under the 2018 Plan, which will become effective upon the completion of this offering, as well as any future increases in the number of shares of common stock reserved for future increases in the number of shares of common stock reserved for future issuances under our 2018 Plan.

Except as otherwise indicated, all information in this prospectus assumes or gives effect to:

 

    the conversion of all outstanding shares of our redeemable convertible preferred stock into an aggregate of 23,375,405 shares of our common stock upon the completion of this offering;

 

    no exercise of the outstanding options described above;

 

    no exercise by the underwriters of their option to purchase up to an additional 1,000,000 shares of our common stock in this offering;

 

    A one-for-2.58398 reverse split of our common stock, which will become effective prior to the completion of this offering; and

 

    the filing of our amended and restated certificate of incorporation and the adoption of our amended and restated bylaws, which will occur immediately prior to the completion of this offering.


 

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SUMMARY FINANCIAL DATA

You should read the following summary financial data together with our financial statements and the related notes appearing at the end of this prospectus and the “Selected Financial Data” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of this prospectus. We have derived the statement of operations data for the years ended December 31, 2016 and 2017 and the balance sheet data as of December 31, 2017 from our audited financial statements appearing at the end of this prospectus. Our historical results are not necessarily indicative of the results that may be expected in the future. We have derived the statement of operations data for the three months ended March 31, 2017 and 2018 and the balance sheet data as of March 31, 2018 from our unaudited interim financial statements appearing at the end of this prospectus. The unaudited interim financial statements have been prepared on the same basis as the audited financial statements and reflect, in the opinion of management, all adjustments of a normal, recurring nature that are necessary for a fair statement of the financial information included in those unaudited interim financial statements. Our historical results are not necessarily indicative of the results that may be expected in the future, and the results for the three months ended March 31, 2018 are not necessarily indicative of results to be expected for the full year or any other period.

 

     Year Ended December 31,     Three Months Ended March 31,  
     2016     2017     2017     2018  
     (in thousands, except share and per share data)  

Statement of Operations Data:

        

Revenue

   $ —       $ —       $ —       $ —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Operating expenses:

        

Research and development

     5,782       27,899       3,322       7,849  

General and administrative

     3,486       7,828       1,489       3,457  
  

 

 

   

 

 

   

 

 

   

 

 

 

Total operating expenses

     9,268       35,727       4,811       11,306  
  

 

 

   

 

 

   

 

 

   

 

 

 

Loss from operations

     (9,268     (35,727     (4,811     (11,306
  

 

 

   

 

 

   

 

 

   

 

 

 

Other income (expense):

        

Interest expense

     (163     —         —         —    

Interest and other income, net

     —         236       —         145  
  

 

 

   

 

 

   

 

 

   

 

 

 

Total other income (expense), net

     (163     236       —         145  
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss

   $ (9,431   $ (35,491   $ (4,811   $ (11,161

Accretion of redeemable convertible preferred stock to redemption value

     (107     (213     —         —    

Cumulative dividends on redeemable convertible preferred stock

     (197     (437     (354     —    

Reversal of cumulative dividends on redeemable convertible preferred stock

     —         634       —         —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss attributable to common stockholders

   $ (9,735   $ (35,507   $ (5,165   $ (11,161
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss per share attributable to common stockholders—basic and diluted

   $ (65.15   $ (19.12   $ (3.59   $ (4.53
  

 

 

   

 

 

   

 

 

   

 

 

 

Weighted average common shares outstanding—basic and diluted

     149,414       1,856,907       1,438,361       2,466,353  
  

 

 

   

 

 

   

 

 

   

 

 

 

Pro forma net loss per share attributable to common stockholders—basic and diluted (unaudited)

     $ (2.07     $ (0.52
    

 

 

     

 

 

 

Pro forma weighted average common shares outstanding—basic and diluted (unaudited)

       17,141,918         21,498,419  
    

 

 

     

 

 

 


 

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     At March 31, 2018  
     Actual     Pro Forma(2)      Pro Forma
As Adjusted(3)
 
     (in thousands)  

Balance Sheet Data:

       

Cash and cash equivalents

   $ 41,462     $ 93,762      $ 183,758  

Working capital(1)

     37,134       89,434        180,596  

Total assets

     46,078       98,378        187,042  

Redeemable convertible preferred stock

     92,439       —          —    

Total stockholders’ equity (deficit)

     (51,854     92,885        182,715  

 

(1) We define working capital as current assets less current liabilities.
(2) The pro forma balance sheet data give effect to (i) our sale of 11,223,102 shares of Series C redeemable convertible preferred stock in April 2018 for gross proceeds of $52.3 million and (ii) the automatic conversion of all outstanding shares of our redeemable convertible preferred stock into an aggregate of 23,375,405 shares of our common stock upon the completion of this offering.
(3) The pro forma as adjusted balance sheet data give further effect to our issuance and sale of shares of our common stock offered in this offering at an assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

A $1.00 increase (decrease) in the assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted amount of each of cash and cash equivalents, working capital, total assets and total stockholders’ equity by $6.2 million, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions. An increase (decrease) of 1,000,000 shares in the number of shares offered by us, as set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted amount of each of cash and cash equivalents, working capital, total assets and total stockholders’ equity by $14.0 million, assuming no change in the assumed initial public offering price per share and after deducting estimated underwriting discounts and commissions.



 

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RISK FACTORS

Investing in our common stock involves a high degree of risk. You should carefully consider the risks described below, as well as the other information in this prospectus, including our financial statements and the related notes and “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” before deciding whether to invest in our common stock. The occurrence of any of the events or developments described below could harm our business, financial condition, results of operations and growth prospects. In such an event, the market price of our common stock could decline and you may lose all or part of your investment. Additional risks and uncertainties not presently known to us or that we currently deem immaterial also may impair our business operations.

Risks Related to Our Financial Position and Need for Additional Capital

We have incurred net losses in every year since our inception and anticipate that we will continue to incur net losses in the future.

We are a clinical-stage biotechnology company developing novel medicines to bring the curative power of bone marrow transplant to more patients, and have a limited operating history. Investment in biopharmaceutical product development is highly speculative because it entails substantial upfront capital expenditures and significant risk that any potential product candidate will fail to demonstrate adequate effect or an acceptable safety profile, gain regulatory approval and become commercially viable. We have no products approved for commercial sale and have not generated any revenue from product sales to date, and we continue to incur significant research and development and other expenses related to our ongoing operations. As a result, we are not profitable and have incurred losses in each period since our inception in June 2015. For the years ended December 31, 2016 and 2017 and the three months ended March 31, 2018, we reported a net loss of $9.4 million, $35.5 million and $11.2 million, respectively. As of March 31, 2018, we had an accumulated deficit of $56.4 million. We expect to continue to incur significant losses for the foreseeable future, and we expect these losses to increase as we continue our research and development of, and seek regulatory approvals for, our product candidates.

Even if we succeed in commercializing one or more of our product candidates, we will continue to incur substantial research and development and other expenditures to develop and market additional product candidates. We may encounter unforeseen expenses, difficulties, complications, delays and other unknown factors that may adversely affect our business. The size of our future net losses will depend, in part, on the rate of future growth of our expenses and our ability to generate revenue. Our prior losses and expected future losses have had and will continue to have an adverse effect on our stockholders’ equity and working capital.

We will require additional capital to fund our operations and if we fail to obtain necessary financing, we will not be able to complete the development and commercialization of our product candidates.

Our operations have consumed substantial amounts of cash since inception. We expect to continue to spend substantial amounts to conduct further research and development and preclinical testing and clinical trials of our product candidates, to seek regulatory approvals for our product candidates and to launch and commercialize any product candidates for which we receive regulatory approval, including potentially building our own commercial organization to address the United States, the European Union and certain other markets. As of March 31, 2018, we had approximately $41.5 million in cash and cash equivalents. In April 2018, we received gross proceeds of $52.3 million from the sale of our Series C redeemable convertible preferred stock. Based on our current operating plan, we believe that the net proceeds from this offering, together with existing cash and cash equivalents, will be sufficient to fund our anticipated level of operations through at least the first quarter of 2020. However, our future capital requirements and the period for which our existing resources will support our operations may vary significantly from what we expect. Our monthly spending levels will vary based on new and ongoing development and corporate activities. Because the length of time and activities associated with

 

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successful development of our product candidates is highly uncertain, we are unable to estimate the actual funds we will require for development and any approved marketing and commercialization activities. Our future funding requirements, both near and long-term, will depend on many factors, including, but not limited to:

 

    the initiation, progress, timing, costs and results of preclinical studies and clinical trials for our product candidates;

 

    the clinical development plans we establish for these product candidates;

 

    the number and characteristics of product candidates that we develop or may in-license;

 

    the terms of any collaboration agreements we may choose to conclude;

 

    the outcome, timing and cost of meeting regulatory requirements established by the FDA, the European Medical Agency, or EMA, and other comparable foreign regulatory authorities;

 

    the cost of filing, prosecuting, defending and enforcing our patent claims and other intellectual property rights;

 

    the cost of defending intellectual property disputes, including patent infringement actions brought by third parties against us or our product candidates;

 

    the effect of competing technological and market developments;

 

    the cost and timing of completion of commercial-scale outsourced manufacturing activities; and

 

    the cost of establishing sales, marketing and distribution capabilities for any product candidates for which we may receive regulatory approval in regions where we choose to commercialize our products on our own.

We cannot be certain that additional funding will be available on acceptable terms, or at all. If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we may have to significantly delay, scale back or discontinue the development or commercialization of one or more of our product candidates or one or more of our other research and development initiatives. We also could be required to seek collaborators for one or more of our current or future product candidates at an earlier stage than otherwise would be desirable or on terms that are less favorable than might otherwise be available or relinquish or license on unfavorable terms our rights to technologies or product candidates that we otherwise would seek to develop or commercialize ourselves.

Any of the above events could significantly harm our business, prospects, financial condition and results of operations and cause the price of our common stock to decline.

Raising additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

We may seek additional capital through a combination of public and private equity offerings, debt financings, strategic partnerships and alliances and licensing arrangements. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms may include liquidation or other preferences that adversely affect your rights as a stockholder. The incurrence of indebtedness would result in increased fixed payment obligations and could involve certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. If we raise additional funds through strategic partnerships and alliances and licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies or product candidates, or grant licenses on terms unfavorable to us.

 

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Our company has a limited operating history and no history of commercializing pharmaceutical products, which may make it difficult to evaluate the prospects for our future viability.

We are an early-stage company. We were founded and commenced operations in June 2015. Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, acquiring and developing our technology, identifying potential product candidates, and undertaking preclinical studies, and in the case of MGTA-456, clinical trials. Aside from MGTA-456, all of our research programs and product candidates are still in the preclinical or research stage of development, and their risk of failure is high. We have not yet demonstrated an ability to initiate or successfully complete any clinical trials (other than for MGTA-456), including large-scale, pivotal clinical trials, obtain marketing approvals, manufacture a commercial-scale medicine, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful commercialization. Typically, it takes about 10 to 15 years to develop a new medicine from the time it is discovered to when it is available for treating patients. Consequently, any predictions you make about our future success or viability may not be as accurate as they could be if we had a longer operating history.

In addition, as a new business, we may encounter unforeseen expenses, difficulties, complications, delays, and other known and unknown factors. We will need to transition from a company with a research focus to a company capable of supporting commercial activities. We may not be successful in such a transition.

We have never generated revenue from product sales and may never be profitable.

Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with collaborative partners, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize product candidates we may identify for development. We may not generate revenues from product sales for the next several years, if ever. Our ability to generate future revenues from product sales depends heavily on our, or our collaborators’, ability to successfully:

 

    identify product candidates and complete research and preclinical and clinical development of any product candidates we may identify;

 

    seek and obtain regulatory and marketing approvals for any of our product candidates for which we complete clinical trials;

 

    launch and commercialize any of our product candidates for which we obtain regulatory and marketing approval by establishing a sales force, marketing, and distribution infrastructure or, alternatively, collaborating with a commercialization partner;

 

    qualify for adequate coverage and reimbursement by government and third-party payors for any of our product candidates for which we obtain regulatory and marketing approval;

 

    develop, maintain, and enhance a sustainable, scalable, reproducible, and transferable manufacturing process for the product candidates we may develop;

 

    establish and maintain supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical development and the market demand for any of our product candidates for which we obtain regulatory and marketing approval;

 

    obtain market acceptance of any product candidates we may develop as viable treatment options;

 

    address competing technological and market developments;

 

    implement internal systems and infrastructure, as needed;

 

    negotiate favorable terms in any collaboration, licensing, or other arrangements into which we may enter and perform our obligations in such collaborations;

 

    maintain, protect, and expand our portfolio of intellectual property rights, including patents, trade secrets, and know-how;

 

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    avoid and defend against third-party interference or infringement claims; and

 

    attract, hire, and retain qualified personnel.

Even if one or more of the product candidates we may develop is approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate. Our expenses could increase beyond expectations if we are required by the FDA, the EMA, or other regulatory authorities to perform clinical and other studies in addition to those that we currently anticipate. Even if we are able to generate revenues from the sale of any approved products, we may not become profitable and may need to obtain additional funding to continue operations.

Comprehensive tax reform legislation could adversely affect our business and financial condition.

The U.S. government has recently enacted comprehensive tax legislation that includes significant changes to the taxation of business entities. These changes include, among others, a permanent reduction to the corporate income tax rate. Notwithstanding the reduction in the corporate income tax rate, the overall impact of this tax reform is uncertain, and our business and financial condition could be adversely affected. This prospectus does not discuss any such tax legislation or the manner in which it might affect purchasers of our common stock. We urge our stockholders to consult with their legal and tax advisors with respect to any such legislation and the potential tax consequences of investing in our common stock.

Our insurance policies may be inadequate and potentially expose us to unrecoverable risks.

We have limited director and officer insurance and commercial insurance policies. Any significant insurance claims would have a material adverse effect on our business, financial condition and results of operations. Insurance availability, coverage terms and pricing continue to vary with market conditions. We endeavor to obtain appropriate insurance coverage for insurable risks that we identify, however, we may fail to correctly anticipate or quantify insurable risks, we may not be able to obtain appropriate insurance coverage, and insurers may not respond as we intend to cover insurable events that may occur. We have observed rapidly changing conditions in the insurance markets relating to nearly all areas of traditional corporate insurance. Such conditions have resulted in higher premium costs, higher policy deductibles, and lower coverage limits. For some risks, we may not have or maintain insurance coverage because of cost or availability.

Risks Related to Product Development and Regulatory Approval

We are very early in our development efforts. All but one of our product candidates, MGTA-456, are still in preclinical development. If we are unable to advance our product candidates to obtain regulatory approval and ultimately commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.

We are very early in our development efforts and all but one of our product candidates, MGTA-456, are still in preclinical development. We have only recently completed initial preclinical studies for MGTA-145. Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and eventual commercialization of our product candidates, which may never occur. We currently generate no revenue from sales of any product and we may never be able to develop or commercialize a marketable product.

Each of our programs and product candidates will require additional preclinical and clinical development, regulatory approval in multiple jurisdictions, obtaining manufacturing supply, capacity and expertise, building of a commercial organization, substantial investment and significant marketing efforts before we generate any revenue from product sales. Our product candidates must be authorized for marketing by the FDA, or certain other foreign regulatory agencies, such as the EMA, before we may commercialize our product candidates.

 

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The success of our product candidates will depend on several factors, including the following:

 

    successful completion of preclinical studies and successful enrollment and completion of clinical trials, including toxicology studies, biodistribution studies and minimally efficacious dose studies in animals, where applicable, under the FDA’s cGCPs, and the FDA’s current Good Laboratory Practices, or cGLPs;

 

    effective Investigational New Drug applications, or INDs, or Clinical Trial Authorisations, or CTAs, that allow commencement of our planned clinical trials or future clinical trials for our product candidates;

 

    positive results from our future clinical programs that support a finding of safety and effectiveness and an acceptable risk-benefit profile of our product candidates in the intended populations;

 

    receipt of regulatory approvals from applicable regulatory authorities;

 

    establishment of arrangements with third-party manufacturers for clinical supply and, where applicable, commercial manufacturing capabilities;

 

    successful development of our internal manufacturing processes or transfer to larger-scale facilities operated by either a contract manufacturing organization, or CMO, or by us;

 

    establishment and maintenance of patent and trade secret protection or regulatory exclusivity for our product candidates;

 

    commercial launch of our product candidates, if and when approved, whether alone or in collaboration with others;

 

    acceptance of our product candidates, if and when approved, by patients, the medical community and third-party payors;

 

    effective competition with other therapies;

 

    establishment and maintenance of healthcare coverage and adequate reimbursement;

 

    enforcement and defense of intellectual property rights and claims; and

 

    maintenance of a continued acceptable safety profile of our product candidates following approval.

If we do not succeed in one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully commercialize our product candidates, which would materially harm our business. If we do not receive regulatory approvals for our product candidates, we may not be able to continue our operations.

Our planned clinical trials or those of our collaborators may reveal significant adverse events not seen in our preclinical studies and may result in a safety profile that could inhibit regulatory approval or market acceptance of any of our product candidates.

Before obtaining regulatory approvals for the commercial sale of our product candidates we must demonstrate through lengthy, complex and expensive preclinical testing and clinical trials that our product candidates are both safe and effective for use in each target indication. Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain. Failure can occur at any time during the clinical trial process. The results of preclinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials. There is typically an extremely high rate of attrition from the failure of product candidates proceeding through clinical trials. For example, we observed a limited number of serious adverse effects in our existing Phase II clinical trial of MGTA-456 that were considered to be related to the investigational treatment, and there is no guarantee that we will not see more serious adverse effects in the future. Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy profile despite

 

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having progressed through preclinical studies and initial clinical trials. A number of companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or unacceptable safety issues, notwithstanding promising results in earlier trials. Most product candidates that commence clinical trials are never approved as products.

If significant adverse events or other side effects are observed in any of our current or future clinical trials, we may have difficulty recruiting patients to the clinical trial, patients may drop out of our trial, or we may be required to abandon the trial or our development efforts of that product candidate altogether. We, the FDA or other applicable regulatory authorities, or an institutional review board, or IRB, may suspend clinical trials of a product candidate at any time for various reasons, including a belief that subjects in such trials are being exposed to unacceptable health risks or adverse side effects. Some potential therapeutics developed in the biotechnology industry that initially showed therapeutic promise in early-stage studies have later been found to cause side effects that prevented their further development. Even if the side effects do not preclude the drug from obtaining or maintaining marketing approval, undesirable side effects may inhibit market acceptance of the approved product due to its tolerability versus other therapies. Any of these developments could materially harm our business, financial condition and prospects.

Clinical development involves a lengthy and expensive process, with an uncertain outcome. We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of any product candidates.

With the exception of MGTA-456, our other product candidates are still in the preclinical development stage, and their risk of failure is high. It is impossible to predict when or if any of our programs will prove effective and safe in humans or will receive regulatory approval. Before obtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy of any of our future product candidates in humans. Preclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome. We may be unable to establish clinical endpoints that applicable regulatory authorities would consider clinically meaningful, and a clinical trial can fail at any stage of testing. The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.

Successful completion of clinical trials is a prerequisite to submitting a new drug application, or NDA, or a biologics license application, or BLA, to the FDA, a Marketing Authorization Application, or MAA, to the EMA and similar approval filings to comparable foreign regulatory authorities, for each product candidate and, consequently, the ultimate approval and commercial marketing of any product candidates. We do not know whether any of our clinical trials will begin or be completed on schedule, if at all.

We may experience delays in completing our preclinical studies and initiating or completing clinical trials. We also may experience numerous unforeseen events during, or as a result of, any future clinical trials that we could conduct that could delay or prevent our ability to receive marketing approval or commercialize our product candidates, including:

 

    regulators, IRBs, or ethics committees may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;

 

    we may experience delays in reaching, or fail to reach, agreement on acceptable terms with prospective trial sites and prospective contract research organizations, or CROs, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;

 

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    clinical trials of any product candidates may fail to show safety or efficacy, produce negative or inconclusive results and we may decide, or regulators may require us, to conduct additional preclinical studies or clinical trials or we may decide to abandon product development programs;

 

    the number of patients required for clinical trials of any product candidates may be larger than we anticipate, enrollment in these clinical trials may be slower than we anticipate or participants may drop out of these clinical trials or fail to return for post-treatment follow-up at a higher rate than we anticipate;

 

    our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all, or may deviate from the clinical trial protocol or drop out of the trial, which may require that we add new clinical trial sites or investigators;

 

    we may elect to, or regulators, IRBs or ethics committees may require that we or our investigators, suspend or terminate clinical research or trials for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks;

 

    the cost of preclinical studies and clinical trials of any product candidates may be greater than we anticipate;

 

    the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate; and

 

    our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators, IRBs or ethics committees to suspend or terminate the trials, or reports may arise from preclinical or clinical testing of other bone marrow transplant and cell-based therapies that raise safety or efficacy concerns about our product candidates.

We could also encounter delays if a clinical trial is suspended or terminated by us, the IRBs of the institutions in which such trials are being conducted, the Data Safety Monitoring Board, or DSMB, for such trial or FDA or other regulatory authorities. Such authorities may impose such a suspension or termination due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product or treatment, failure to establish or achieve clinically meaningful trial endpoints, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial. For example, in December 2015, prior to our license of MGTA-456 from Novartis International Pharmaceutical Ltd., or Novartis, the FDA imposed a partial clinical hold on the cryopreserved part of the protocol covered by the IND application for MGTA-456 until Novartis demonstrated comparability between the fresh and cryopreserved product. This partial clinical hold was later removed by the FDA in June 2016 after Novartis presented satisfactory comparability data between the fresh and cryopreserved product. We cannot guarantee that we will not be subject to further holds by the FDA or other regulatory authorities in the future. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of our product candidates. Further, the FDA or other regulatory authorities may disagree with our clinical trial design and our interpretation of data from clinical trials, or may change the requirements for approval even after they have reviewed and commented on the design for our clinical trials.

Our product development costs will increase if we experience delays in clinical testing or marketing approvals. We do not know whether any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Significant preclinical or clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our product candidates and may allow our competitors to bring products to market before we do, potentially impairing our ability to successfully commercialize our product candidates and harming our business and results of operations. Any delays in our preclinical or future clinical development programs may harm our business, financial condition and prospects significantly.

 

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We have no experience as a company in obtaining regulatory approval for a drug.

As a company, we have never obtained regulatory approval for, or commercialized, a drug. It is possible that the FDA may refuse to accept any or all future new drug applications, or NDAs, or BLAs for substantive review or may conclude after review of our data that our application is insufficient to obtain regulatory approval for any current or future product candidates. If the FDA does not approve any future NDAs or BLAs, it may require that we conduct additional costly clinical, preclinical or manufacturing validation studies before it will reconsider our applications. Depending on the extent of these or any other FDA-required studies, approval of any NDA or BLA or other application that we submit may be significantly delayed, possibly for several years, or may require us to expend more resources than we have available. Any failure or delay in obtaining regulatory approvals would prevent us from commercializing MGTA-456 or any other product candidate, generating revenues and achieving and sustaining profitability. It is also possible that additional studies, if performed and completed, may not be considered sufficient by the FDA to approve any NDA or other application that we submit. If any of these outcomes occur, we may be forced to abandon the development of our product candidates, which would materially adversely affect our business and could potentially cause us to cease operations. We face similar risks for our applications in foreign jurisdictions.

If serious adverse events, undesirable side effects, or unexpected characteristics are identified during the development of any product candidates we may develop, we may need to abandon or limit our further clinical development of those product candidates.

It is impossible to predict when or if any product candidates we may develop will prove safe in humans. If any product candidates we develop are associated with serious adverse events, or undesirable side effects, or have characteristics that are unexpected, we may need to abandon their development or limit development to certain uses or subpopulations in which the serious adverse events, undesirable side effects or other characteristics are less prevalent, less severe, or more acceptable from a risk-benefit perspective, any of which would have a material adverse effect on our business, financial condition, results of operations, and prospects. It is possible that product candidates that initially showed promise in early stage testing will later have been found to cause side effects that prevent further clinical development of the product candidates.

Bone marrow transplant is a high-risk procedure with curative potential that may result in complications or adverse events for patients in our clinical trials or for patients that use any of our product candidates, if approved.

Bone marrow transplant can cure patients across multiple diseases, but its use carries with it risks of toxicity, serious adverse events and death. Because many of our therapies are used to prepare or treat patients undergoing bone marrow transplant, patients in our clinical trials or patients that use any of our product candidates may be subject to many of the risks that are currently inherent to the bone marrow transplant process. In particular, bone marrow transplant involves certain known potential post-procedure complications that may manifest several weeks or months after a transplant and which may be more common in certain patient populations. For example, up to 20% of patients with inherited metabolic diseases treated with transplant experience primary engraftment failure, resulting in severe complications, including death. The first patient dosed in our ongoing Phase II clinical trial of MGTA-456 in patients with inherited metabolic diseases successfully engrafted, and subsequently developed autoimmune cytopenia, a known potential complication of bone marrow transplant in this patient population, which includes severe side effects and the possibility of death. This has been deemed by the principal investigator overseeing the Phase II study and the chair of our data safety monitoring committee to be unrelated to the use of MGTA-456 specifically but instead is deemed to be related to complications common to transplant. If these or other serious adverse events, undesirable side effects, or unexpected characteristics are identified during the development of any of our product candidates, we may need to limit, delay or abandon our further clinical development of those product candidates, even if such events, effects or characteristics were the result of bone marrow transplant or related procedures generally, and not directly or specifically caused or exacerbated by our product candidates. All serious adverse events or unexpected side effects are continually monitored per the

 

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clinical study’s approved protocol. If serious adverse events are determined to be directly or specifically caused or exacerbated by our product candidates, we would follow the study protocol’s requirements, which call for our data safety monitoring committee to review all available clinical data in making a recommendation regarding the study’s continuation.

If we are not able to identify a safe and effective dose for any of our ADCs, we may need to delay, abandon or limit our development of any potential product candidates.

ADCs utilize toxins to kill cells, and we may not be able to identify a safe and effective dose for some of our potential product candidates. ADCs, including those that have received marketing approval, have dose-dependent safety findings that can include liver toxicity, depending on the target of the ADC and the drug used in the conjugate. In addition, ADCs may have other adverse side effects including fatalities. In our initial proof of mechanism non-human primate study, designed to test the ability of a probe CD117-ADC designed to deplete HSCs, we observed some instances of transient elevation of liver enzymes that were dose- and toxin-dependent. Out of the twelve non-human primates treated with the probe CD117-ADC in the initial study, one treated with the highest dose was euthanized subsequent to receiving scheduled pain medication before a planned bone marrow aspirate. In addition, one non-human primate in each of the two highest dose groups in the initial study showed the anticipated signs of bone marrow failure resulting from HSC depletion and were euthanized prior to the end of the study. We have initiated a second dose-escalation study in non-human primates with a CD117-ADC probe compound engineered to have a shorter half-life and a lower number of drugs per antibody. In the first phase of this second study, one of the three non-human primates tested at the highest of the three dose levels showed elevated liver enzymes and was subsequently euthanized. Although these ongoing studies may potentially validate the non-human primate as a suitable model for efficacy and tolerability, if we are not able to ultimately show that an optimized CD117-ADC can deplete HSCs at a safe and effective dose, we may need to delay, abandon or limit these development efforts.

Even if we obtain regulatory approval of any of our product candidates, the approved products may be subject to post-approval studies and will remain subject to ongoing regulatory requirements. If we fail to comply, or if concerns are identified in subsequent studies, our approval could be withdrawn and our product sales could be suspended.

If we are successful at obtaining regulatory approval for MGTA-456 or any of our other product candidates, regulatory agencies in the United States and other countries where a product will be sold may require extensive additional clinical trials or post-approval clinical trials that are expensive and time-consuming to conduct. In particular, therapeutic products administered for the treatment of certain inherited metabolic diseases, such as Hurler’s syndrome and leukodystrophies, are likely to require extensive follow-up studies and close monitoring of patients after regulatory approval has been granted, for any signs of adverse effects that occur over a long period of time. These studies may be expensive and time-consuming to conduct and may reveal side effects or other harmful effects in patients that use our therapeutic products after they are on the market, which may result in the limitation or withdrawal of our drugs from the market. Alternatively, we may not be able to conduct such additional trials, which might force us to abandon our efforts to develop or commercialize certain product candidates. Even if post-approval studies are not requested or required, after our products are approved and on the market, there might be safety issues that emerge over time that require a change in product labeling or that require withdrawal of the product from the market, which would cause our revenue to decline.

Additionally, any products that we may successfully develop will be subject to ongoing regulatory requirements after they are approved. These requirements will govern the manufacturing, packaging, marketing, distribution, and use of our products. If we fail to comply with such regulatory requirements, approval for our products may be withdrawn, and product sales may be suspended. We may not be able to regain compliance, or we may only be able to regain compliance after a lengthy delay, significant expense, lost revenues and damage to our reputation.

 

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Because we are developing product candidates for the treatment of diseases in which there is little clinical experience using new technologies, there is increased risk that the FDA, the EMA, or other regulatory authorities may not consider the endpoints of our clinical trials to provide clinically meaningful results and that these results may be difficult to analyze.

During the regulatory review process, we will need to identify success criteria and endpoints such that the FDA, the EMA, or other regulatory authorities will be able to determine the clinical efficacy and safety profile of any product candidates we may develop. As we are initially seeking to identify and develop product candidates to treat diseases in which there is little clinical experience using new technologies, there is heightened risk that the FDA, the EMA, or other regulatory authorities may not consider the clinical trial endpoints that we propose to provide clinically meaningful results (reflecting a tangible benefit to patients). In addition, the resulting clinical data and results may be difficult to analyze. Even if the FDA does find our success criteria to be sufficiently validated and clinically meaningful, we may not achieve the pre-specified endpoints to a degree of statistical significance. This may be a particularly significant risk for many of the genetically defined diseases for which we plan to develop product candidates because many of these diseases have small patient populations, and designing and executing a rigorous clinical trial with appropriate statistical power is more difficult than with diseases that have larger patient populations. Further, even if we do achieve the pre-specified criteria, we may produce results that are unpredictable or inconsistent with the results of the non-primary endpoints or other relevant data. The FDA also weighs the benefits of a product against its risks, and the FDA may view the efficacy results in the context of safety as not being supportive of regulatory approval. Other regulatory authorities in the European Union and other countries, such as the Committee for Advanced Therapies, or CAT, may make similar comments with respect to these endpoints and data. Any product candidates we may develop will be based on a novel technology that makes it difficult to predict the time and cost of development and of subsequently obtaining regulatory approval.

A Breakthrough Therapy Designation by the FDA, even if granted for any of our product candidates, may not lead to a faster development or regulatory review or approval process and it does not increase the likelihood that our product candidates will receive marketing approval.

We plan to seek a Breakthrough Therapy Designation for our product candidates if the clinical data support such a designation for one or more product candidates. A breakthrough therapy is defined as a drug or biologic that is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug, or biologic, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For product candidates that have been designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens. Biologics designated as breakthrough therapies by the FDA may also be eligible for accelerated approval.

Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if we believe one of our product candidates meets the criteria for designation as a breakthrough therapy, the FDA may disagree and instead determine not to make such designation. In any event, the receipt of a Breakthrough Therapy Designation for a product candidate may not result in a faster development process, review or approval compared to drugs considered for approval under non-expedited FDA review procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of our product candidates qualify as breakthrough therapies, the FDA may later decide that the product no longer meets the conditions for qualification.

Our current product candidates and any future product candidates may not be eligible for Orphan Drug status.

The United States and Europe may designate drugs for relatively small patient populations as orphan drugs. Orphan Drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and

 

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approval process, but does make the product eligible for orphan drug exclusivity, reduced filing fees and specific tax credits. Generally, if a company receives the first marketing approval for a product with an Orphan Drug designation in the clinical indication for which it has such designation, the product is entitled to orphan drug exclusivity. Orphan drug exclusivity means that the FDA will not approve another application to market the same drug for the same indication, except in limited circumstances, for a period of seven years in the United States. This exclusivity, however, could block the approval of our proposed product candidates if a competitor obtains marketing approval before us. However, even if we obtain orphan drug exclusivity for any of our proposed product candidates, we may not be able to maintain it. For example, if a competitive product is shown to be clinically superior to our product candidates, any orphan drug exclusivity we have will not block the approval of such competitive product.

If we encounter difficulties enrolling patients in our clinical trials, our clinical development activities could be delayed or otherwise adversely affected.

We may experience difficulties in patient enrollment in our clinical trials for a variety of reasons. The timely completion of clinical trials in accordance with their protocols depends, among other things, on our ability to enroll a sufficient number of patients who remain in the study until its conclusion. The enrollment of patients depends on many factors, including:

 

    the patient eligibility criteria defined in the protocol;

 

    the size of the patient population required for analysis of the trial’s primary endpoints;

 

    the proximity of patients to study sites;

 

    the design of the trial;

 

    our ability to recruit clinical trial investigators with the appropriate competencies and experience;

 

    our ability to obtain and maintain patient consents; and

 

    the risk that patients enrolled in clinical trials will drop out of the trials before completion.

In addition, our clinical trials will compete with other clinical trials for product candidates that are in the same therapeutic areas as our product candidates, and this competition will reduce the number and types of patients available to us, because some patients who might have opted to enroll in our trials may instead opt to enroll in a trial being conducted by one of our competitors. Since the number of qualified clinical investigators is limited, we expect to conduct some of our clinical trials at the same clinical trial sites that some of our competitors use, which will reduce the number of patients who are available for our clinical trials in such clinical trial site.

Delays in patient enrollment may result in increased costs or may affect the timing or outcome of the planned clinical trials, which could prevent completion of these trials and adversely affect our ability to advance the development of our product candidates.

We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

Because we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific indications among many potential options. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial medicines or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable medicines. If we do not accurately evaluate the commercial potential or target market for a particular product

 

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candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing, or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate. Any such event could have a material adverse effect on our business, financial condition, results of operations, and prospects.

Even if we complete the necessary clinical trials, we cannot predict when, or if, we will obtain regulatory approval to commercialize a product candidate we may develop, and any such approval may be for a more narrow indication than we seek.

We cannot commercialize a product candidate until the appropriate regulatory authorities have reviewed and approved the product candidate. Even if any product candidates we may develop meet their safety and efficacy endpoints in clinical trials, the regulatory authorities may not complete their review processes in a timely manner, or we may not be able to obtain regulatory approval. Additional delays may result if an FDA Advisory Committee or other regulatory authority recommends non-approval or restrictions on approval. In addition, we may experience delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory authority policy during the period of product development, clinical trials, and the review process.

Regulatory authorities also may approve a product candidate for more limited indications than requested or they may impose significant limitations in the form of narrow indications, warnings or a Risk Evaluation and Mitigation Strategy, or REMS. These regulatory authorities may require precautions or contra-indications with respect to conditions of use, or they may grant approval subject to the performance of costly post-marketing clinical trials. In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of any product candidates we may develop. Any of the foregoing scenarios could materially harm the commercial prospects for any product candidates we may develop and materially adversely affect our business, financial condition, results of operations, and prospects.

A Fast Track Designation by the FDA, even if granted for any of our product candidates, may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our product candidates will receive marketing approval.

If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA Fast Track Designation for a particular indication. Marketing applications filed by sponsors of products in Fast Track development may qualify for priority review under the policies and procedures offered by the FDA, but the Fast Track Designation does not assure any such qualification or ultimate marketing approval by the FDA. Receipt of Fast Track Designation may not result in a faster development process, review or approval compared to drugs considered for approval under conventional FDA procedures. In addition, the FDA may withdraw any Fast Track Designation at any time. We may seek Fast Track Designation for MGTA-456 or any other product candidates, but there is no assurance that the FDA will grant this status to any of our proposed product candidates.

We may seek priority review designation for MGTA-456 or our other product candidates, but we might not receive such designation, and even if we do, such designation may not lead to a faster development or regulatory review or approval process.

If the FDA determines that a product candidate offers a treatment for a serious condition and, if approved, the product would provide a significant improvement in safety or effectiveness, the FDA may designate the product candidate for priority review. A priority review designation means that the goal for the FDA to review an application is six months, rather than the standard review period of ten months. We may request priority review for our product candidates, however, we cannot assume that MGTA-456 or our other product candidates will meet the criteria for that designation. The FDA has broad discretion with respect to whether or not to grant priority review status to a product candidate, so even if we believe a particular product candidate is eligible for

 

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such designation or status, the FDA may decide not to grant it. Moreover, a priority review designation does not necessarily mean a faster development or regulatory review or approval process or necessarily confer any advantage with respect to approval compared to conventional FDA procedures. Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all.

Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials, and such results do not guarantee approval of a product candidate by regulatory authorities.

The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and interim results of clinical trials do not necessarily predict success in the results of completed clinical trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier development, and we could face similar setbacks. The design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. In addition, preclinical and clinical data are often susceptible to varying interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain regulatory approval for their product candidates. Even if we complete clinical development of MGTA-456, there can be no assurance that the FDA, EMA, or other regulatory authorities will approve MGTA-456 for marketing.

In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen and other clinical trial procedures and the rate of dropout among clinical trial participants. If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced product candidate, and, correspondingly, our business and financial prospects would be negatively impacted.

Our product candidates for which we intend to seek approval may face competition from generic drugs or biosimilars sooner than anticipated.

With the enactment of the Biologics Price Competition and Innovation Act of 2009, or BPCIA, an abbreviated pathway for the approval of biosimilar and interchangeable biological products was created. The abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as interchangeable based on its similarity to an existing reference product. Under the BPCIA, an application for a biosimilar product cannot be approved by the FDA until 12 years after the original branded product is approved under a BLA. On March 6, 2015, the FDA approved the first biosimilar product under the BPCIA. However, the law is complex and is still being interpreted and implemented by the FDA. As a result, its ultimate impact, implementation, and meaning are subject to uncertainty. While it is uncertain when such processes intended to implement BPCIA may be fully adopted by the FDA, any such processes could have a material adverse effect on the future commercial prospects for our biological products.

We believe that if any of our product candidates are approved as a biological product under a BLA it should qualify for the 12-year period of exclusivity. However, there is a risk that the FDA will not consider any of our product candidates to be reference products for competing products, potentially creating the opportunity for biosimilar competition sooner than anticipated. Additionally, this period of regulatory exclusivity does not apply to companies pursuing regulatory approval via their own traditional BLA, rather than via the abbreviated pathway. Moreover, the extent to which a biosimilar, once approved, will be substituted for any one of our reference products in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing. Finally, there has been public discussion of potentially decreasing the period of exclusivity from the current 12 years. If such a change were to be enacted, our product candidates, if approved, could have a shorter period of exclusivity than anticipated.

 

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Enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our product candidates and may affect the prices we may set.

In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any products for which we obtain marketing approval.

For example, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the Affordable Care Act, or the ACA, was enacted to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for health care and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms. As implementation of the ACA is ongoing, the law appears likely to continue the downward pressure on pharmaceutical pricing, especially under the Medicare program, and may also increase our regulatory burdens and operating costs.

Moreover, the Drug Supply Chain Security Act imposes new obligations on manufacturers of pharmaceutical products related to product tracking and tracing. Legislative and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products. We are not sure whether additional legislative changes will be enacted, or whether the current regulations, guidance or interpretations will be changed, or what the impact of such changes on our business, if any, may be.

As an early stage small company that will be competing against numerous large, established companies that have substantially greater financial, technical, research manufacturing, marketing, distribution and other resources than us, we will be at a significant competitive disadvantage.

The pharmaceutical and biopharmaceutical industry is characterized by intense competition and rapid and significant technological changes and advancements. Many companies, research institutions and universities are doing research and development work in a number of areas similar to those that we focus on that could lead to the development of new products which could compete with and be superior to our product candidates.

Most of the companies with which we compete have substantially greater financial, technical, research, manufacturing, marketing, distribution and other resources than those of ours. A number of these companies may have or may develop technologies for developing products for treating various diseases, including certain inherited metabolic diseases such as Hurler’s syndrome and leukodystrophies, that could prove to be superior to ours. We expect technological developments in the pharmaceutical and biopharmaceutical and related fields to occur at a rapid rate, and we believe competition will intensify as advances in these fields are made. Accordingly, we will be required to continue to devote substantial resources and efforts to research and development activities in order to potentially achieve and maintain a competitive position in this field. Products that we develop may become obsolete before we are able to market them or to recover all or any portion of our research and development expenses. We will be competing with respect to our products with companies that have significantly more experience and expertise in undertaking preclinical testing and human clinical trials with new or improved therapeutic products and obtaining regulatory approvals of such products. A number of these companies already market and may be in advanced phases of clinical testing of various drugs that will or may compete with our current product candidates or other future potential product candidates. Our competitors may develop or commercialize products more rapidly than we do or with significant advantages over any products we develop. Our competitors may therefore be more successful in commercializing their products than we are, which could adversely affect our competitive position and business.

In addition to larger pharmaceutical or biopharmaceutical companies that may develop different competing technologies or technologies within the transplant field, we will be competing with a number of smaller

 

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biotechnology companies that are focused on transplant technologies, which may include among others Gamida Cell Ltd., Nohla Therapeutics, Inc., and ExCellThera Inc. We are aware of Novartis’ collaboration with Intellia Therapeutics, Inc. which includes efforts relating to expansion of HSCs that have been modified using CRISPR/Cas9 technology to express therapeutic proteins and delivered to patients for the treatment of potential treatment of blood disorders or primary immune deficiencies. Any programs and technology that develop as a result of this collaboration would likely compete directly with our E478 program.

Colleges, universities, governmental agencies and other public and private research organizations are becoming more active in seeking patent protection and licensing arrangements to collect royalties for use of technologies that they have developed, some of which may be directly competitive with our programs and product candidates, including our lead product candidate, MGTA-456.

Risks Related to Manufacturing and Commercialization

We rely on third parties to conduct our preclinical and clinical trials and will rely on them to perform other tasks for us. If these third parties do not successfully carry out their contractual duties, meet expected deadlines or comply with regulatory requirements, we may not be able to obtain regulatory approval for or commercialize our product candidates and our business could be substantially harmed.

Although we have recruited a team that has experience with clinical trials, as a company we have no experience in conducting clinical trials. Moreover, we do not have the ability to independently conduct preclinical studies and clinical trials, and we have relied upon, and plan to continue to rely upon medical institutions, clinical investigators, contract laboratories and other third parties, or our CROs, to conduct preclinical studies and future clinical trials for our product candidates. We expect to rely heavily on these parties for execution of preclinical and future clinical trials for our product candidates and control only certain aspects of their activities. Nevertheless, we will be responsible for ensuring that each of our preclinical and clinical trials is conducted in accordance with the applicable protocol, legal and regulatory requirements and scientific standards and our reliance on CROs will not relieve us of our regulatory responsibilities. For any violations of laws and regulations during the conduct of our preclinical studies and clinical trials, we could be subject to warning letters or enforcement action that may include civil penalties up to and including criminal prosecution.

We and our CROs will be required to comply with regulations, including cGCPs for conducting, monitoring, recording and reporting the results of preclinical and clinical trials to ensure that the data and results are scientifically credible and accurate and that the trial patients are adequately informed of the potential risks of participating in clinical trials and their rights are protected. These regulations are enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area and comparable foreign regulatory authorities for any drugs in clinical development. The FDA enforces cGCP regulations through periodic inspections of clinical trial sponsors, principal investigators and trial sites. If we or our CROs fail to comply with applicable cGCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA or comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We cannot assure you that, upon inspection, the FDA will determine that any of our future clinical trials will comply with cGCPs. In addition, our clinical trials must be conducted with product candidates produced in accordance with the requirements in cGMP regulations. Our failure or the failure of our CROs to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process and could also subject us to enforcement action.

Although we intend to design our planned clinical trials for our product candidates, for the foreseeable future CROs will conduct all of our planned clinical trials. As a result, many important aspects of our development programs, including their conduct and timing, will be outside of our direct control. Our reliance on third parties to conduct future preclinical studies and clinical trials will also result in less day-to-day control over the management of data developed through preclinical studies and clinical trials than would be the case if we were relying entirely upon our own staff.

 

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If any of our relationships with these third-party CROs terminate, we may not be able to enter into arrangements with alternative CROs. If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, any preclinical studies or clinical trials with which such CROs are associated with may be extended, delayed or terminated. In such cases, we may not be able to obtain regulatory approval for or successfully commercialize our product candidates. As a result, our financial results and the commercial prospects for our product candidates in the subject indication could be harmed, our costs could increase and our ability to generate revenue could be delayed.

The successful development of biopharmaceuticals and cell-based therapies, is highly uncertain.

Successful development of biopharmaceuticals and cell-based therapies, is highly uncertain and is dependent on numerous factors, many of which are beyond our control. Bone marrow transplant and cell-based therapies that appear promising in the early phases of development may fail to reach the market for several reasons including:

 

    preclinical study results may show the therapies to be less effective than desired or to have harmful or problematic side effects;

 

    clinical trial results may show the therapies to be less effective than expected (e.g., the trial failed to meet its primary endpoint) or to have unacceptable side effects or toxicities;

 

    failure to receive the necessary regulatory approvals or a delay in receiving such approvals. Among other things, such delays may be caused by slow enrollment in clinical trials, length of time to achieve study endpoints, additional time requirements for data analysis, or biologics license application, or BLA, preparation, discussions with the FDA, an FDA request for additional preclinical or clinical data, or unexpected safety or manufacturing issues;

 

    manufacturing costs, formulation issues, pricing or reimbursement issues, or other factors that make the therapy uneconomical; and

 

    the proprietary rights of others and their competing products and technologies that may prevent the therapy from being commercialized.

Success in preclinical studies and early clinical trials do not ensure that large-scale clinical trials will be successful. The length of time necessary to complete clinical trials and to submit an application for marketing approval for a final decision by a regulatory authority varies significantly from one therapy to the next, and may be difficult to predict.

Even if we are successful in getting market approval, commercial success of any of our product candidates will also depend in large part on the availability of coverage and adequate reimbursement from third-party payers, including government payers such as the Medicare and Medicaid programs and managed care organizations, which may be affected by existing and future health care reform measures designed to reduce the cost of health care. Third-party payers could require us to conduct additional studies, including post-marketing studies related to the cost effectiveness of a product, to qualify for reimbursement, which could be costly and divert our resources. If government and other health care payers were not to provide adequate coverage and reimbursement levels for any of our products if approved, market acceptance and commercial success would be reduced.

In addition, if one of our product candidates is approved for marketing, we will be subject to significant regulatory obligations regarding the submission of safety and other post-marketing information and reports and registration, and will need to continue to comply (or ensure that our third party providers) comply with the FDA’s current Good Manufacturing Practices, or cGMPs, and the FDA’s current Good Clinical Practices, or GCPs, for any clinical trials that we conduct post-approval. In addition, there is always the risk that we or a regulatory authority might identify previously unknown problems with a product post-approval, such as adverse

 

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events of unanticipated severity or frequency. Compliance with these requirements is costly, and any failure to comply or other issues with our product candidates’ post-market approval could have a material adverse effect on our business, financial condition and results of operations.

We may never obtain FDA approval for any of our product candidates in the United States, and even if we do, we may never obtain approval for or commercialize any of our product candidates in any other jurisdiction, which would limit our ability to realize their full market potential.

In order to eventually market any of our product candidates in any particular foreign jurisdiction, we must establish and comply with numerous and varying regulatory requirements on a jurisdiction-by-jurisdiction basis regarding safety and efficacy. Approval by the FDA in the United States, if obtained, does not ensure approval by regulatory authorities in other countries or jurisdictions. In addition, clinical trials conducted in one country may not be accepted by regulatory authorities in other countries, and regulatory approval in one country does not guarantee regulatory approval in any other country. Approval processes vary among countries and can involve additional product testing and validation and additional administrative review periods. Seeking foreign regulatory approval could result in difficulties and costs for us and require additional preclinical studies or clinical trials which could be costly and time-consuming. Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our products in those countries. The foreign regulatory approval process involves all of the risks associated with FDA approval. We do not have any product candidates approved for sale in any jurisdiction, including international markets, and we do not have experience in obtaining regulatory approval in international markets. If we fail to comply with regulatory requirements in international markets or to obtain and maintain required approvals, or if regulatory approvals in international markets are delayed, our target market will be reduced and our ability to realize the full market potential of our products will be unrealized.

MGTA-456 has been affected by contamination issues in the past, and any future contamination in our or our third parties’ manufacturing process, shortages of raw materials or reagents or failure of any of our key suppliers to deliver necessary components of our product candidates could result in delays in our clinical development or marketing schedules.

Given the nature of biologics manufacturing, there is a risk of contamination. For example, prior to our 2017 license of the product candidate from Novartis, our third-party manufacturer for MGTA-456 experienced contaminations, including microbial contaminations, in connection with the clinical manufacture of MGTA-456 which required disposal of contaminated product and led to delays in the manufacturing process. While we have not experienced contamination events in connection with the manufacture of MGTA-456 for our clinical use since licensing the product candidate, we cannot guarantee that we or our third-party vendors will be able to successfully prevent and remediate contaminations in the future in connection with the manufacture of MGTA-456 or our other current or future product candidates. Any contamination could materially adversely affect our or our third-party vendors’ ability to produce our product candidates on schedule and could therefore harm our results of operations and cause reputational damage.

The raw materials required in our and our third-party vendors’ manufacturing processes are derived from biological sources. We cannot assure you that we or our third-party vendors have, or will be able to obtain on commercially reasonable terms, or at all, sufficient rights to these materials derived from biological sources. Such raw materials are difficult to procure and may also be subject to contamination or recall or be of insufficient quality. For example, if a selected umbilical cord blood unit is of insufficient quality for manufacture of MGTA-456, we may experience a delay in our clinical trial while MGTA-456 is manufactured using an alternative, back-up umbilical cord blood unit. A material shortage, contamination, recall, or restriction on the use of biologically derived substances in the manufacture of our product candidates could adversely impact or disrupt the clinical and commercial manufacturing of our product candidates, which could materially and adversely affect our operating results and development timelines.

 

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We rely on third-party suppliers for the supply and manufacture of certain components of our technology and product candidates, including a single supplier in some cases. For example, an affiliate of the University of Minnesota is our only manufacturing partner for MGTA-456, and Bachem Americas, Inc. is currently the sole manufacturer of MGTA-145. See “Business—Licenses and Collaborations” for additional information regarding these relationships. Should our ability to procure the necessary components for our product candidates from our suppliers be compromised, our ability to continuously operate would be impaired until an alternative supplier is sourced, qualified and tested, which could delay or limit our ability to produce a clinical and commercial supply of our product candidates and harm our business.

If we use biological materials in a manner that causes injury, we may be liable for damages.

Our research and development activities involve the use of biological and hazardous materials. Although we believe our safety procedures for handling and disposing of these materials complies with federal, state and local laws and regulations, we cannot entirely eliminate the risk of accidental injury or contamination from the use, storage, handling or disposal of these materials. We do not carry specific biological waste insurance coverage, workers compensation or property and casualty and general liability insurance policies that include coverage for damages and fines arising from biological exposure or contamination. Accordingly, in the event of contamination or injury, we could be held liable for damages or penalized with fines in an amount exceeding our resources, and our clinical trials or regulatory approvals could be suspended or terminated.

Third-party manufacturers and any third-party collaborators may be unable to successfully scale-up manufacturing of MGTA-456 or our other current or future product candidates in sufficient quality and quantity, which would delay or prevent us from developing MGTA-456 or our other product candidates and commercializing approved products, if any.

In order to conduct clinical trials of MGTA-456 and our other current and future product candidates, we will need to work with third-party manufacturers to manufacture them in sufficient quantities. Our manufacturing partners or our third-party collaborators may be unable to successfully increase the manufacturing capacity of MGTA-456 and our other current or future product candidates in a timely or cost-effective manner, or at all. In addition, quality issues may arise during scale-up activities. If our manufacturing partners or collaborators are unable to successfully scale up the manufacture of our current or future product candidates in sufficient quality and quantity, the development, testing, and clinical trials of that product candidate may be delayed or infeasible, and marketing approval or commercial launch of any resulting product may be delayed or not obtained, which could significantly harm our business.

The commercial success of any of our product candidates will depend upon the degree of market acceptance by physicians, patients, third-party payors and others in the medical community.

Even with the requisite approvals from the FDA in the United States, the EMA in the European Union and other regulatory authorities internationally, the commercial success of our product candidates will depend, in part, on the acceptance of physicians, patients and health care payors of our product candidates as medically necessary, cost-effective and safe. Any product that we commercialize may not gain acceptance by physicians, patients, health care payors and others in the medical community. If these products do not achieve an adequate level of acceptance, we may not generate significant product revenue and may not become profitable. The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on several factors, including:

 

    the efficacy, durability and safety of such product candidates as demonstrated in clinical trials;

 

    the potential and perceived advantages of product candidates over alternative treatments;

 

    the cost of treatment relative to alternative treatments;

 

    the clinical indications for which the product candidate is approved by the FDA or the European Commission;

 

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    the willingness of physicians to prescribe new therapies;

 

    the willingness of the target patient population to try new therapies;

 

    the prevalence and severity of any side effects;

 

    product labeling or product insert requirements of the FDA, EMA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling;

 

    relative convenience and ease of administration;

 

    the strength of marketing and distribution support;

 

    the timing of market introduction of competitive products;

 

    publicity concerning our products or competing products and treatments; and

 

    sufficient third-party payor coverage and adequate reimbursement.

Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product will not be fully known until after it is launched.

If we are unable to successfully develop our current programs into a comprehensive portfolio of product candidates, or experience significant delays in doing so, we may not realize the full commercial potential of our current and future product candidates.

We are developing our product candidates so that they can each be used individually or in combination with each other. In particular, we are focused on a product development strategy that includes leveraging the synergies among a comprehensive portfolio of our product candidates. Our success may depend, in part, on our ability to develop a complementary product portfolio with product candidates that, together or individually, will address the major unmet needs inherent to the existing bone marrow transplant process. Given our limited experience in developing product candidates that have received marketing approval, we may not be successful in developing some of our product candidates. The failure of one of our product candidates to obtain regulatory approval or market acceptance may affect our ability to expand our market opportunities for our other product candidates or programs. Although we may develop product candidates that ultimately obtain marketing approval, if we are unable to successfully develop our current programs into a comprehensive portfolio of product candidates, or experience significant delays in doing so, we may not realize the full commercial potential of our current and future product candidates.

Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, if approved, which could make it difficult for us to sell any product candidates or therapies profitably.

The success of our product candidates, if approved, depends on the availability of adequate coverage and reimbursement from third-party payors. In addition, because our product candidates represent new approaches to bone marrow transplant, we cannot be sure that coverage and reimbursement will be available for, or accurately estimate the potential revenue from our product candidates or assure that coverage and reimbursement will be available for any product that we may develop.

Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment. Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors are critical to new product acceptance.

Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drugs and treatments they will cover and the amount of reimbursement. Coverage

 

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and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:

 

    a covered benefit under its health plan;

 

    safe, effective and medically necessary;

 

    appropriate for the specific patient;

 

    cost-effective; and

 

    neither experimental nor investigational.

In the U.S., no uniform policy of coverage and reimbursement for products exists among third-party payors. As a result, obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical and cost-effectiveness data for the use of our products on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained. Even if we obtain coverage for a given product, the resulting reimbursement payment rates might not be adequate for us to achieve or sustain profitability or may require co-payments that patients find unacceptably high. Additionally, third-party payors may not cover, or provide adequate reimbursement for, long-term follow-up evaluations required following the use of product candidates. Patients are unlikely to use our product candidates unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our product candidates. Because our product candidates may have a higher cost of goods than conventional therapies, and may require long-term follow up evaluations, the risk that coverage and reimbursement rates may be inadequate for us to achieve profitability may be greater. There is significant uncertainty related to insurance coverage and reimbursement of newly approved products. It is difficult to predict at this time what third-party payors will decide with respect to the coverage and reimbursement for our product candidates.

Payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives. For example, the Middle Class Tax Relief and Job Creation Act of 2012 required that the Centers for Medicare & Medicaid Services, the agency responsible for administering the Medicare program, or CMS, reduce the Medicare clinical laboratory fee schedule by 2% in 2013, which served as a base for 2014 and subsequent years. In addition, effective January 1, 2014, CMS also began bundling the Medicare payments for certain laboratory tests ordered while a patient received services in a hospital outpatient setting. Additional state and federal healthcare reform measures are expected to be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for certain pharmaceutical products or additional pricing pressures.

Moreover, increasing efforts by governmental and third-party payors in the United States and abroad to cap or reduce healthcare costs may cause such organizations to limit both coverage and the level of reimbursement for newly approved products and, as a result, they may not cover or provide adequate payment for our product candidates. There has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices. Specifically, there have been several recent U.S. Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs. We expect to experience pricing pressures in connection with the sale of any of our product candidates due to the trend toward managed healthcare, the increasing influence of health maintenance organizations, cost containment initiatives and additional legislative changes.

Ongoing healthcare legislative and regulatory reform measures may have a material adverse effect on our business and results of operations.

Changes in regulations, statutes or the interpretation of existing regulations could impact our business in the future by requiring, for example: (i) changes to our manufacturing arrangements; (ii) additions or modifications

 

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to product labeling; (iii) the recall or discontinuation of our products; or (iv) additional record-keeping requirements. If any such changes were to be imposed, they could adversely affect the operation of our business.

In the United States, there have been and continue to be a number of legislative initiatives to contain healthcare costs. For example, in March 2010, the Affordable Care Act was passed, which substantially changes the way health care is financed by both governmental and private insurers, and significantly impacts the U.S. pharmaceutical industry. The Affordable Care Act, or the ACA, among other things, subjects biological products to potential competition by lower-cost biosimilars, addresses a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increases the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extends the rebate program to individuals enrolled in Medicaid managed care organizations, establishes annual fees and taxes on manufacturers of certain branded prescription drugs, and creates a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts (which will be increased to 70% effective January 1, 2019) off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

Some of the provisions of the ACA have yet to be fully implemented, while certain provisions have been subject to judicial and Congressional challenges, as well as efforts by the Trump administration to repeal or replace certain aspects of the ACA. For example, in Congress, the U.S. House of Representatives passed Affordable Care Act replacement legislation known as the American Health Care Act of 2017 in May 2017, which was not introduced in the Senate. However, The Tax Cuts and Jobs Act of 2017 includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” Congress may consider other legislation to repeal or replace certain elements of the Affordable Care Act. In addition, since January 2017, President Trump has signed two Executive Orders designed to delay the implementation of certain provisions of the ACA or otherwise circumvent some of the requirements for health insurance mandated by the ACA. Further, the Trump administration has concluded that cost-sharing reduction (CSR) payments to insurance companies required under the ACA have not received necessary appropriations from Congress and announced that it will discontinue these payments immediately until such appropriations are made. The loss of the CSR payments is expected to increase premiums on certain policies issued by qualified health plans under the ACA. A bipartisan bill to appropriate funds for CSR payments was introduced in the Senate, but the future of that bill is uncertain. Several state Attorneys General filed suit to stop the administration from terminating the subsidies, but their request for a restraining order was denied by a federal judge in California on October 25, 2017. Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

Other legislative changes have been proposed and adopted in the United States since the ACA was enacted. On August 2, 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to providers of 2% per fiscal year. These reductions went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2027 unless additional congressional action is taken. On January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers.

These laws, and future state and federal healthcare reform measures may be adopted in the future, any of which may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

 

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European Union drug marketing and reimbursement regulations may materially affect our ability to market and receive coverage for our products in the European member states.

We intend to seek approval to market our product candidates in both the United States and in selected foreign jurisdictions. If we obtain approval in one or more foreign jurisdictions for our product candidates, we will be subject to rules and regulations in those jurisdictions. In some foreign countries, particularly those in the European Union, the pricing of biologics is subject to governmental control and other market regulations which could put pressure on the pricing and usage of our product candidates. In these countries, pricing negotiations with governmental authorities can take considerable time after obtaining marketing approval of a product candidate. In addition, market acceptance and sales of our product candidates will depend significantly on the availability of adequate coverage and reimbursement from third-party payors for our product candidates and may be affected by existing and future health care reform measures.

Much like the Anti-Kickback Statue prohibition in the United States, the provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union. The provision of benefits or advantages to physicians is governed by the national anti-bribery laws of European Union Member States, such as the UK Bribery Act 2010. Infringement of these laws could result in substantial fines and imprisonment.

Payments made to physicians in certain European Union Member States must be publically disclosed. Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual European Union Member States. These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the European Union Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

In addition, in most foreign countries, including the European Economic Area, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing and reimbursement vary widely from country to country. For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices. A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. In some countries, we may be required to conduct a clinical study or other studies that compare the cost-effectiveness of any of our product candidates to other available therapies in order to obtain or maintain reimbursement or pricing approval. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products. Historically, products launched in the European Union do not follow price structures of the United States and generally prices tend to be significantly lower. Publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries. If pricing is set at unsatisfactory levels or if reimbursement of our products is unavailable or limited in scope or amount, our revenues from sales by us or our strategic partners and the potential profitability of any of our product candidates in those countries would be negatively affected.

European data collection is governed by restrictive regulations governing the use, processing, and cross-border transfer of personal information.

The collection and use of personal health data in the European Union is governed by the provisions of the Data Protection Directive, and as of May 2018 the General Data Protection Regulation, or GDPR. These directive imposes several requirements relating to the consent of the individuals to whom the personal data relates, the

 

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information provided to the individuals, notification of data processing obligations to the competent national data protection authorities and the security and confidentiality of the personal data. The Data Protection Directive and GDPR also impose strict rules on the transfer of personal data out of the European Union to the United States. Failure to comply with the requirements of the Data Protection Directive, the GDPR, and the related national data protection laws of the European Union Member States may result in fines and other administrative penalties. The GDPR introduces new data protection requirements in the European Union and substantial fines for breaches of the data protection rules. The GDPR regulations may impose additional responsibility and liability in relation to personal data that we process and we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules. This may be onerous and adversely affect our business, financial condition, results of operations and prospects.

Laws and regulations governing international operations may preclude us from developing, manufacturing and selling certain products outside of the United States and require us to develop, implement and maintain costly compliance programs.

If we further expand our operations outside of the United States, we must dedicate additional resources to comply with numerous laws and regulations in each jurisdiction in which we plan to operate. The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S. individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with certain accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a recognized problem. In addition, the FCPA presents particular challenges in the pharmaceutical industry, because, in many countries, hospitals are operated by the government, and doctors and other hospital employees are considered foreign officials. Certain payments to hospitals in connection with clinical trials and other work have been deemed to be improper payments to government officials and have led to FCPA enforcement actions.

Various laws, regulations and executive orders also restrict the use and dissemination outside of the United States, or the sharing with certain non-U.S. nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products. If we expand our presence outside of the United States, it will require us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain products and product candidates outside of the United States, which could limit our growth potential and increase our development costs.

The failure to comply with laws governing international business practices may result in substantial civil and criminal penalties and suspension or debarment from government contracting. The Securities and Exchange Commission, or SEC, also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions.

We currently have no marketing and sales organization and have no experience in marketing products. If we are unable to establish marketing and sales capabilities or enter into agreements with third parties to market and sell our product candidates, we may not be able to generate product revenue.

We currently have no sales, marketing or distribution capabilities and have no experience in marketing products. We intend to develop an in-house marketing organization and sales force, which will require significant capital expenditures, management resources and time. We will have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain marketing and sales personnel.

 

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If we are unable or decide not to establish internal sales, marketing and distribution capabilities, we will pursue collaborative arrangements regarding the sales and marketing of our products, however, there can be no assurance that we will be able to establish or maintain such collaborative arrangements, or if we are able to do so, that they will have effective sales forces. Any revenue we receive will depend upon the efforts of such third parties, which may not be successful. We may have little or no control over the marketing and sales efforts of such third parties and our revenue from product sales may be lower than if we had commercialized our product candidates ourselves. We also face competition in our search for third parties to assist us with the sales and marketing efforts of our product candidates.

There can be no assurance that we will be able to develop in-house sales and distribution capabilities or establish or maintain relationships with third-party collaborators to commercialize any product in the United States or overseas.

Even if we are able to commercialize any product candidates, such products may become subject to unfavorable pricing regulations, third-party reimbursement practices, or healthcare reform initiatives, which would harm our business.

The regulations that govern marketing approvals, pricing, and reimbursement for new medicines vary widely from country to country. In the United States, recently enacted legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals. Some countries require approval of the sale price of a medicine before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a result, we might obtain marketing approval for a medicine in a particular country, but then be subject to price regulations that delay our commercial launch of the medicine, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the medicine in that country. Adverse pricing limitations may hinder our ability to recoup our investment in one or more product candidates, even if any product candidates we may develop obtain marketing approval.

Our ability to commercialize any medicines successfully also will depend in part on the extent to which reimbursement for these medicines and related treatments will be available from government health administration authorities, private health insurers, and other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. We cannot be sure that reimbursement will be available for any medicine that we commercialize and, if reimbursement is available, the level of reimbursement. Reimbursement may impact the demand for, or the price of, any product candidate for which we obtain marketing approval. If reimbursement is not available or is available only to limited levels, we may not be able to successfully commercialize any product candidate for which we obtain marketing approval.

There may be significant delays in obtaining reimbursement for newly approved medicines, and coverage may be more limited than the purposes for which the medicine is approved by the FDA or similar regulatory authorities outside the United States. Moreover, eligibility for reimbursement does not imply that any medicine will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale, and distribution. Interim reimbursement levels for new medicines, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement rates may vary according to the use of the medicine and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost medicines and may be incorporated into existing payments for other services. Net prices for medicines may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by

 

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any future relaxation of laws that presently restrict imports of medicines from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies. Our inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved medicines we may develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize medicines, and our overall financial condition.

If product liability lawsuits are brought against us, we may incur substantial liabilities and may be required to limit commercialization of our product candidates.

We face an inherent risk of product liability as a result of the clinical testing of our product candidates and will face an even greater risk if we commercialize any products. For example, we may be sued if our product candidates cause or are perceived to cause injury or are found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercialization of our product candidates. Even successful defense would require significant financial and management resources. Regardless of the merits or eventual outcome, liability claims may result in:

 

    decreased demand for our products;

 

    injury to our reputation;

 

    withdrawal of clinical trial participants and inability to continue clinical trials;

 

    initiation of investigations by regulators;

 

    costs to defend the related litigation;

 

    a diversion of management’s time and our resources;

 

    substantial monetary awards to trial participants or patients;

 

    product recalls, withdrawals or labeling, marketing or promotional restrictions;

 

    loss of revenue;

 

    exhaustion of any available insurance and our capital resources;

 

    the inability to commercialize any product candidate; and

 

    a decline in our share price.

Our inability to obtain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of products we develop, alone or with collaborators. Although we currently carry $5,000,000 of clinical trial insurance, the amount of such insurance coverage may not be adequate, we may be unable to maintain such insurance, or we may not be able to obtain additional or replacement insurance at a reasonable cost, if at all. Our insurance policies may also have various exclusions, and we may be subject to a product liability claim for which we have no coverage. We may have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts. Even if our agreements with any future corporate collaborators entitle us to indemnification against losses, such indemnification may not be available or adequate should any claim arise.

 

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Failure to obtain marketing approval in foreign jurisdictions would prevent any product candidates we may develop from being marketed in such jurisdictions, which, in turn, would materially impair our ability to generate revenue.

In order to market and sell any product candidates we may develop in the European Union and many other foreign jurisdictions, we or our third-party collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA approval. The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside the United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country. We or these third parties may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our medicines in any jurisdiction, which would materially impair our ability to generate revenue.

Foreign governments often impose strict price controls on approved products, which may adversely affect our future profitability in those countries, and the re-importation of drugs to the United States from foreign countries that impose price controls may adversely affect our future profitability.

Frequently foreign governments impose strict price controls on newly approved therapeutic products. If we obtain regulatory approval to sell products in foreign countries, we may be unable to obtain a price that provides an adequate financial return on our investment. Furthermore, legislation in the United States may permit re-importation of drugs from foreign countries into the United States, including re-importation from foreign countries where the drugs are sold at lower prices than in the United States due to foreign government-mandated price controls. Such a practice, especially if it is conducted on a widespread basis, may significantly reduce our potential United States revenues from any drugs that we are able to develop.

Even if we, or any collaborators we may have, obtain marketing approvals for any product candidates we develop, the terms of approvals and ongoing regulation of our products could require the substantial expenditure of resources and may limit how we, or they, manufacture and market our products, which could materially impair our ability to generate revenue.

Any product candidate for which we obtain marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, advertising, and promotional activities for such medicine, will be subject to continual requirements of and review by the FDA and other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to quality control, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distribution of samples to physicians and recordkeeping. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine.

Accordingly, assuming we, or any collaborators we may have, receive marketing approval for one or more product candidates we develop, we, and such collaborators, and our and their contract manufacturers will continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing, production, product surveillance, and quality control. If we and such collaborators are not able to comply with post-approval regulatory requirements, we and such collaborators could have the marketing approvals for our products withdrawn by regulatory authorities and our, or such collaborators’, ability to market any future products could be limited, which could adversely affect our ability to achieve or sustain profitability. Further, the

 

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cost of compliance with post-approval regulations may have a negative effect on our business, operating results, financial condition, and prospects.

Risks Related to Intellectual Property

We are highly dependent on intellectual property licensed from third parties and termination of any of these licenses could result in the loss of significant rights, which would harm our business.

In April 2017, we entered into a license agreement with Novartis pursuant to which we were granted a worldwide license to certain intellectual property rights owned or controlled by Novartis, including patents, patent applications, proprietary information, know-how and other intellectual property, to develop, commercialize and sell one or more therapeutic products comprising MGTA-456 in the field of non-gene-edited/-modified HSCs. In addition, in November 2016, we entered into a license agreement with Harvard University, or Harvard, pursuant to which we were granted a worldwide license to research, develop and commercialize one or more therapeutic products under certain conditioning- and mobilization-related patents and patent applications owned or controlled by Harvard. Furthermore, in March 2018, we entered into a research, development option and license agreement with Heidelberg Pharma Research GmbH, or Heidelberg Pharma, pursuant to which we intend to combine our proprietary antibodies and Heidelberg Pharma’s amanitin conjugates platform. We are dependent on the patents, know-how and proprietary technology, licensed from Novartis and Harvard. Furthermore, if we commercialize any products utilizing Heidelberg Pharma’s amanitin conjugates platform, we will be dependent on the intellectual property rights we license from Heidelberg Pharma. Any termination of these licenses, or a finding that such intellectual property lacks legal effect, could result in the loss of significant rights and could harm our ability to commercialize MGTA-456, C100, C200, C300, G100, MGTA-145, and other product candidates.

Certain of our license agreements, including our agreements with Novartis, Harvard and Heidelberg Pharma, require us to use diligent efforts or meet development thresholds to maintain the license, including establishing a set timeline for developing and commercializing products. If we fail to comply with the obligations under our license agreements, including payment terms and diligence terms, our licensors may have the right to terminate our agreements, in which event we may not be able to develop, manufacture, market or sell the products covered by our agreements or may face other penalties under our agreements. Such an occurrence could materially adversely affect the value of the product candidate being developed under any such agreement. Termination of our license agreements or reduction or elimination of our rights under them may result in our having to negotiate a new or reinstated agreement, which may not be available to us on equally favorable terms, or at all, which may mean we are unable to develop or commercialize the affected product candidate or cause us to lose our rights under the agreement. In addition with respect to our license agreement with Novartis, Novartis has granted an exclusive license to Intellia Therapeutics, Inc., or Intellia, in the field of gene-modified HSCs under the same intellectual property that Novartis licensed to us. Accordingly, such rights are unavailable to us and in prosecuting, maintaining, enforcing and defending the licensed patents, Novartis may make decisions that may not be in our best interest. Moreover, if Novartis or Intellia take any action with respect to the licensed patents that results in a successful challenge to the licensed patents by any third party, such patents may be invalidated or held to be unenforceable and we may lose our rights under such patents, which would harm our business. See the section entitled “Business—Licenses and Collaborations” for additional information regarding our license agreements.

Further, the agreements under which we currently license intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations. Accordingly, disputes may arise between us and our licensor, our licensor and its licensors, regarding intellectual property subject to a license agreement, including those relating to:

 

    the scope of rights, if any, granted under the license agreement and other interpretation-related issues;

 

    whether and the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the license agreement;

 

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    whether our licensor or its licensor had the right to grant the license agreement;

 

    whether third parties are entitled to compensation or equitable relief, such as an injunction, for our use of the intellectual property without their authorization;

 

    our right to sublicense patent and other rights to third parties under collaborative development relationships;

 

    whether we are complying with our obligations with respect to the use of the licensed technology in relation to our development and commercialization of product candidates;

 

    our involvement in the prosecution of the licensed patents and our licensors’ overall patent enforcement strategy;

 

    the allocation of ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and by us and our partners; and

 

    the amounts of royalties, milestones or other payments due under the license agreement.

The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement. If disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, or are insufficient to provide us the necessary rights to use the intellectual property, we may be unable to successfully develop and commercialize the affected product candidates. If we or any such licensors fail to adequately protect this intellectual property, our ability to commercialize our products could suffer. Any disputes with our licensors or any termination of the licenses on which we depend could have a material adverse effect on our business, financial condition, results of operations and prospects.

Our commercial success depends on our ability to obtain, maintain and protect our intellectual property and proprietary technology.

Our commercial success depends in large part on our ability to obtain, maintain and protect intellectual property protection through patents, trademarks, and trade secrets in the United States and other countries with respect to our proprietary product candidates. If we do not adequately protect our intellectual property rights, competitors may be able to erode, negate or preempt any competitive advantage we may have, which could harm our business and ability to achieve profitability.

To protect our proprietary position, we have submitted patent applications and may file other patent applications in the United States or abroad related to our product candidates that are important to our business. Although we in-license certain issued patents from Novartis related to our MGTA-456 product candidate, we do not own any issued patents related to our product candidates in any major market and most of the patent applications that we own in the United States are provisional patent applications. Provisional patent applications are not eligible to become issued patents until, among other things, we file a non-provisional patent application within 12 months of the filing of one or more of our related provisional patent applications. If we do not timely file any non-provisional patent applications, we may lose our priority date with respect to our provisional patent applications and any patent protection on the inventions disclosed in our provisional patent applications. While we intend to timely file non-provisional patent applications relating to our provisional patent applications, we cannot predict whether any such patent applications will result in the issuance of patents that provide us with any competitive advantage. Moreover, the patent application and approval process is expensive and time-consuming. We may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner.

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claims are amended, and may not be able to secure, maintain, or successfully enforce necessary or desirable patent protection from those patent rights. We have not had and do not have primary control over patent prosecution and maintenance for certain of the patents and patent applications we license, including under our agreement with Novartis, and therefore cannot guarantee that these patents and applications will be prosecuted or maintained in a manner consistent with the best interests of our business. We cannot be certain that patent prosecution and maintenance activities by our licensors have been or will be conducted in compliance with applicable laws and regulations or will result in valid and enforceable patents. Moreover, some of our in-licensed patents and patent applications are, and our future owned and licensed patents may be, co-owned with third parties. If we are unable to obtain an exclusive license to any such third party co-owners’ interest in such patents or patent applications, such co-owners may be able to license their rights to other third parties, including our competitors, and our competitors could market competing products and technology. In addition, we may need the cooperation of any such co-owners of our patents in order to enforce such patents against third parties, and such cooperation may not be provided to us.

If the scope of the patent protection we or our licensors obtain is not sufficiently broad, we may not be able to prevent others from developing and commercializing technology and products similar or identical to ours. The degree of patent protection we require to successfully compete in the marketplace may be unavailable or severely limited in some cases and may not adequately protect our rights or permit us to gain or keep any competitive advantage. We cannot provide any assurances that any of our licensed patents have, or that any of our pending owned or licensed patent applications that mature into issued patents will include, claims with a scope sufficient to protect our product candidates or otherwise provide any competitive advantage, nor can we assure you that our licenses will remain in force. Other parties have developed or may develop technologies that may be related or competitive with our approach, and may have filed or may file patent applications and may have been issued or may be issued patents with claims that overlap or conflict with our patent applications, either by claiming the same compounds, formulations or methods or by claiming subject matter that could dominate our patent position. In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the United States. Furthermore, patents have a limited lifespan. In the United States, the natural expiration of a patent is generally twenty years after it is filed. Various extensions may be available; however, the life of a patent, and the protection it affords, is limited. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our patent portfolio may not provide us with adequate and continuing patent protection sufficient to exclude others from commercializing products similar to our product candidates. In addition, the patent portfolio licensed to us is, or may be, licensed to third parties, such as outside our field, and such third parties may have certain enforcement rights. Thus, patents licensed to us and any patents we own in the future could be put at risk of being invalidated or interpreted narrowly in litigation filed by or against another licensee or in administrative proceedings brought by or against another licensee in response to such litigation or for other reasons.

The patent protection we obtain for our product candidates may not be sufficient enough to provide us with any competitive advantage or our patents may be challenged.

Our owned and licensed patents and pending patent applications, if issued, may not provide us with any meaningful protection or prevent competitors from designing around our patent claims to circumvent our patents by developing similar or alternative technologies or therapeutics in a non-infringing manner. For example, a third party may develop a competitive therapy that provides benefits similar to one or more of our product candidates but falls outside the scope of our patent protection or license rights. If the patent protection provided by the patents and patent applications we hold or pursue with respect to our product candidates is not sufficiently broad to impede such competition, our ability to successfully commercialize our product candidates could be negatively affected, which would harm our business. Currently, a significant portion of our patents and patent applications are in-licensed, though similar risks would apply to any patents or patent applications that we now own or may own or in-license in the future.

 

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We, or any future partners, collaborators, or licensees, may fail to identify patentable aspects of inventions made in the course of development and commercialization activities before it is too late to obtain patent protection on them. Therefore, we may miss potential opportunities to strengthen our patent position.

It is possible that defects of form in the preparation or filing of our patents or patent applications may exist, or may arise in the future, for example with respect to proper priority claims, inventorship, claim scope, or requests for patent term adjustments. If we or our partners, collaborators, licensees, or licensors, whether current or future, fail to establish, maintain or protect such patents and other intellectual property rights, such rights may be reduced or eliminated. If our partners, collaborators, licensees, or licensors, are not fully cooperative or disagree with us as to the prosecution, maintenance or enforcement of any patent rights, such patent rights could be compromised. If there are material defects in the form, preparation, prosecution, or enforcement of our patents or patent applications, such patents may be invalid and/or unenforceable, and such applications may never result in valid, enforceable patents. Any of these outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business.

The patent position of biotechnology and pharmaceutical companies carries uncertainty. In addition, the determination of patent rights with respect to pharmaceutical compounds commonly involves complex legal and factual questions, which are dependent upon the current legal and intellectual property context, extant legal precedent and interpretations of the law by individuals. As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are characterized by uncertainty.

Pending patent applications cannot be enforced against third parties practicing the technology claimed in such applications unless and until a patent issues from such applications. Assuming the other requirements for patentability are met, currently, the first to file a patent application is generally entitled to the patent. However, prior to March 16, 2013, in the United States, the first to invent was entitled to the patent. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are not published until 18 months after filing, or in some cases not at all. Therefore, we cannot be certain that we were the first to make the inventions claimed in our patents or pending patent applications, or that we were the first to file for patent protection of such inventions. Similarly, we cannot be certain that parties from whom we do or may license or purchase patent rights were the first to make relevant claimed inventions, or were the first to file for patent protection for them. If third parties have filed prior patent applications on inventions claimed in our patents or applications that were filed on or before March 15, 2013, an interference proceeding in the United States can be initiated by such third parties to determine who was the first to invent any of the subject matter covered by the patent claims of our applications. If third parties have filed such prior applications after March 15, 2013, a derivation proceeding in the United States can be initiated by such third parties to determine whether our invention was derived from theirs.

Moreover, because the issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, our owned and licensed patents or pending patent applications may be challenged in the courts or patent offices in the United States and abroad. There is no assurance that all of the potentially relevant prior art relating to our patents and patent applications has been found. If such prior art exists, it may be used to invalidate a patent, or may prevent a patent from issuing from a pending patent application. For example, such patent filings may be subject to a third-party submission of prior art to the U.S. Patent and Trademark Office, or USPTO, or to other patent offices around the world. Alternately or additionally, we may become involved in post-grant review procedures, oppositions, derivation proceedings, ex parte reexaminations, inter partes review, supplemental examinations, or interference proceedings or challenges in district court, in the United States or in various foreign patent offices, including both national and regional, challenging patents or patent applications in which we have rights, including patents on which we rely to protect our business. An adverse determination in any such challenges may result in loss of the patent or in patent or patent application claims being narrowed, invalidated or held unenforceable, in whole or in part, or in denial of the patent application or loss or reduction in the scope of one or more claims of the patent or patent application, any of which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent

 

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protection of our technology and products. In addition, given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized.

Pending and future patent applications may not result in patents being issued that protect our business, in whole or in part, or which effectively prevent others from commercializing competitive products. Competitors may also be able to design around our patents. Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents or narrow the scope of our patent protection. In addition, the laws of foreign countries may not protect our rights to the same extent or in the same manner as the laws of the United States. For example, patent laws in various jurisdictions, including significant commercial markets such as Europe, restrict the patentability of methods of treatment of the human body more than United States law does. If these developments were to occur, they could have a material adverse effect on our ability to generate revenue.

The patent application process is subject to numerous risks and uncertainties, and there can be no assurance that we or any of our future development partners will be successful in protecting our product candidates by obtaining and defending patents. These risks and uncertainties include the following:

 

    the USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other provisions during the patent process. There are situations in which noncompliance can result in abandonment or lapse of a patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. In such an event, competitors might be able to enter the market earlier than would otherwise have been the case;

 

    patent applications may not result in any patents being issued;

 

    patents that may be issued or in-licensed may be challenged, invalidated, modified, revoked, circumvented, found to be unenforceable or otherwise may not provide any competitive advantage;

 

    our competitors, many of whom have substantially greater resources and many of whom have made significant investments in competing technologies, may seek or may have already obtained patents that will limit, interfere with or eliminate our ability to make, use, and sell our potential product candidates;

 

    there may be significant pressure on the U.S. government and international governmental bodies to limit the scope of patent protection both inside and outside the United States for disease treatments that prove successful, as a matter of public policy regarding worldwide health concerns; and

 

    countries other than the United States may have patent laws less favorable to patentees than those upheld by U.S. courts, allowing foreign competitors a better opportunity to create, develop and market competing product candidates.

Issued patents that we have or may obtain or license may not provide us with any meaningful protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage. Our competitors may be able to circumvent our patents by developing similar or alternative technologies or products in a non-infringing manner. Our competitors may also seek approval to market their own products similar to or otherwise competitive with our products. Alternatively, our competitors may seek to market generic versions of any approved products by submitting Abbreviated New Drug Applications, or ANDAs, to the FDA in which they claim that patents owned or licensed by us are invalid, unenforceable or not infringed. In these circumstances, we may need to defend or assert our patents, or both, including by filing lawsuits alleging patent infringement. In any of these types of proceedings, a court or other agency with jurisdiction may find our patents invalid or unenforceable, or that our competitors are competing in a non-infringing manner. Thus, even if we have valid and enforceable patents, these patents still may not provide protection against competing products or processes sufficient to achieve our business objectives. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

 

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If we are unable to protect the confidentiality of our trade secrets, our business and competitive position may be harmed.

In addition to the protection afforded by patents, we rely upon unpatented trade secret protection, unpatented know-how and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our contractors, collaborators, scientific advisors, employees and consultants and invention assignment agreements with our consultants and employees. However, we may not obtain these agreements in all circumstances, and individuals with whom we have these agreements may not comply with their terms. The assignment of intellectual property rights under these agreements may not be self-executing or the assignment agreements may be breached, and we may be forced to bring claims against third parties, or defend claims that they may bring against us, to determine the ownership of what we regard as our intellectual property. In addition, we may not be able to prevent the unauthorized disclosure or use of our technical know-how or other trade secrets by the parties to these agreements despite the existence generally of confidentiality agreements and other contractual restrictions. Monitoring unauthorized uses and disclosures is difficult and we do not know whether the steps we have taken to protect our proprietary technologies will be effective. If any of the contractors, collaborators, scientific advisors, employees and consultants who are parties to these agreements breaches or violates the terms of any of these agreements, we may not have adequate remedies for any such breach or violation. As a result, we could lose our trade secrets. Enforcing a claim against a third party that illegally obtained and is using our trade secrets, like patent litigation, is expensive and time-consuming and the outcome is unpredictable. In addition, courts outside the United States are sometimes less willing or unwilling to protect trade secrets.

Moreover, our trade secrets could otherwise become known or be independently discovered by our competitors or other third parties. Competitors and other third parties could purchase our product candidates and attempt to replicate some or all of the competitive advantages we derive from our development efforts, willfully infringe our intellectual property rights, design around our protected technology or develop their own competitive technologies that fall outside of our intellectual property rights. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor or other third party, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us. If our trade secrets are not adequately protected or sufficient to provide an advantage over our competitors, our competitive position could be adversely affected, as could our business. Additionally, if the steps taken to maintain our trade secrets are deemed inadequate, we may have insufficient recourse against third parties for misappropriating our trade secrets.

Third-party claims of intellectual property infringement, misappropriation or other violations may prevent or delay our product discovery and development efforts and have a material adverse effect on our business.

Our commercial success depends in part on our avoiding infringement, misappropriation and other violations of the patents and proprietary rights of third parties. There is a substantial amount of litigation involving patents and other intellectual property rights in the biotechnology and pharmaceutical industries, as well as administrative proceedings for challenging patents, including interference and reexamination proceedings before the USPTO or oppositions and other comparable proceedings in foreign jurisdictions. Recently, under U.S. patent reform, new procedures including inter partes review and post grant review have been implemented. As stated above, this reform will bring uncertainty to the possibility of challenge to our patents in the future. Numerous U.S. and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are developing our product candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates may give rise to claims of infringement of the patent rights of others.

Third parties may assert that we are employing their proprietary technology without authorization. For example, we are aware of certain patent applications owned by a third party with claims that if issued in their present form could be construed to cover C200. If such patent claims are issued, the third party may seek to allege that our development

 

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and commercialization of C200 infringes such patents and file a patent infringement lawsuit against us in the future. While we believe we would have valid defenses against any such allegation or lawsuit, such defenses may be unsuccessful. In this regard, patents issued in the U.S. by law enjoy a presumption of validity that can be rebutted only with evidence that is “clear and convincing,” a heightened standard of proof. There may also be third-party patents of which we are currently unaware with claims to materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our product candidates. Because patent applications can take many years to issue, there may be currently pending patent applications which may later result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents. If any third-party patents were held by a court of competent jurisdiction to cover the manufacturing process of our product candidates, constructs or molecules used in or formed during the manufacturing process, or any final product itself, the holders of any such patents may be able to block our ability to commercialize the product candidate unless we obtained a license under the applicable patents, or until such patents expire or they are finally determined to be held invalid or unenforceable. Similarly, if any third-party patent were held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture or methods of use, including combination therapy or patient selection methods, the holders of any such patent may be able to block our ability to develop and commercialize the product candidate unless we obtained a license or until such patent expires or is finally determined to be held invalid or unenforceable. In either case, such a license may not be available on commercially reasonable terms or at all. Even if we obtained such a license, it may only be non-exclusive, which would permit third parties to use the same intellectual property and compete with us. If we are unable to obtain a necessary license to a third-party patent on commercially reasonable terms, or at all, we may be unable to commercialize our product candidates or such efforts may be impaired or delayed, which could in turn significantly harm our business.

Parties making claims against us may seek and obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize our product candidates. Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from our business. We may not have sufficient resources to bring these actions to a successful conclusion. There could also be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of shares of our common stock.

In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing products, which may be impossible or require substantial time and monetary expenditure. We cannot predict whether any such license would be available at all or whether it would be available on commercially reasonable terms. Furthermore, even in the absence of litigation, we may need to obtain licenses from third parties to advance our research or allow commercialization of our product candidates. We may fail to obtain any of these licenses at a reasonable cost or on reasonable terms, if at all. In that event, we would be unable to further develop and commercialize our product candidates, which could harm our business significantly. Any of the foregoing may have a material adverse effect on our business, financial condition, results of operations and prospects.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance fees on any issued patent are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime of the patent. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in

 

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the relevant jurisdiction. Noncompliance events that could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents. In such an event, our competitors might be able to enter the market, which would have a material adverse effect on our business.

Some intellectual property that we have in-licensed may have been discovered through government funded programs and thus may be subject to federal regulations such as “march-in” rights, certain reporting requirements and a preference for U.S.-based companies. Compliance with such regulations may limit our exclusive rights, and limit our ability to contract with non-U.S. manufacturers.

Many of the intellectual property rights we have licensed are generated through the use of U.S. government funding and are therefore subject to certain federal regulations. As a result, the U.S. government may have certain rights to intellectual property embodied in our current or future product candidates pursuant to the Bayh-Dole Act of 1980, or Bayh-Dole Act. These U.S. government rights in certain inventions developed under a government-funded program include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. In addition, the U.S. government has the right to require us to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (i) adequate steps have not been taken to commercialize the invention; (ii) government action is necessary to meet public health or safety needs; or (iii) government action is necessary to meet requirements for public use under federal regulations (also referred to as “march-in rights”). The U.S. government also has the right to take title to these inventions if we, or the applicable licensor, fail to disclose the invention to the government and fail to file an application to register the intellectual property within specified time limits. Intellectual property generated under a government funded program is also subject to certain reporting requirements, compliance with which may require us or the applicable licensor to expend substantial resources. In addition, the U.S. government requires that any products embodying the subject invention or produced through the use of the subject invention be manufactured substantially in the United States. The manufacturing preference requirement can be waived if the owner of the intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be likely to manufacture substantially in the United States or that under the circumstances domestic manufacture is not commercially feasible. This preference for U.S. manufacturers may limit our ability to contract with non-U.S. product manufacturers for products covered by such intellectual property. To the extent any of our current or future intellectual property is generated through the use of U.S. government funding, the provisions of the Bayh-Dole Act may similarly apply.

We may become involved in lawsuits to protect or enforce our patents or other intellectual property, which could be expensive, time-consuming and unsuccessful.

Competitors may infringe our patents, trademarks, copyrights or other intellectual property. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time-consuming and divert the time and attention of our management and scientific personnel. Any claims we assert against perceived infringers could provoke these parties to assert counterclaims against us alleging that we infringe their patents, in addition to counterclaims asserting that our patents are invalid or unenforceable, or both. In any patent infringement proceeding, there is a risk that a court will decide that a patent of ours is invalid or unenforceable, in whole or in part, and that we do not have the right to stop the other party from using the invention at issue. There is also a risk that, even if the validity of such patents is upheld, the court will construe the patent’s claims narrowly or decide that we do not have the right to stop the other party from using the invention at issue on the grounds that our patent claims do not cover the invention. An adverse outcome in a litigation or proceeding involving our patents could limit our ability to assert our patents against those parties or other competitors, and may curtail or preclude our ability to exclude third parties from making and selling similar or competitive products. Any of these occurrences could adversely affect our competitive business position, business prospects and financial condition. Similarly, if we assert trademark infringement claims, a court may determine that the marks we have asserted are invalid or unenforceable, or that the party against whom we have asserted trademark infringement has superior rights to the marks in question. In this case, we could ultimately be forced to cease use of such trademarks.

 

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Even if we establish infringement, the court may decide not to grant an injunction against further infringing activity and instead award only monetary damages, which may or may not be an adequate remedy Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during litigation. There could also be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of shares of our common stock. Moreover, there can be no assurance that we will have sufficient financial or other resources to file and pursue such infringement claims, which typically last for years before they are concluded. Even if we ultimately prevail in such claims, the monetary cost of such litigation and the diversion of the attention of our management and scientific personnel could outweigh any benefit we receive as a result of the proceedings. Any of the foregoing may have a material adverse effect on our business, financial condition, results of operations and prospects.

Changes to the patent law in the United States and other jurisdictions could diminish the value of patents in general, thereby impairing our ability to protect our product candidates.

As is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property, particularly patents. Obtaining and enforcing patents in the biopharmaceutical industry involve both technological and legal complexity, and is therefore costly, time-consuming and inherently uncertain. In addition, the United States has recently enacted and is currently implementing wide-ranging patent reform legislation. Recent U.S. Supreme Court rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners in certain situations. In addition to increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the value of patents, once obtained. Depending on decisions by the U.S. Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future. For example, in the case, Assoc. for Molecular Pathology v. Myriad Genetics, Inc., the U.S. Supreme Court held that certain claims to DNA molecules are not patentable. While we do not believe that any of the patents owned or licensed by us will be found invalid based on this decision, we cannot predict how future decisions by the courts, the U.S. Congress or the USPTO may impact the value of our patents.

We may not be able to protect our intellectual property rights throughout the world.

Filing, prosecuting, maintaining, defending and enforcing patents on our product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States can be less extensive than those in the United States. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own drugs and may export otherwise infringing drugs to territories where we have patent protection, but enforcement rights are not as strong as those in the United States. These drugs may compete with our product candidates and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of some countries do not favor the enforcement of patents and other intellectual property protection, which could make it difficult for us to stop the infringement of our patents generally. Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful.

 

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Many countries have compulsory licensing laws under which a patent owner may be compelled under specified circumstances to grant licenses to third parties. In addition, many countries limit the enforceability of patents against government agencies or government contractors. In those countries, we may have limited remedies if patents are infringed or if we are compelled to grant a license to a third party, which could materially diminish the value of those patents. This could limit our potential revenue opportunities. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license, which could adversely affect our business, financial condition, results of operations, and prospects.

Patent terms may be inadequate to protect our competitive position on our product candidates for an adequate amount of time.

Patents have a limited lifespan. In the U.S., if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from its earliest U.S. non-provisional filing date. Various extensions may be available, but the life of a patent, and the protection it affords, is limited. Even if patents covering our product candidates are obtained, once the patent life has expired for a product candidate, we may be open to competition from competitive medications, including generic medications. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such product candidates might expire before or shortly after such product candidates are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing product candidates similar or identical to ours.

Depending upon the timing, duration and conditions of any FDA marketing approval of our product candidates, one or more of our U.S. patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Amendments, and similar legislation in the European Union. The Hatch-Waxman Amendments permit a patent term extension of up to five years for a patent covering an approved product as compensation for effective patent term lost during product development and the FDA regulatory review process. However, we may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. Only one patent per approved product can be extended, the extension cannot extend the total patent term beyond 14 years from approval and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended. If we are unable to obtain patent term extension or the term of any such extension is less than we request, the period during which we can enforce our patent rights for the applicable product candidate will be shortened and our competitors may obtain approval to market competing products sooner. As a result, our revenue from applicable products could be reduced. Further, if this occurs, our competitors may take advantage of our investment in development and trials by referencing our clinical and preclinical data and launch their product earlier than might otherwise be the case, and our competitive position, business, financial condition, results of operations, and prospects could be materially harmed.

Third parties may assert that our employees or consultants have wrongfully used or disclosed confidential information or misappropriated trade secrets.

We employ individuals who were previously employed at universities or other biopharmaceutical companies, including our competitors or potential competitors. Although we try to ensure that our employees and consultants do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or our employees, consultants or independent contractors have inadvertently or otherwise used or disclosed intellectual property, including trade secrets or other proprietary information, of a former employer or other third parties. Litigation may be necessary to defend against these claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

 

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Intellectual property rights do not necessarily address all potential threats.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations and may not adequately protect our business or permit us to maintain our competitive advantage. For example:

 

    others may be able to make products that are similar to any product candidates we may develop or utilize similar technology but that are not covered by the claims of the patents that we license or may own in the future;

 

    we, or our current or future licensors might not have been the first to make the inventions covered by the issued patent or pending patent application that we license or may own in the future;

 

    we, or our current or future licensors might not have been the first to file patent applications covering certain of our or their inventions;

 

    others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned or licensed intellectual property rights;

 

    it is possible that our pending owned or licensed patent applications or those that we may own or license in the future will not lead to issued patents;

 

    issued patents that we hold rights to may be held invalid or unenforceable, including as a result of legal challenges by our competitors;

 

    our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets;

 

    we may not develop additional proprietary technologies that are patentable;

 

    the patents of others may harm our business; and

 

    we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent covering such intellectual property.

Should any of these events occur, they could harm our business, financial condition, results of operations, and prospects.

Risks Related to Our Dependence on Third Parties

We expect to depend on collaborations with third parties for the research, development, and commercialization of certain of the product candidates we may develop. If any such collaborations are not successful, we may not be able to capitalize on the market potential of those product candidates.

We anticipate seeking third-party collaborators for the research, development, and commercialization of certain of the product candidates we may develop. Our likely collaborators for any other collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies, and biotechnology companies. If we enter into any such arrangements with any third parties, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of any product candidates we may seek to develop with them. Our ability to generate revenues from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements. We cannot predict the success of any collaboration that we enter into.

Collaborations involving our research programs or any product candidates we may develop, pose the following risks to us:

 

    Collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations.

 

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    Collaborators may not pursue development and commercialization of any product candidates we may develop or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities.

 

    Collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials, or require a new formulation of a product candidate for clinical testing.

 

    Collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our medicines or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours.

 

    Collaborators with marketing and distribution rights to one or more medicines may not commit sufficient resources to the marketing and distribution of such medicine or medicines.

 

    Collaborators may not properly obtain, maintain, enforce, or defend our intellectual property or proprietary rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our proprietary information or expose us to potential litigation.

 

    Disputes may arise between the collaborators and us that result in the delay or termination of the research, development, or commercialization of our medicines or product candidates or that result in costly litigation or arbitration that diverts management attention and resources.

 

    We may lose certain valuable rights under circumstances identified in our collaborations, including if we undergo a change of control.

 

    Collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization of the applicable product candidates.

 

    Collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner or at all. If a present or future collaborator of ours were to be involved in a business combination, the continued pursuit and emphasis on our product development or commercialization program under such collaboration could be delayed, diminished, or terminated.

If our collaborations do not result in the successful development and commercialization of products, or if one of our collaborators terminates its agreement with us, we may not receive any future research funding or milestone or royalty payments under the collaboration. If we do not receive the funding we expect under these agreements, our development of product candidates could be delayed, and we may need additional resources to develop product candidates. In addition, if one of our collaborators terminates its agreement with us, we may find it more difficult to find a suitable replacement collaborator or attract new collaborators, and our development programs may be delayed or the perception of us in the business and financial communities could be adversely affected. All of the risks relating to product development, regulatory approval, and commercialization described in this prospectus apply to the activities of our collaborators.

We have in the past and may in the future decide to collaborate with pharmaceutical and biotechnology companies for the development and potential commercialization of any product candidates we may develop. These relationships, or those like them, may require us to incur non-recurring and other charges, increase our near- and long-term expenditures, issue securities that dilute our existing stockholders, or disrupt our management and business. In addition, we could face significant competition in seeking appropriate collaborators, and the negotiation process is time-consuming and complex. Our ability to reach a definitive collaboration agreement will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration, and the proposed collaborator’s evaluation of several factors. If we license rights to any product candidates we or our collaborators may develop, we may not be able to realize the benefit of such transactions if we are unable to successfully integrate them with our existing operations and company culture.

 

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We are developing E478 specifically to partner with gene therapy and genome editing companies. If we are unable to find willing collaborators, this may adversely affect the development of E478 and our business.

We are developing E478 specifically to partner and collaborate with gene therapy and genome editing companies. In particular, we seek to selectively pursue collaboration arrangements with companies that have particular technology, expertise or resources for the development of E478, if approved. However, we may not be able to execute on such collaboration and any collaboration that we may enter into may not be successful. If we are unable to identify partners whose capabilities complement and integrate well with ours and reach collaboration arrangements with such partners on a timely basis, on acceptable terms or at all, or if the arrangements we establish are unproductive for us, we may fail to meet our business and development objectives for E478, which may adversely affect our business.

If we are not able to establish collaborations on commercially reasonable terms, we may have to alter our development and commercialization plans.

Our product development and research programs and the potential commercialization of any product candidates we may develop will require substantial additional cash to fund expenses. For some of the product candidates we may develop, we may decide to collaborate with other pharmaceutical and biotechnology companies for the development and potential commercialization of those product candidates. For example, in connection with our license agreement with Novartis, we issued to Novartis, 2,500,000 shares of Series A redeemable convertible preferred stock and 643,550 shares of Series B redeemable convertible preferred stock, causing our stockholders to experience dilution. If in the future, we enter into collaborations with other third parties, we may issue additional equity as part of such collaboration.

We face significant competition in seeking appropriate collaborators. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration, and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, the existence of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally. The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us.

Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business combinations among large pharmaceutical companies that have resulted in a reduced number of potential future collaborators.

If any party to which we have outsourced certain functions fails to perform its obligations under agreements with us, the development and commercialization of our product candidates and any future product candidates could be delayed or terminated.

To the extent that we rely on third party individuals or other companies to manage the day-to-day conduct of our clinical trials or to manufacture, sell or market our current product candidates or any future product candidates, we will be dependent on the timeliness and effectiveness of their efforts. If a clinical research management organization that we might utilize is unable to allocate sufficient qualified personnel to our studies or if the work performed by it does not fully satisfy the rigorous requirements of the FDA, we may encounter substantial delays and increased costs in completing our clinical trials. If a firm producing humanized forms of our molecular antibody product candidates or a manufacturer of the raw material or finished product for our clinical trials is unable to meet our time schedules or cost parameters, the timing of our clinical trials and development of our

 

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product candidates may be adversely affected. Any manufacturer that we select may encounter difficulties in scaling-up the manufacture of new products in commercial quantities, including problems involving product yields, product stability or shelf life, quality control, adequacy of control procedures and policies, compliance with FDA regulations and the need for further FDA approval of any new manufacturing processes and facilities. The manufacture of clinical supplies for studies and commercial quantities of our current product candidates and any future product candidates are likely to be inherently more difficult and costly than typical chemical pharmaceuticals. This could delay commercialization of any of our product candidates, if approved, or reduce the profitability of these candidates for us. If any of these occur, the development and commercialization of our product candidates could be delayed, curtailed or terminated because we may not have sufficient financial resources or capabilities to continue such development and commercialization on our own.

We expect to continue to rely on third parties to manufacture our clinical product supplies, and we intend to rely on third parties to produce and process our product candidates, if approved.

We do not currently own any facility that may be used as our clinical-scale manufacturing and processing facility and must eventually rely on outside vendors to manufacture supplies and process our product candidates. We have not yet caused any product candidates to be manufactured or processed on a commercial scale and may not be able to do so for any of our product candidates. We will make changes as we work to optimize the manufacturing process, and we cannot be sure that even minor changes in the process will result in therapies that are safe and effective.

The facilities used by our contract manufacturers to manufacture our product candidates must be approved by the FDA or other foreign regulatory agencies pursuant to inspections that will be conducted after we submit an application to the FDA or other foreign regulatory agencies. We do not control the manufacturing process of, and will be completely dependent on, our contract manufacturing partners for compliance with regulatory requirements, known as cGMP requirements for manufacture of our product candidates. If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA or other regulatory authorities, they will not be able to secure and/or maintain regulatory approval for their manufacturing facilities. In addition, we have no control over the ability of our contract manufacturers to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or a comparable foreign regulatory authority does not approve these facilities for the manufacture of our product candidates or if it withdraws any such approval in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if approved.

In addition, should any of our agreements with our contract manufacturers terminate, in particular the agreements with the University of Minnesota and Heidelberg Pharma, they may be difficult to replace if we were no longer able to rely on them.

Risks Related to Employee Matters, Managing Growth and Other Risks Related to Our Business

We will need to grow the size of our organization, and we may experience difficulties in managing this growth.

As of April 30, 2018, we had 48 full-time employees. As our development, manufacturing and commercialization plans and strategies develop, and as we transition into operating as a public company, we expect to need and are actively recruiting additional managerial, operational, sales, marketing, financial and other personnel. Future growth would impose significant added responsibilities on members of management, including:

 

    identifying, recruiting, integrating, maintaining and motivating additional employees;

 

    managing our internal development efforts effectively, including the clinical, FDA and international regulatory review process for our product candidates, while complying with our contractual obligations to contractors and other third parties; and

 

    improving our operational, financial and management controls, reporting systems and procedures.

 

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Our future financial performance and our ability to develop, manufacture and commercialize our product candidates will depend, in part, on our ability to effectively manage any future growth, and our management may also have to divert financial and other resources, and a disproportionate amount of its attention away from day-to-day activities in order to devote a substantial amount of time, to managing these growth activities.

We currently rely, and for the foreseeable future will continue to rely, in substantial part on certain independent organizations, advisors and consultants to provide certain services, including substantially all aspects of regulatory approval, clinical management and manufacturing. We cannot assure you that the services of independent organizations, advisors and consultants will continue to be available to us on a timely basis when needed, or that we can find qualified replacements. In addition, if we are unable to effectively manage our outsourced activities or if the quality or accuracy of the services provided by consultants is compromised for any reason, our clinical trials may be extended, delayed or terminated, and we may not be able to obtain regulatory approval of our product candidates or otherwise advance our business. We cannot assure you that we will be able to manage our existing consultants or find other competent outside contractors and consultants on economically reasonable terms, or at all.

If we are not able to effectively expand our organization by hiring new employees and expanding our groups of consultants and contractors, we may not be able to successfully implement the tasks necessary to further develop and commercialize our product candidates and, accordingly, may not achieve our research, development and commercialization goals.

We expect to expand our development, regulatory, and future sales and marketing capabilities, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.

We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of drug development, regulatory affairs, and sales and marketing. To manage our anticipated future growth, we must continue to implement and improve our managerial, operational, and financial systems, expand our facilities, and continue to recruit and train additional qualified personnel. Due to our limited financial resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to effectively manage the expected expansion of our operations or recruit and train additional qualified personnel. Moreover, the expected physical expansion of our operations may lead to significant costs and may divert our management and business development resources. Any inability to manage growth could delay the execution of our business plans or disrupt our operations.

If we lose key management personnel, or if we fail to recruit additional highly skilled personnel, such as a Chief Financial Officer, our ability to identify and develop new or next generation product candidates will be impaired, which could result in loss of market opportunities or market share and could make us less competitive.

Our ability to compete in the highly competitive biotechnology and pharmaceutical industries depends upon our ability to attract and retain highly qualified managerial, scientific and medical personnel. We are highly dependent on our management, particularly our Chief Executive Officer, the members of our executive team listed under “Management” located elsewhere in this prospectus, and key scientific and medical personnel employees. We do not currently have a Chief Financial Officer. The inability to attract and retain a Chief Financial Officer and the loss of the services of any of our executive officers, key employees, and scientific and medical advisors, and our inability to find suitable replacements, could result in delays in product development and harm our business.

We conduct our operations at our facility in Cambridge, Massachusetts. This region is headquarters to many other biopharmaceutical companies and many academic and research institutions. Competition for skilled personnel in our market is intense and may limit our ability to hire and retain highly qualified personnel on acceptable terms or at all.

 

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To induce valuable employees to remain at our company, in addition to salary and cash incentives, we have provided stock options that vest over time. The value to employees of stock options that vest over time may be significantly affected by movements in our stock price that are beyond our control, and may at any time be insufficient to counteract more lucrative offers from other companies. Despite our efforts to retain valuable employees, members of our management, scientific and development teams may terminate their employment with us on short notice. Although we have employment offer letters with our key employees, these agreements provide for at-will employment, which means that any of our employees could leave our employment at any time, with or without notice. We do not maintain “key man” insurance policies on the lives of these individuals or the lives of any of our other employees. Our success also depends on our ability to continue to attract, retain and motivate highly skilled junior, mid-level and senior managers as well as junior, mid-level and senior scientific and medical personnel.

If we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial results or prevent fraud. As a result, stockholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of our common stock.

Effective internal controls over financial reporting are necessary for us to provide reliable financial reports and, together with adequate disclosure controls and procedures, are designed to prevent fraud. Any failure to implement required new or improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations. In addition, any testing by us conducted in connection with Section 404 of the Sarbanes-Oxley Act of 2002, or any subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our financial statements or identify other areas for further attention or improvement. Inferior internal controls could also cause investors to lose confidence in our reported financial information, which could have a negative effect on the trading price of our stock.

We will be required to disclose changes made in our internal controls and procedures on a quarterly basis and our management will be required to assess the effectiveness of these controls annually. However, for as long as we are an “emerging growth company” under the JOBS Act, our independent registered public accounting firm will not be required to attest to the effectiveness of our internal controls over financial reporting pursuant to Section 404. We could be an “emerging growth company” for up to five years. An independent assessment of the effectiveness of our internal controls over financial reporting could detect problems that our management’s assessment might not. Undetected material weaknesses in our internal controls over financial reporting could lead to financial statement restatements and require us to incur the expense of remediation.

Unstable market and economic conditions may have serious adverse consequences on our business, financial condition and stock price.

As widely reported, global credit and financial markets have experienced extreme volatility and disruptions in the past several years, including severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about economic stability. There can be no assurance that further deterioration in credit and financial markets and confidence in economic conditions will not occur. Our general business strategy may be adversely affected by any such economic downturn, volatile business environment or continued unpredictable and unstable market conditions. If the current equity and credit markets deteriorate, or do not improve, it may make any necessary debt or equity financing more difficult, more costly, and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our growth strategy, financial performance and stock price and could require us to delay or abandon clinical development plans. In addition, there is a risk that one or more of our current service providers, manufacturers and other partners may not survive these difficult economic times, which could directly affect our ability to attain our operating goals on schedule and on budget.

 

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At March 31, 2018, we had approximately $41.5 million of cash and cash equivalents. While we are not aware of any downgrades, material losses, or other significant deterioration in the fair value of our cash equivalents since March 31, 2018, no assurance can be given that further deterioration of the global credit and financial markets would not negatively impact our current portfolio of cash equivalents or our ability to meet our financing objectives. Furthermore, our stock price may decline due in part to the volatility of the stock market and the general economic downturn.

Business disruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.

Our operations, and those of our CMOs, our CROs and other contractors and consultants, could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, medical epidemics and other natural or man-made disasters or business interruptions, for which we are predominantly self-insured. The occurrence of any of these business disruptions could seriously harm our operations and financial condition and increase our costs and expenses. Our ability to obtain clinical supplies of our product candidates could be disrupted if the operations of these suppliers are affected by a man-made or natural disaster or other business interruption.

Our internal computer systems, or those used by our CMOs, CROs or other contractors or consultants, may fail or suffer security breaches.

Despite the implementation of security measures, our internal computer systems and those of our future CMOs, future CROs and other contractors and consultants are vulnerable to damage from computer viruses and unauthorized access. While we have not experienced any such material system failure or security breach to date, if such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our development programs and our business operations. For example, the loss of clinical trial data from completed or future clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. Likewise, we may rely on third parties for the manufacture of our product candidates and to conduct clinical trials, and similar events relating to their computer systems could also have a material adverse effect on our business. To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability and the further development and commercialization of our product candidates could be delayed.

Our employees, independent contractors, consultants, commercial partners and vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.

We are exposed to the risk of employee fraud or other illegal activity by our employees, independent contractors, consultants, commercial partners and vendors. Misconduct by these parties could include intentional, reckless and/or negligent conduct that fails to comply with the laws of the FDA and other similar foreign regulatory bodies, provide true, complete and accurate information to the FDA and other similar foreign regulatory bodies, comply with manufacturing standards we have established, comply with healthcare fraud and abuse laws in the United States and similar foreign fraudulent misconduct laws, or report financial information or data accurately or to disclose unauthorized activities to us. If we obtain FDA approval of any of our product candidates and begin commercializing those products in the United States, our potential exposure under such laws will increase significantly, and our costs associated with compliance with such laws are also likely to increase. These laws may impact, among other things, our current activities with principal investigators and research patients, as well as proposed and future sales, marketing and education programs.

 

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Our relationships with healthcare providers and physicians and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and third-party payors in the United States and elsewhere play a primary role in the recommendation and prescription of pharmaceutical products. Arrangements with third-party payors and customers can expose pharmaceutical manufacturers to broadly applicable fraud and abuse and other healthcare laws and regulations, including, without limitation, the federal Anti-Kickback Statute and the federal False Claims Act, which may constrain the business or financial arrangements and relationships through which such companies sell, market and distribute pharmaceutical products. In particular, the promotion, sales and marketing of healthcare items and services, as well as certain business arrangements in the healthcare industry, are subject to extensive laws designed to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, structuring and commission(s), certain customer incentive programs and other business arrangements generally. Activities subject to these laws also involve the improper use of information obtained in the course of patient recruitment for clinical trials. The applicable federal, state and foreign healthcare laws and regulations laws that may affect our ability to operate include, but are not limited to:

 

    the federal Anti-Kickback Statute, which prohibits, among other things, knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe, or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, either the referral of an individual, or the purchase, lease, order or recommendation of any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs. A person or entity can be found guilty of violating the statute without actual knowledge of the statute or specific intent to violate it. In addition, a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act. The Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers, and formulary managers on the other. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution;

 

    federal civil and criminal false claims laws and civil monetary penalty laws, including the False Claims Act, or FCA, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, false or fraudulent claims for payment to, or approval by Medicare, Medicaid, or other federal healthcare programs, knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim or an obligation to pay or transmit money to the federal government, or knowingly concealing or knowingly and improperly avoiding or decreasing an obligation to pay money to the federal government. Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery;

 

    the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters. Similar to the federal Anti-Kickback Statute, a person or entity can be found guilty of violating HIPAA without actual knowledge of the statute or specific intent to violate it;

 

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    HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose, among other things, requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses as well as their respective business associates that perform services for them that involve the use, or disclosure of, individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information without appropriate authorization. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions;

 

    the federal Physician Payment Sunshine Act, created under the Health Reform Law, and its implementing regulations, which require manufacturers of drugs, devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to the United States Department of Health and Human Services, or HHS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members; and

 

    federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.

Additionally, we are subject to state and foreign equivalents of each of the healthcare laws described above, among others, some of which may be broader in scope and may apply regardless of the payor.

Pricing and rebate programs must comply with the Medicaid rebate requirements of the U.S. Omnibus Budget Reconciliation Act of 1990 and more recent requirements in the Affordable Care Act. If products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply. Products must meet applicable child-resistant packaging requirements under the U.S. Poison Prevention Packaging Act. Manufacturing, sales, promotion and other activities also are potentially subject to federal and state consumer protection and unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations. Federal and state enforcement bodies often scrutinize interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry. Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert a company’s attention from the business.

The failure to comply with any of these laws or regulatory requirements subjects entities to possible legal or regulatory action. Depending on the circumstances, failure to meet applicable regulatory requirements can result in civil, criminal and administrative penalties, damages, fines, disgorgement, individual imprisonment, possible exclusion from participation in federal and state funded healthcare programs, contractual damages and the curtailment or restricting of our operations, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws. Any action for violation of these laws, even if successfully defended, could cause a pharmaceutical manufacturer to incur significant legal expenses and divert management’s attention from the

 

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operation of the business. Prohibitions or restrictions on sales or withdrawal of future marketed products could materially affect business in an adverse way. Effective upon the completion of this offering, we will adopt a code of business conduct and ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent inappropriate conduct may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. Efforts to ensure that our business arrangements will comply with applicable healthcare laws may involve substantial costs. It is possible that governmental and enforcement authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of our operations, any of which could adversely affect our ability to operate our business and our results of operations. In addition, the approval and commercialization of any of our product candidates outside the United States will also likely subject us to foreign equivalents of the healthcare laws mentioned above, among other foreign laws.

Our ability to utilize our net operating loss carryforwards and certain other tax attributes may be limited.

Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, if a corporation undergoes an “ownership change” (generally defined as a greater than 50% change (by value) in its equity ownership over a three-year period), the corporation’s ability to use its pre-change net operating loss carryforwards and other pre-change tax attributes to offset its post-change income may be limited. As a result of our most recent private placements and other transactions that have occurred over the past three years, we may have experienced, and, upon completion of this offering, may experience, an “ownership change.” We may also experience ownership changes in the future as a result of subsequent shifts in our stock ownership. As of December 31, 2017, we had U.S. net operating loss carryforwards of approximately $18.7 million and U.S. research and development credits of $1.0 million, which could be limited if we experience an “ownership change.”

We may not be successful in finding strategic collaborators for continuing development of certain of our product candidates or successfully commercializing or competing in the market for certain indications.

Because we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific indications. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to timely capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate. and industry and market conditions generally. The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for our product candidate. The terms of any additional collaborations or other arrangements that we may establish may not be favorable to us.

We may also be restricted under existing collaboration agreements from entering into future agreements on certain terms with potential collaborators. Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business combinations among large pharmaceutical companies that have resulted in a reduced number of potential future collaborators.

 

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We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. If we are unable to do so, we may have to curtail the development of the product candidate for which we are seeking to collaborate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we may not be able to further develop our product candidates or bring them to market and generate product revenue.

In addition, any collaborations that we enter into may not be successful. The success of our collaboration arrangements will depend heavily on the efforts and activities of our collaborators. Collaborators generally have significant discretion in determining the efforts and resources that they will apply to these collaborations. Disagreements between parties to a collaboration arrangement regarding clinical development and commercialization matters can lead to delays in the development process or commercializing the applicable product candidate and, in some cases, termination of the collaboration arrangement. These disagreements can be difficult to resolve if neither of the parties has final decision-making authority. Collaborations with pharmaceutical or biotechnology companies and other third parties often are terminated or allowed to expire by the other party. Any such termination or expiration would adversely affect us financially and could harm our business reputation.

We face significant competition from other biotechnology and pharmaceutical companies, and our operating results will suffer if we fail to compete effectively.

The biopharmaceutical industry is characterized by intense competition and rapid innovation. Our competitors may be able to develop other compounds or drugs that are able to achieve similar or better results. Our potential competitors include major multinational pharmaceutical companies, established biotechnology companies, specialty pharmaceutical companies and universities and other research institutions. Many of our competitors have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations and well-established sales forces. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large, established companies. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our competitors. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors, either alone or with collaborative partners, may succeed in developing, acquiring or licensing on an exclusive basis drug or biologic products that are more effective, safer, more easily commercialized or less costly than our product candidates or may develop proprietary technologies or secure patent protection that we may need for the development of our technologies and products. We believe the key competitive factors that will affect the development and commercial success of our product candidates are efficacy, safety, tolerability, reliability, convenience of use, price and reimbursement.

Our competitors include companies focused on developing technologies to improve the distinct steps of bone marrow transplant.

Competitors in our stem cell expansion programs include: Gamida Cell Ltd., Nohla Therapeutics, Inc., ExCellThera Inc., Angiocrine Bioscience, Inc. and Intellia Therapeutics, Inc. In particular, Intellia Therapeutics, Inc. has exclusively licensed from Novartis the AHR antagonist that we use to manufacture MGTA-456 for expansion of gene-modified HSCs only, and it is likely that the programs developed under this license would compete directly with our E478 program.

We also face competition in our conditioning programs from Actinium Pharmaceuticals, Inc., Stanford University, Forty Seven, Inc. and Molecular Templates, Inc., and in our post-transplant complications program

 

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(GvHD) from Bellicum Pharmaceuticals, Inc., Kiadis Pharma NV and Abbvie Inc. Additionally, BioLineRx Ltd. is a competitor in our mobilization program.

In addition, we anticipate competing with the largest pharmaceutical companies in the world, such as Novartis, which is currently conducting research relating to expansion of HSCs that have been modified using CRISPR/Cas9 technology to express therapeutic proteins and delivered to patients for the treatment of potential treatment of blood disorders or primary immune deficiencies, which has greater financial and human resources than we currently have.

Even if we obtain regulatory approval of our product candidates, the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our product candidates. We may not be able to implement our business plan if the acceptance of our product candidates is inhibited by price competition or the reluctance of physicians to switch from existing methods of treatment to our product candidates, or if physicians switch to other new drug or biologic products or choose to reserve our product candidates for use in limited circumstances. For additional information regarding our competition, see “Business—Competition.”

If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations involve the use of hazardous and flammable materials, including chemicals and biological materials. Our operations also produce hazardous waste products. We generally contract with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials, which could cause an interruption of our commercialization efforts, research and development efforts and business operations, environmental damage resulting in costly clean-up and liabilities under applicable laws and regulations governing the use, storage, handling and disposal of these materials and specified waste products. Although we believe that the safety procedures utilized by our third-party manufacturers for handling and disposing of these materials generally comply with the standards prescribed by these laws and regulations, we cannot guarantee that this is the case or eliminate the risk of accidental contamination or injury from these materials. In such an event, we may be held liable for any resulting damages and such liability could exceed our resources and state or federal or other applicable authorities may curtail our use of certain materials and/or interrupt our business operations. Furthermore, environmental laws and regulations are complex, change frequently and have tended to become more stringent. We cannot predict the impact of such changes and cannot be certain of our future compliance. In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development or production efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions. We do not currently carry biological or hazardous waste insurance coverage.

Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide adequate coverage against potential liabilities.

We may not be successful in our efforts to identify additional product candidates. Due to our limited resources and access to capital, we must prioritize development of certain product candidates; these decisions may prove to be wrong and may adversely affect our business.

Although we intend to explore other therapeutic opportunities, in addition to the product candidates that we are currently developing, we may fail to identify successful product candidates for clinical development for a number of reasons. If we fail to identify additional potential product candidates, our business could be materially harmed.

 

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Research programs to pursue the development of our planned product candidates for additional indications and to identify new product candidates and disease targets require substantial technical, financial and human resources whether or not they are ultimately successful. Our research programs may initially show promise in identifying potential indications and/or product candidates, yet fail to yield results for clinical development for a number of reasons, including:

 

    the research methodology used may not be successful in identifying potential indications and/or product candidates;

 

    potential product candidates may, after further study, be shown to have harmful adverse effects or other characteristics that indicate they are unlikely to be effective drugs; or

 

    it may take greater human and financial resources than we will possess to identify additional therapeutic opportunities for our product candidates or to develop suitable potential product candidates through internal research programs, thereby limiting our ability to develop, diversify and expand our product portfolio.

Because we have limited financial and human resources, we intend to initially focus on research programs and product candidates for a limited set of indications. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential or a greater likelihood of success. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities.

Accordingly, there can be no assurance that we will ever be able to identify additional therapeutic opportunities for our product candidates or to develop suitable potential product candidates through internal research programs, which could materially adversely affect our future growth and prospects. We may focus our efforts and resources on potential product candidates or other potential programs that ultimately prove to be unsuccessful.

Risks Related to Our Common Stock and This Offering

An active trading market for our common stock may not develop or be sustainable. If an active trading market does not develop, investors may not be able to resell their shares at or above the initial public offering price and our ability to raise capital in the future may be impaired.

Prior to this offering, there has been no public market for our common stock. The initial public offering price for our common stock will be determined through negotiations with the underwriters. This price may not reflect the price at which investors in the market will be willing to buy and sell our shares following this offering. Although we intend to list our common stock on The NASDAQ Global Market, an active trading market for our shares may never develop or, if developed, be maintained following this offering. If an active market for our common stock does not develop or is not maintained, it may be difficult for you to sell shares you purchase in this offering without depressing the market price for the shares or at all. An inactive trading market may also impair our ability to raise capital to continue to fund operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration.

If you purchase shares of common stock in this offering, you will suffer immediate dilution in the net tangible book value of your investment.

The initial public offering price of our common stock is substantially higher than the net tangible book value per share of our common stock. Therefore, if you purchase shares of our common stock in this offering, you will pay a price per share that substantially exceeds our net tangible book value per share after this offering. Based on the assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, you will experience immediate dilution of $9.70 per share, representing the difference between our pro forma net tangible book value per share after giving effect to this offering and the assumed initial

 

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public offering price. Purchasers of common stock in this offering will have contributed approximately 40.8% of the aggregate price paid by all purchasers of our capital stock and will own approximately 19.3% of our common stock outstanding after this offering, excluding any shares of our common stock that they may have acquired prior to this offering. Furthermore, if our previously issued options and other rights to acquire common stock at prices below the assumed initial public offering price are exercised, you will experience further dilution. For additional information on the dilution that you will experience immediately after this offering, see the section titled “Dilution.”

The trading price of our common stock is likely to be highly volatile, which could result in substantial losses for purchasers of our common stock in this offering. Securities class action or other litigation involving our company or members of our management team could also substantially harm our business, financial condition and results of operations.

Our stock price is likely to be highly volatile. The stock market in general and the market for smaller pharmaceutical and biotechnology companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. As a result of this volatility, you may not be able to sell your common stock at or above the initial public offering price and you may lose some or all of your investment. The market price for our common stock may be influenced by many factors, including:

 

    the success of existing or new competitive products or technologies;

 

    regulatory actions with respect to our product candidates or our competitors’ products and product candidates;

 

    announcements by us or our competitors of significant acquisitions, strategic partnerships, joint ventures, collaborations or capital commitments;

 

    the timing and results of preclinical studies for any of our product candidates;

 

    the timing and results of clinical trials of MGTA-456 and any other product candidates;

 

    commencement or termination of collaborations for E478 or any of our current and future programs and product candidates;

 

    failure or discontinuation of any of our development programs;

 

    results of clinical trials of product candidates of our competitors;

 

    regulatory or legal developments in the United States and other countries;

 

    developments or disputes concerning patent applications, issued patents or other proprietary rights;

 

    the recruitment or departure of key personnel;

 

    the level of expenses related to any of our product candidates or clinical development programs;

 

    the results of our efforts to develop additional product candidates or products;

 

    actual or anticipated changes in estimates as to financial results or development timelines;

 

    announcement or expectation of additional financing efforts;

 

    sales of our common stock by us, our insiders or other stockholders;

 

    variations in our financial results or those of companies that are perceived to be similar to us;

 

    changes in estimates or recommendations by securities analysts, if any, that cover us;

 

    changes in the structure of healthcare payment systems;

 

    market conditions in the pharmaceutical and biotechnology sectors;

 

    general economic, industry and market conditions; and

 

    the other factors described in this “Risk Factors” section.

 

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In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for biopharmaceutical companies, which have experienced significant stock price volatility in recent years.

We have broad discretion in the use of the net proceeds from this offering and may invest or spend the proceeds in ways with which you do not agree and in ways that may not yield a return on your investment.

Although we currently intend to use the net proceeds from this offering in the manner described in the section titled “Use of Proceeds” in this prospectus, our management will have broad discretion in the application of the net proceeds from this offering and could spend the proceeds in ways that do not improve our results of operations or enhance the value of our common stock. You will not have the opportunity to influence our decisions on how to use the net proceeds from this offering. The failure by our management to apply these funds effectively could result in financial losses that could harm our business, cause the price of our common stock to decline and delay the development of our product candidates. Pending their use, we may invest the net proceeds from this offering in a manner that does not produce income or that loses value.

We are an “emerging growth company,” and the reduced disclosure requirements applicable to emerging growth companies may make our common stock less attractive to investors.

We are an emerging growth company, as defined in the Jumpstart Our Business Startups Act, or the JOBS Act, enacted in April 2012. For as long as we continue to be an emerging growth company, we may take advantage of exemptions from various reporting requirements that are applicable to other public companies that are not emerging growth companies, including not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act of 2002, as amended, or the Sarbanes-Oxley Act, reduced disclosure obligations regarding executive compensation in this prospectus and our periodic reports and proxy statements and exemptions from the requirements of holding nonbinding advisory votes on executive compensation and stockholder approval of any golden parachute payments not previously approved. We could be an emerging growth company for up to five years following the year in which we complete this offering, although circumstances could cause us to lose that status earlier. We will remain an emerging growth company until the earlier of (1) the last day of the fiscal year (a) following the fifth anniversary of the completion of this offering, (b) in which we have total annual gross revenue of at least $1.07 billion or (c) in which we are deemed to be a large accelerated filer, which requires the market value of our common stock that is held by non-affiliates to exceed $700 million as of the prior June 30th, and (2) the date on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.

Even after we no longer qualify as an emerging growth company, we may still qualify as a “smaller reporting company” which would allow us to take advantage of many of the same exemptions from disclosure requirements including not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act and reduced disclosure obligations regarding executive compensation in this prospectus and our periodic reports and proxy statements. We cannot predict if investors will find our common stock less attractive because we may rely on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and our stock price may be more volatile.

Under the JOBS Act, emerging growth companies can also delay adopting new or revised accounting standards until such time as those standards apply to private companies. Under the JOBS Act, emerging growth companies can delay adopting new or revised accounting standards issued subsequent to the enactment of the JOBS Act until such time as those standards apply to private companies. We have elected not to “opt out” of such extended transition period, which means that when a standard is issued or revised and it has different application dates for public or private companies, we will adopt the new or revised standard at the time private companies adopt the new or revised standard and will do so until such time that we either (1) irrevocably elect to “opt out” of such extended transition period or (2) no longer qualify as an emerging growth company.

 

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We will incur increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives and corporate governance practices.

As a public company, and particularly after we are no longer an “emerging growth company,” we will incur significant legal, accounting and other expenses that we did not incur as a private company, including costs associated with public company reporting requirements. We also anticipate that we will incur costs associated with relatively recently adopted corporate governance requirements, including requirements of the SEC, and The NASDAQ Global Market. We expect these rules and regulations to increase our legal and financial compliance costs and to make some activities more time-consuming and costly. We also expect that these rules and regulations may make it more difficult and more expensive for us to obtain director and officer liability insurance and we may be required to accept reduced policy limits and coverage or incur substantially higher costs to obtain the same or similar coverage. As a result, it may be more difficult for us to attract and retain qualified individuals to serve on our board of directors or as executive officers.

We are currently evaluating and monitoring developments with respect to these rules, and we cannot predict or estimate the amount of additional costs we may incur or the timing of such costs. These rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.

Pursuant to Section 404 of the Sarbanes-Oxley Act, or Section 404, we will be required to furnish a report by our management on our internal control over financial reporting beginning with our second filing of an Annual Report on Form 10-K with the SEC after we become a public company. However, while we remain an emerging growth company, we will not be required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm. To achieve compliance with Section 404 within the prescribed period, we will be engaged in a process to document and evaluate our internal control over financial reporting, which is both costly and challenging. In this regard, we will need to continue to dedicate internal resources, potentially engage outside consultants and adopt a detailed work plan to assess and document the adequacy of internal control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that controls are functioning as documented and implement a continuous reporting and improvement process for internal control over financial reporting. Despite our efforts, there is a risk that we will not be able to conclude, within the prescribed timeframe or at all, that our internal control over financial reporting is effective as required by Section 404. If we identify one or more material weaknesses, it could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of our financial statements.

Sales of a substantial number of shares of our common stock by our existing stockholders in the public market could cause our stock price to fall.

If our existing stockholders sell, or indicate an intention to sell, substantial amounts of our common stock in the public market after the lock-up and other legal restrictions on resale discussed in this prospectus lapse, the trading price of our common stock could decline. Based on shares of common stock outstanding as of April 30, 2018, upon the closing of this offering we will have outstanding a total of 34,370,267 shares of common stock. Of these shares, only the shares of common stock sold in this offering by us, plus any shares sold upon exercise of the underwriters’ option to purchase additional shares, will be freely tradable without restriction in the public market immediately following this offering. J.P. Morgan Securities LLC and Goldman Sachs & Co. LLC, however, may, in their sole discretion, permit our officers, directors and other stockholders who are subject to these lock-up agreements to sell shares prior to the expiration of the lock-up agreements.

We expect that the lock-up agreements pertaining to this offering will expire 180 days from the date of this prospectus. In addition, shares of common stock that are either subject to outstanding options or reserved for

 

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future issuance under our 2018 Stock Option and Incentive Plan, as amended, will become eligible for sale in the public market to the extent permitted by the provisions of various vesting schedules, the lock-up agreements and Rule 144 and Rule 701 under the Securities Act of 1933, as amended (the “Securities Act”). Additionally, the number of shares of our common stock reserved for issuance under our 2018 Stock Option and Incentive Plan will automatically increase each January 1, beginning on January 1, 2019, by 4% of the total number of shares of our common stock outstanding on December 31 of the preceding calendar year, or a lesser number of shares determined by our board of directors. Unless our board of directors elects not to increase the number of shares available for future grant each year, our stockholders may experience additional dilution. If these additional shares of common stock are sold, or if it is perceived that they will be sold, in the public market, the trading price of our common stock could decline.

After this offering, the holders of 23,375,405 shares of our common stock as of April 30, 2018 will be entitled to rights with respect to the registration of their shares under the Securities Act, subject to the 180-day lock-up agreements described above. See “Description of Capital Stock—Registration Rights.” Registration of these shares under the Securities Act would result in the shares becoming freely tradable without restriction under the Securities Act, except for shares held by affiliates, as defined in Rule 144 under the Securities Act. Any sales of securities by these stockholders could have a material adverse effect on the trading price of our common stock.

We do not anticipate paying any cash dividends on our capital stock in the foreseeable future. Accordingly, stockholders must rely on capital appreciation, if any, for any return on their investment.

We have never declared nor paid cash dividends on our capital stock. We currently plan to retain all of our future earnings, if any, to finance the operation, development and growth of our business. In addition, the terms of any future debt or credit agreements may preclude us from paying dividends. As a result, capital appreciation, if any, of our common stock will be your sole source of gain for the foreseeable future.

Concentration of ownership of our common stock among our existing executive officers, directors and principal stockholders may prevent new investors from influencing significant corporate decisions.

Based upon shares outstanding as of April 30, 2018, and after giving effect to the conversion of all outstanding shares of preferred stock into shares of our common stock, upon the closing of this offering, our executive officers and directors, combined with our stockholders who owned more than 5% of our outstanding common stock before this offering and their affiliates, will, in the aggregate, beneficially own shares representing approximately 60.2% of our common stock. Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to approximately $40.0 million of shares of our common stock in this offering at the initial public offering price. However, because indications of interest are not binding agreements or commitments to purchase, the underwriters may determine to sell more, less or no shares in this offering to such stockholders, and such stockholders could determine to purchase more, less or no shares in this offering. This concentration of ownership control may:

 

    delay, defer or prevent a change in control;

 

    entrench our management or the board of directors; or

 

    impede a merger, consolidation, takeover or other business combination involving us that other stockholders may desire.

Some of these persons or entities may have interests different than yours. For example, because many of these stockholders purchased their shares at prices substantially below the price at which shares are being sold in this offering and have held their shares for a longer period, they may be more interested in selling our company to an acquirer than other investors or they may want us to pursue strategies that deviate from the interests of other stockholders.

 

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Provisions in our corporate charter documents and under Delaware law may prevent or frustrate attempts by our stockholders to change our management or hinder efforts to acquire a controlling interest in us.

Provisions in our corporate charter and our bylaws that will become effective upon the closing of this offering may discourage, delay or prevent a merger, acquisition or other change in control of us that stockholders may consider favorable, including transactions in which you might otherwise receive a premium for your shares. These provisions could also limit the price that investors might be willing to pay in the future for shares of our common stock, thereby depressing the market price of our common stock. In addition, because our board of directors is responsible for appointing the members of our management team, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our board of directors. Among other things, these provisions:

 

    establish a classified board of directors such that all members of the board are not elected at one time;

 

    allow the authorized number of our directors to be changed only by resolution of our board of directors;

 

    limit the manner in which stockholders can remove directors from the board;

 

    establish advance notice requirements for nominations for election to the board of directors or for proposing matters that can be acted on at stockholder meetings;

 

    require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written consent;

 

    limit who may call a special meeting of stockholders;

 

    authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and

 

    require the approval of the holders of at least 66.67% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws.

Moreover, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the General Corporation Law of the State of Delaware, which prohibits a person who owns in excess of 15% of our outstanding voting stock from merging or combining with us for a period of three years after the date of the transaction in which the person acquired in excess of 15% of our outstanding voting stock, unless the merger or combination is approved in a prescribed manner. This could discourage, delay or prevent someone from acquiring us or merging with us, whether or not it is desired by, or beneficial to, our stockholders. This could also have the effect of discouraging others from making tender offers for our common stock, including transactions that may be in your best interests. These provisions may also prevent changes in our management or limit the price that investors are willing to pay for our stock.

Our amended and restated bylaws will provide that, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the State of Delaware will be the sole and exclusive forum for most legal actions between us and our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers, employees or agents.

Pursuant to our amended and restated bylaws, as will be in effect upon the completion of this offering, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the State of Delaware will be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of or based on a breach of a fiduciary duty owed by any of our current or former directors, officers or other employees to us or our stockholders, (3) any action asserting a claim against us or any of our current or former directors, officers, employees or stockholders arising pursuant to any provision of the Delaware General Corporation Law, our amended and restated certificate of incorporation or our amended and restated bylaws or (4) any action asserting a claim governed by the internal affairs doctrine. Our amended and restated

 

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bylaws will further provide that the United States District Court for the District of Massachusetts will be the exclusive forum for resolving any complaint asserting a cause of action arising under the Securities Act. In addition, our amended and restated bylaws will provide that any person or entity purchasing or otherwise acquiring any interest in shares of our common stock is deemed to have notice of and consented to the foregoing provisions. We have chosen the United States District Court for the District of Massachusetts as the exclusive forum for such causes of action because our principal executive offices are located in Cambridge, Massachusetts. Some companies that have adopted similar federal district court forum selection provisions are currently subject to a suit in the Court of Chancery of the State of Delaware brought by stockholders who assert that the federal district court forum selection provision is not enforceable. We recognize that the federal district court forum selection clause may impose additional litigation costs on stockholders who assert the provision is not enforceable and may impose more general additional litigation costs in pursuing any such claims, particularly if the stockholders do not reside in or near the Commonwealth of Massachusetts. Additionally, the forum selection clauses in our amended and restated bylaws may limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us. Alternatively, if the federal district court forum selection provision is found inapplicable to, or unenforceable in respect of, one or more of the specified types of actions or proceedings, we may incur additional costs associated with resolving such matters in other jurisdictions, which could have an adverse effect on our business, financial condition or results of operations. The United States District Court for the District of Massachusetts may also reach different judgments or results than would other courts, including courts where a stockholder considering an action may be located or would otherwise choose to bring the action, and such judgments may be more or less favorable to us than our stockholders.

If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our share price and trading volume could decline.

The trading market for our common stock will be influenced by the research and reports that industry or securities analysts publish about us or our business. We do not currently have and may never obtain research coverage by securities and industry analysts. If no or few securities or industry analysts commence coverage of us, or one or more of the analysts who cover us issues an adverse opinion about our company, our stock price would likely decline. If one or more of these analysts ceases research coverage of us or fails to regularly publish reports on us, we could lose visibility in the financial markets, which in turn could cause our stock price or trading volume to decline.

 

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CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS

This prospectus, including the sections entitled “Prospectus Summary,” “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and “Business,” contains forward-looking statements that are based on our management’s belief and assumptions and on information currently available to our management. Although we believe that the expectations reflected in these forward-looking statements are reasonable, these statements relate to our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management and expected market growth, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements in this prospectus include, but are not limited to, statements about:

 

    our expected uses of the net proceeds to us from this offering;

 

    the timing and the success of clinical trials of MGTA-456 and any other product candidates;

 

    the outcomes of our preclinical studies, including under our C200 program;

 

    our ability to enroll patients in our clinical trials at the pace that we project;

 

    whether the results of our trials will be sufficient to support domestic or foreign regulatory approvals for MGTA-456 or any other product candidates we may develop;

 

    our ability to establish clinical programs moving forward in multiple indications by 2020, with a rapidly advancing portfolio and sustainable platform;

 

    regulatory actions with respect to our product candidates or our competitors’ products and product candidates;

 

    our ability to obtain, including on an expedited basis, and maintain regulatory approval of MGTA-456 or any other product candidates we may develop;

 

    the level of expenses related to any of our product candidates or clinical development programs;

 

    our expectation that our existing capital resources and the net proceeds from this offering will be sufficient to enable us to fund our planned development of MGTA-456 and any other product candidates we may identify and pursue;

 

    the benefits of the use of MGTA-456 or any other product candidate, if approved;

 

    our ability to successfully commercialize MGTA-456 or any other product candidates we may identify and pursue, if approved;

 

    our ability to successfully find collaborators for E478 or any of our current and future programs and product candidates;

 

    the rate and degree of market acceptance of MGTA-456 or any other product candidates we may identify and pursue;

 

    our ability to obtain orphan drug designation for any of our product candidates we may identify;

 

    our expectations regarding government and third-party payor coverage and reimbursement;

 

    our ability to manufacture MGTA-456 or any other product candidate in conformity with the Food and Drug Administration’s requirements and to scale up manufacturing of our product candidates to commercial scale, if approved;

 

    our ability to successfully build a specialty sales force and commercial infrastructure;

 

    our ability to compete with companies currently producing or engaged in the clinical development of treatments for the disease indications that we pursue and treatment modalities that we develop;

 

    our reliance on third parties to conduct our clinical trials;

 

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    our reliance on third-party contract manufacturers to manufacture and supply our product candidates for us;

 

    our ability to retain and recruit key personnel;

 

    our ability to obtain and maintain intellectual property protection for MGTA-456 or any other product candidates we may identify and pursue;

 

    our estimates of our expenses, ongoing losses, future revenue, capital requirements and our needs for or ability to obtain additional financing;

 

    our expectations regarding the time during which we will be an emerging growth company under the JOBS Act;

 

    our financial performance; and

 

    developments and projections relating to our competitors or our industry.

In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “could”, “should,” “expects,” “intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “projects”, “potential,” “continue” or the negative of these terms or other comparable terminology. These statements are only predictions. You should not place undue reliance on forward-looking statements because they involve known and unknown risks, uncertainties and other factors, which are, in some cases, beyond our control and which could materially affect results. Factors that may cause actual results to differ materially from current expectations include, among other things, those listed under “Risk Factors” and elsewhere in this prospectus. If one or more of these risks or uncertainties occur, or if our underlying assumptions prove to be incorrect, actual events or results may vary significantly from those implied or projected by the forward-looking statements. No forward-looking statement is a guarantee of future performance. You should read this prospectus and the documents that we reference in this prospectus and have filed with the SEC as exhibits to the registration statement, of which this prospectus is a part, completely and with the understanding that our actual future results may be materially different from any future results expressed or implied by these forward-looking statements.

The forward-looking statements in this prospectus represent our views as of the date of this prospectus. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we assume no obligation to update or revise any forward-looking statements except to the extent required by applicable law. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this prospectus.

This prospectus also contains estimates, projections and other information concerning our industry, our business, and the markets for certain diseases, including data regarding the estimated size of those markets, and the incidence and prevalence of certain medical conditions. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances reflected in this information. Unless otherwise expressly stated, we obtained this industry, business, market and other data from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and similar sources.

 

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USE OF PROCEEDS

We estimate that our net proceeds from the sale of shares of our common stock in this offering will be approximately $89.8 million, or $103.8 million if the underwriters exercise in full their option to purchase additional shares, assuming an initial public offering price of $15.00 per share, the midpoint of the price range set forth on the cover page of this prospectus, and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

A $1.00 increase (decrease) in the assumed initial public offering price of $15.00 per share, the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the net proceeds to us from this offering by $6.2 million, assuming the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. An increase (decrease) of 1,000,000 shares in the number of shares offered by us, as set forth on the cover page of this prospectus, would increase (decrease) our net proceeds from this offering by $14.0 million, assuming no change in the assumed initial public offering price per share and after deducting underwriting discounts and commissions and estimated offering expenses payable by us.

As of March 31, 2018, we had approximately $41.5 million in cash and cash equivalents. In April 2018, we received gross proceeds of $52.3 million from the sale of our Series C redeemable convertible preferred stock. We intend to use the net proceeds from this offering and our cash and cash equivalents on hand as follows:

 

    Approximately $39.0 million to fund the development of our lead conditioning programs and related product candidates, including GMP manufacturing and completing IND enabling studies for our lead conditioning program;

 

    Approximately $14.0 million to fund development of MGTA-456, including the completion of our ongoing Phase II clinical trial in patients with inherited metabolic diseases, initiation of a pivotal clinical trial for inherited metabolic diseases, evaluation of additional indications beyond inherited metabolic diseases such as sickle cell disease and blood cancers, and planned expansion of our late stage clinical and early commercial manufacturing capabilities through third parties;

 

    Approximately $9.0 million to fund the development of MGTA-145, including GMP manufacturing, initiation and completion of a first-in-human study and initiation of a proof-of-concept clinical trial; and

 

    The remaining proceeds, if any, to fund new and ongoing research and development activities, our new product engine, working capital and other general corporate purposes, which may include funding for the hiring of additional personnel, capital expenditures and the costs of operating as a public company.

Based on our current plans, we believe our cash and cash equivalents, together with the net proceeds to us from this offering, will be sufficient to fund our operations through at least the first quarter of 2020.

We may also use a portion of the net proceeds to in-license, acquire or invest in new businesses, technology or assets. Although we have no specific agreements, commitments or understandings with respect to any in-license or acquisition, we evaluate such opportunities and engage in related discussions with other companies from time to time.

This expected use of the net proceeds from this offering represents our intentions based upon our current plans and business conditions. As of the date of this prospectus, we cannot predict with certainty all of the particular uses for the net proceeds to be received upon the completion of this offering or the amounts that we will actually spend on the uses set forth above. The amounts and timing of our actual expenditures and the extent of our preclinical and clinical development activities may vary significantly depending on numerous factors, including the progress of our development efforts, the status of and results from preclinical studies and our ongoing clinical trial or any clinical trials we may commence in the future, our ability to take advantage of expedited programs or to obtain regulatory approval for MGTA-456 and any other product candidates we may identify and pursue, the timing and costs associated with the manufacture and supply of MGTA-456 and any other product candidates we may identify and

 

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pursue for clinical development or commercialization, and any unforeseen cash needs. As a result, our management will retain broad discretion over the allocation of the net proceeds from this offering.

Pending our use of the net proceeds from this offering, we intend to invest the net proceeds in a variety of capital preservation investments, including short-term, investment-grade, interest-bearing instruments and U.S. government securities.

 

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DIVIDEND POLICY

We have never declared or paid dividends on our capital stock. We do not anticipate paying any dividends on our capital stock in the foreseeable future. We currently intend to retain all available funds and any future earnings to fund the development and growth of our business. Any future determination to declare dividends will be subject to the discretion of our board of directors and will depend on various factors, including applicable laws, our results of operations, financial condition, future prospects and any other factors deemed relevant by our board of directors. Investors should not purchase our common stock with the expectation of receiving cash dividends.

 

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CAPITALIZATION

The following table sets forth our cash and cash equivalents and our capitalization as of March 31, 2018:

 

    on an actual basis;

 

    on a pro forma basis to give effect to:

 

    our sale of 11,223,102 shares of Series C redeemable convertible preferred stock in April 2018 for gross proceeds of $52.3 million;

 

    the automatic conversion of all outstanding shares of our redeemable convertible preferred stock into an aggregate of 23,375,405 shares of our common stock upon the closing of this offering; and

 

    the filing and effectiveness of our amended and restated certificate of incorporation; and

 

    on a pro forma as adjusted basis to give further effect to our issuance and sale of 6,666,667 shares of our common stock in this offering at an assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

The pro forma as adjusted information below is illustrative only, and our capitalization following the closing of this offering will be adjusted based on the actual initial public offering price and other terms of this offering determined at pricing. You should read this table together with our financial statements and the related notes appearing at the end of this prospectus and the sections of this prospectus titled “Selected Financial Data” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.”

 

     At March 31, 2018  
     Actual     Pro
Forma
    Pro Forma
As Adjusted
 
     (In thousands, except share and per
share data)
 

Cash and cash equivalents

   $ 41,462     $ 93,762     $ 183,758  
  

 

 

   

 

 

   

 

 

 

Redeemable convertible preferred stock (Series A and B), $0.001 par value; 49,178,527 shares authorized, issued and outstanding, actual; no shares authorized, issued or outstanding, pro forma and pro forma as adjusted

     92,439       —         —    
  

 

 

   

 

 

   

 

 

 

Stockholders’ Equity (Deficit)

      

Preferred stock, $0.001 par value; no shares authorized, issued or outstanding, actual; 10,000,000 shares authorized and no shares issued or outstanding, pro forma and pro forma as adjusted

     —         —         —    

Common stock, $0.001 par value; 70,000,000 shares authorized, 4,448,467 shares issued and 2,620,279 shares outstanding, actual; 150,000,000 shares authorized, 27,823,872 shares issued and 25,995,684 shares outstanding, pro forma; 150,000,000 shares authorized, 34,490,539 shares issued and 32,662,351 shares outstanding, pro forma as adjusted

     3       26       32  

Additional paid-in capital

     4,515       149,231       239,055  

Accumulated deficit

     (56,372     (56,372     (56,372
  

 

 

   

 

 

   

 

 

 

Total stockholders’ equity (deficit)

     (51,854     92,885       182,715  
  

 

 

   

 

 

   

 

 

 

Total capitalization

   $ 40,585     $ 92,885     $ 182,715  
  

 

 

   

 

 

   

 

 

 

A $1.00 increase (decrease) in the assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted amount of each of cash and cash equivalents, total stockholders’ equity and total capitalization

 

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by $6.2 million, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions. An increase (decrease) of 1,000,000 shares in the number of shares offered by us, as set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted amount of each of cash and cash equivalents, total stockholders’ equity and total capitalization by $14.0 million, assuming no change in the assumed initial public offering price per share and after deducting estimated underwriting discounts and commissions.

The table above does not include:

 

    1,386,577 shares of common stock issuable upon the exercise of stock options outstanding as of March 31, 2018 under the 2016 Plan at a weighted average exercise price of $6.41 per share (which does not include options to purchase an aggregate of 1,923,713 shares of common stock, at an exercise price of $9.49 per share, that were granted subsequent to March 31, 2018);

 

    1,004,147 shares of common stock reserved and available for future issuance under the 2016 Plan, as of March 31, 2018 (which does not include an increase of 1,884,850 shares of common stock reserved for future issuance under our 2016 Plan effected in April 2018 or account for options to purchase 1,923,713 shares of common stock that were granted subsequent to March 31, 2018). Shares of common stock remaining available for issuance under the 2016 Plan will be made available for issuance under the 2018 Plan upon the effectiveness of the 2018 Plan); and

 

    1,765,162 shares of our common stock reserved for future issuance under our 2018 Plan, which will become effective upon the completion of this offering, as well as any future increases in the number of shares of common stock reserved for future increases in the number of shares of common stock reserved for future issuances under our 2018 Plan.

 

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DILUTION

If you invest in our common stock in this offering, your ownership interest will be diluted immediately to the extent of the difference between the initial public offering price per share of our common stock and the pro forma as adjusted net tangible book value per share of our common stock immediately after this offering.

Our historical net tangible book value (deficit) as of March 31, 2018 was $(53.3) million, or $(11.97) per share of our common stock. Our historical net tangible book value (deficit) is the amount of our total tangible assets less our total liabilities and preferred stock, which is not included within our stockholders’ equity (deficit). Historical net tangible book value per share represents historical net tangible book value (deficit) divided by the 4,448,467 shares of our common stock outstanding as of March 31, 2018, including 1,828,188 shares of unvested restricted stock subject to repurchase by us.

Our pro forma net tangible book value as of March 31, 2018 was $91.5 million, or $3.29 per share of our common stock. Pro forma net tangible book value represents the amount of our total tangible assets less our total liabilities, after giving effect to (i) our sale of 11,223,102 shares of Series C redeemable convertible preferred stock in April 2018 for gross proceeds of $52.3 million and (ii) the automatic conversion of all outstanding shares of our redeemable convertible preferred stock into an aggregate of 23,375,405 shares of our common stock upon the closing of this offering. Pro forma net tangible book value per share represents pro forma net tangible book value divided by the total number of shares outstanding as of March 31, 2018 after giving effect to the pro forma adjustment described above.

After giving further effect to our issuance and sale of 6,666,667 shares of our common stock in this offering at an assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us, our pro forma as adjusted net tangible book value as of March 31, 2018 would have been $182.7 million, or $5.30 per share. This represents an immediate increase in pro forma as adjusted net tangible book value per share of $2.01 to existing stockholders and immediate dilution of $9.70 per share in pro forma as adjusted net tangible book value per share to new investors purchasing common stock in this offering. Dilution per share to new investors is determined by subtracting pro forma as adjusted net tangible book value per share after this offering from the assumed initial public offering price per share paid by new investors. The following table illustrates this dilution on a per share basis:

 

Assumed initial public offering price per share

      $ 15.00  

Historical net tangible book value (deficit) per share as of March 31, 2018

   $ (11.97   

Increase per share attributable to the pro forma adjustment described above

     15.26     
  

 

 

    

Pro forma net tangible book value per share as of March 31, 2018

   $ 3.29     

Increase in pro forma as adjusted net tangible book value per share attributable to new investors purchasing common stock in this offering

     2.01     
  

 

 

    

Pro forma as adjusted net tangible book value per share after this offering

        5.30  
     

 

 

 

Dilution per share to new investors purchasing common stock in this offering

      $ 9.70  
     

 

 

 

A $1.00 increase (decrease) in the assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) our pro forma as adjusted net tangible book value per share after this offering by $0.18 and dilution per share to new investors purchasing common stock in this offering by $0.82, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting

 

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discounts and commissions. An increase of 1,000,000 shares in the number of shares offered by us, as set forth on the cover page of this prospectus, would increase our pro forma as adjusted net tangible book value per share after this offering by $0.24 and decrease the dilution per share to new investors purchasing common stock in this offering by $0.24, assuming no change in the assumed initial public offering price per share and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. A decrease of 1,000,000 shares in the number of shares offered by us, as set forth on the cover page of this prospectus, would decrease our pro forma as adjusted net tangible book value per share after this offering by $0.26 and increase the dilution per share to new investors purchasing common stock in this offering by $0.26, assuming no change in the assumed initial public offering price and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

If the underwriters fully exercise their option to purchase 1,000,000 additional shares of common stock in this offering, our pro forma as adjusted net tangible book value per share after this offering would be $5.54 and the dilution in pro forma as adjusted net tangible book value per share to new investors purchasing common stock in this offering would be $9.46, assuming no change in the initial public offering price per share and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

The following table summarizes, as of March 31, 2018, on the pro forma as adjusted basis described above, the total number of shares of common stock purchased from us on an as converted to common stock basis, the total consideration paid, or to be paid, and the average price per share paid or to be paid by existing shareholders and by new investors in this offering at an assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, before deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. As the table shows, new investors purchasing common stock in this offering will pay an average price per share substantially higher than our existing stockholders paid.

 

     Shares Purchased     Total Consideration     Average
Price

Per
Share
 
     Number      Percent     Amount      Percentage    

Existing stockholders

     27,823,872        80.7   $ 145,230,633        59.2   $ 5.22  

New investors

     6,666,667        19.3       100,000,005        40.8     $ 15.00  
  

 

 

    

 

 

   

 

 

    

 

 

   

Total

     34,490,539        100.0   $ 245,230,638        100.0  
  

 

 

    

 

 

   

 

 

    

 

 

   

Certain of our existing stockholders have indicated an interest in purchasing an aggregate of up to approximately $40.0 million of shares of our common stock in this offering at the initial public offering price. However, because indications of interest are not binding agreements or commitments to purchase, the underwriters may determine to sell more, less or no shares in this offering to such stockholders, and such stockholders could determine to purchase more, less or no shares in this offering.

A $1.00 increase (decrease) in the assumed initial public offering price of $15.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the total consideration paid by new investors by $6.7 million and, in the case of an increase, would increase the percentage of total consideration paid by new investors by 1.5 percentage points and, in the case of a decrease, would decrease the percentage of total consideration paid by new investors by 1.7 percentage points, assuming that the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same. An increase (decrease) of 1,000,000 shares in the number of shares offered by us, as set forth on the cover page of this prospectus, would increase (decrease) the total consideration paid by new investors by $15.0 million and, in the case of an increase, would increase the percentage of total consideration paid by new investors by 3.4 percentage points and, in the case of a decrease, would decrease the percentage of total consideration paid by new investors by 3.9 percentage points, assuming no change in the assumed initial public offering price per share.

 

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The table above assumes no exercise of the underwriters’ option to purchase additional shares in this offering. If the underwriters’ option to purchase additional shares is fully exercised, the number of shares of our common stock held by existing stockholders would be reduced to 78.4% of the total number of shares of our common stock outstanding after this offering, and the number of shares of common stock held by new investors purchasing common stock in this offering would be increased to 21.6% of the total number of shares of our common stock outstanding after this offering.

The number of shares of common stock to be outstanding after this offering is based on 34,490,539 shares of common stock outstanding as of March 31, 2018, which includes 1,828,188 shares of unvested restricted stock subject to repurchase by us, after giving effect to (i) our sale of 11,223,102 shares of Series C redeemable convertible preferred stock in April 2018, for gross proceeds of $52.3 million and (ii) the automatic conversion of all outstanding shares of our preferred stock and excludes:

 

    1,386,577 shares of common stock issuable upon the exercise of stock options outstanding as of March 31, 2018 under the 2016 Plan, at a weighted average exercise price of $6.41 per share (which does not include options to purchase an aggregate of 1,923,713 shares of common stock, at an exercise price of $9.49 per share, that were granted subsequent to March 31, 2018);

 

    1,004,147 shares of common stock reserved and available for future issuance under the 2016 Plan, as of March 31, 2018 (which does not include an increase of 1,884,850 shares of common stock reserved for future issuance under our 2016 Plan effected in April 2018 or account for options to purchase 1,923,713 shares of common stock that were granted subsequent to March 31, 2018). Shares of common stock remaining available for issuance under the 2016 Plan will be made available for issuance under the 2018 Plan upon the effectiveness of the 2018 Plan); and

 

    1,765,162 shares of our common stock reserved for future issuance under our 2018 Plan, which will become effective upon the completion of this offering, as well as any future increases in the number of shares of common stock reserved for future increases in the number of shares of common stock reserved for future issuances under our 2018 Plan.

If additional shares are issued in connection with the exercise of outstanding options, if new stock options are issued under our equity incentive plan, or if we issue additional shares of common stock in the future, there will be further dilution to investors purchasing common stock in this offering. In addition, we may choose to raise additional capital because of market conditions or strategic considerations, even if we believe that we have sufficient funds for our current or future operating plans. If we raise additional capital through the sale of equity or convertible debt securities, the issuance of these securities could result in further dilution to our stockholders.

 

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SELECTED FINANCIAL DATA

You should read the following selected financial data together with our financial statements and the related notes appearing at the end of this prospectus and the “Management’s Discussion and Analysis of Financial Condition and Results of Operations” section of this prospectus. We have derived the statement of operations data for the years ended December 31, 2016 and 2017 and the balance sheet data as of December 31, 2016 and 2017 from our audited financial statements appearing at the end of this prospectus. Our historical results are not necessarily indicative of the results that may be expected in the future. We have derived the statement of operations data for the three months ended March 31, 2017 and 2018 and the balance sheet data as of March 31, 2018 from our unaudited interim financial statements appearing at the end of this prospectus. The unaudited interim financial statements have been prepared on the same basis as the audited financial statements and reflect, in the opinion of management, all adjustments of a normal, recurring nature that are necessary for a fair statement of the financial information included in those unaudited interim financial statements. Our historical results are not necessarily indicative of the results that may be expected in the future, and the results for the three months ended March 31, 2018 are not necessarily indicative of results to be expected for the full year or any other period.

 

     Year Ended December 31,     Three Months Ended March 31,  
     2016     2017     2017     2018  
     (in thousands, except share and per share data)  

Statement of Operations Data:

        

Revenue

   $ —       $ —       $ —       $ —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Operating expenses:

        

Research and development

     5,782       27,899       3,322       7,849  

General and administrative

     3,486       7,828       1,489       3,457  
  

 

 

   

 

 

   

 

 

   

 

 

 

Total operating expenses

     9,268       35,727       4,811       11,306  
  

 

 

   

 

 

   

 

 

   

 

 

 

Loss from operations

     (9,268     (35,727     (4,811     (11,306
  

 

 

   

 

 

   

 

 

   

 

 

 

Other income (expense):

        

Interest expense

     (163     —         —         —    

Interest and other income, net

     —         236       —         145  
  

 

 

   

 

 

   

 

 

   

 

 

 

Total other income (expense), net

     (163     236       —         145  
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss

   $ (9,431   $ (35,491   $ (4,811   $ (11,161

Accretion of redeemable convertible preferred stock to redemption value

     (107     (213     —         —    

Cumulative dividends on redeemable convertible preferred stock

     (197     (437     (354     —    

Reversal of cumulative dividends on redeemable convertible preferred stock

     —         634       —         —    
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss attributable to common stockholders

   $ (9,735   $ (35,507   $ (5,165   $ (11,161
  

 

 

   

 

 

   

 

 

   

 

 

 

Net loss per share attributable to common stockholders—basic and diluted

   $ (65.15   $ (19.12   $ (3.59   $ (4.53
  

 

 

   

 

 

   

 

 

   

 

 

 

Weighted average common shares outstanding—basic and diluted

     149,414       1,856,907       1,438,361       2,466,353  
  

 

 

   

 

 

   

 

 

   

 

 

 

Pro forma net loss per share attributable to common stockholders—basic and diluted (unaudited)

     $ (2.07     $ (0.52
    

 

 

     

 

 

 

Pro forma weighted average common shares outstanding—basic and diluted (unaudited)

       17,141,918         21,498,419  
    

 

 

     

 

 

 

 

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     December 31,     March 31,
2018
 
     2016     2017    
     (in thousands)  

Balance Sheet Data:

      

Cash and cash equivalents

   $ 4,513     $ 51,402     $ 41,462  

Working capital(1)

     8,534       48,361       37,134  

Total assets

     11,342       54,463       46,078  

Redeemable convertible preferred stock

     17,916       92,439       92,439  

Total stockholders’ deficit

     (8,874     (42,118     (51,854

 

(1) We define working capital as current assets less current liabilities.

 

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MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL

CONDITION AND RESULTS OF OPERATIONS

You should read the following discussion and analysis of our financial condition and results of operations together with the section entitled “Selected Financial Data” and our financial statements and related notes appearing at the end of this prospectus. Some of the information contained in this discussion and analysis or set forth elsewhere in this prospectus, including information with respect to our plans and strategy for our business and related financing, includes forward-looking statements that involve risks and uncertainties. As a result of many factors, including those factors set forth in the “Risk Factors” section of this prospectus, our actual results could differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.

Overview

We are a clinical-stage biotechnology company developing novel medicines to bring the curative power of bone marrow transplant to more patients. Transplant is a well-established and often curative medical procedure, and emerging data on stem cell gene therapy, which is bone marrow transplant using gene-modified stem cells, suggest the potential for meaningful benefit with this newer form of transplant. Bone marrow transplant and stem cell gene therapies use the same widely-adopted decades old transplant process. As it exists today, bone marrow transplant is a large market opportunity, and improvements to the current approaches could extend bone marrow transplant to more patients. The ability to treat patients with a bone marrow transplant is limited by the challenge of obtaining sufficient cells to perform the procedure, the inherent morbidity and mortality of current methods used to prepare patients for transplant, and complications following transplant.

At Magenta, we believe we are uniquely positioned to overcome these challenges and to lead a new era in transplant medicine. Our portfolio of product candidates includes biologics, small molecules and a cell therapy designed to address deficiencies in existing approaches and extend the curative power of bone marrow transplant to more patients across many diseases. Currently, only a fraction of eligible patients with these diseases receive a transplant because the risks and challenges outweigh the potential for a cure. These include diseases where bone marrow transplant is a standard of care (e.g., blood cancers such as acute myelogenous leukemia, myelodysplastic syndromes, multiple myeloma, and non-Hodgkin lymphoma), diseases where transplant is performed but limited in use (e.g., hemoglobinopathies such as sickle cell disease and beta-thalassemia), and autoimmune diseases. Emerging clinical data suggest that bone marrow transplant may represent a breakthrough approach with curative potential for patients with severe autoimmune diseases. For example, recent results from multiple clinical trials show that patients with autoimmune diseases, including multiple sclerosis and scleroderma, can be cured with a transplant. However, based on our epidemiology analyses, currently only approximately 1 to 2% of eligible patients with multiple sclerosis or scleroderma in the United States and Europe receive a bone marrow transplant.

To address the major unmet medical needs in the existing bone marrow transplant process, we are developing a stem cell biology discovery platform and building a comprehensive portfolio of novel therapeutics. Our programs will improve stem cell dose (expansion), stem cell collection (mobilization), patient preparation for transplant (conditioning) and potential post-transplant complications, to address key limitations of the bone marrow transplant process to allow more patients to benefit. Within our expansion program, MGTA-456, our most advanced clinical product candidate, is a cell therapy that has achieved clinical proof of concept in 36 patients with blood cancers and is now being studied in patients with fatal inherited metabolic diseases. MGTA-456 is produced by significantly expanding the number of stem cells in cord blood units, and has the potential to allow product candidate more patients to have a better chance for a successful stem cell transplant. Within our mobilization program, MGTA-145 is focused on enabling physicians to more easily harvest a greater number of blood stem cells, known as hematopoietic stem cells or HSCs, from patients and donors to improve patient outcomes. Our targeted transplant conditioning programs, which prepare the patient for transplant, are designed to selectively remove stem and/or immune cells from a patient prior to transplant, and to be far less toxic than the

 

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decades-old radiation and chemotherapy-based approaches which are still the only available options. Our post-transplant complications program is designed to target the donor immune cells within the patient that cause Graft vs. Host Disease, or GvHD, which can be a fatal complication of transplant.

We intend to become a fully integrated discovery, development and commercial company in the field of transplant medicine. We believe that our product portfolio will offer significant commercial synergies. We are developing our products so that they can each be used individually or in combination with each other. As a result, our portfolio could be utilized in a manner tailored to the patient’s disease, such that a patient may receive more than one Magenta therapy as part of their individual transplant journey.

Since our inception in 2015, we have focused substantially all of our efforts and financial resources on organizing and staffing our company, business planning, raising capital, acquiring and developing our technology, identifying potential product candidates, and undertaking preclinical studies, and in the case of MGTA-456, clinical trials. We do not have any products approved for sale and have not generated any revenue from product sales. To date, we have funded our operations primarily with proceeds from the sales of redeemable convertible preferred stock and issuance of convertible notes. Through March 31, 2018, we had received net proceeds of $82.7 million from sales of our redeemable convertible preferred stock (including proceeds from convertible notes, which converted into redeemable convertible preferred stock in 2016). In April 2018, we received gross proceeds of $52.3 million from our sale of our Series C redeemable convertible preferred stock, or Series C preferred stock.

Since our inception, we have incurred significant operating losses. Our ability to generate product revenue sufficient to achieve profitability will depend heavily on the successful development and eventual commercialization of one or more of our product candidates. Our net loss was $9.4 million for the year ended December 31, 2016, $35.5 million for the year ended December 31, 2017 and $11.2 million for the three months ended March 31, 2018. As of March 31, 2018, we had an accumulated deficit of $56.4 million. We expect to continue to incur significant expenses and increasing operating losses for at least the next several years. We expect our expenses and capital requirements will increase substantially in connection with our ongoing activities, particularly as we:

 

    continue enrollment in our Phase II clinical trial of MGTA-456;

 

    prepare for and initiate our preclinical studies and clinical trials of our product candidates;

 

    develop any other future product candidates we may choose to pursue;

 

    continue research and development and drug discovery and initiate additional clinical trials;

 

    seek marketing approval for any of our product candidates that successfully complete clinical development;

 

    maintain compliance with applicable regulatory requirements;

 

    develop and scale up our capabilities to support our ongoing preclinical activities and clinical trials for our product candidates and commercialization of any of our product candidates for which we obtain marketing approval;

 

    maintain, expand, protect and enforce our intellectual property portfolio;

 

    develop and expand our sales, marketing and distribution capabilities for our product candidates for which we obtain marketing approval, if any; and

 

    expand our operational, financial and management systems and increase personnel, including to support our clinical development and commercialization efforts and our operations as a public company.

We will not generate revenue from product sales unless and until we successfully complete clinical development and obtain regulatory approval for our product candidates. If we obtain regulatory approval for any of our

 

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product candidates, we expect to incur significant expenses related to developing our commercialization capability to support product sales, marketing and distribution. Further, upon the closing of this offering, we expect to incur additional costs associated with operating as a public company.

As a result, we will need substantial additional funding to support our continuing operations and pursue our growth strategy. Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution or licensing arrangements. We may be unable to raise additional funds or enter into such other agreements or arrangements when needed on favorable terms, or at all. If we fail to raise capital or enter into such agreements as, and when, needed, we may have to significantly delay, scale back or discontinue the development and commercialization of one or more of our product candidates.

Because of the numerous risks and uncertainties associated with pharmaceutical product development, we are unable to accurately predict the timing or amount of increased expenses or when or if we will be able to achieve or maintain profitability. Even if we are able to generate product sales, we may not become profitable. If we fail to become profitable or are unable to sustain profitability on a continuing basis, then we may be unable to continue our operations at planned levels and be forced to reduce or terminate our operations.

As of March 31, 2018, we had cash and cash equivalents of $41.5 million. In April 2018, we received gross proceeds of $52.3 million from the sale of our Series C preferred stock. We believe that the net proceeds from this offering, together with our existing cash and cash equivalents, will enable us to fund our operating expenses and capital expenditure requirements through at least the first quarter of 2020. See “—Liquidity and Capital Resources.”

Components of Our Results of Operations

Revenue

To date, we have not generated any revenue from product sales and do not expect to generate any revenue from the sale of products in the foreseeable future. If our development efforts for our product candidates are successful and result in regulatory approval, we may generate revenue in the future from product sales. If we enter into license or collaboration agreements for any of our product candidates or intellectual property, we may generate revenue in the future from payments as a result of such license or collaboration agreements. We cannot predict if, when, or to what extent we will generate revenue from the commercialization and sale of our product candidates. We may never succeed in obtaining regulatory approval for any of our product candidates.

Operating Expenses

Research and Development Expenses

Research and development expenses consist primarily of costs incurred for our research activities, including our drug discovery efforts, and the development of our product candidates, which include:

 

    employee-related expenses, including salaries and related costs, and stock-based compensation expense, for employees engaged in research and development functions;

 

    expenses incurred in connection with the preclinical and clinical development of our product candidates, including under agreements with contract research organizations, or CROs;

 

    the cost of consultants and contract manufacturing organizations, or CMOs, that manufacture drug products for use in our preclinical studies and clinical trials;

 

    facilities, depreciation and other expenses, which include direct and allocated expenses for rent and maintenance of facilities, insurance and supplies; and

 

    payments made under third-party licensing agreements.

 

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We expense research and development costs to operations as incurred. Advance payments for goods or services to be received in the future for use in research and development activities are recorded as prepaid expenses. The prepaid amounts are expensed as the related goods are delivered or the services are performed.

Our direct research and development expenses are tracked on a program-by-program basis and consist primarily of external costs, such as fees paid to consultants, central laboratories, contractors, CMOs and CROs in connection with our preclinical and clinical development activities. We do not allocate employee costs, costs associated with our platform technology or facility expenses, including depreciation or other indirect costs, to specific product development programs because these costs are deployed across multiple product development programs and, as such, are not separately classified.

The table below summarizes our research and development expenses incurred by development program:

 

     Year Ended
December 31,
     Three Months Ended
March 31,
 
     2016      2017      2017      2018  
     (in thousands)  

Conditioning

   $ 303      $ 6,259      $ 1,208      $ 2,797  

Mobilization

     431        1,416        319        437  

Expansion

     13        11,045        156        866  

GvHD

     —          —          —          228  

Unallocated expenses

     5,035        9,179        1,639        3,521  
  

 

 

    

 

 

    

 

 

    

 

 

 

Total research and development expenses

   $   5,782      $ 27,899      $ 3,322        7,849  
  

 

 

    

 

 

    

 

 

    

 

 

 

The successful development and commercialization of our product candidates is highly uncertain. This is due to the numerous risks and uncertainties, including the following:

 

    successful completion of preclinical studies and clinical trials;

 

    receipt and related terms of marketing approvals from applicable regulatory authorities;

 

    raising additional funds necessary to complete clinical development of and commercialize our product candidates;

 

    obtaining and maintaining patent, trade secret and other intellectual property protection and regulatory exclusivity for our product candidates;

 

    making arrangements with third-party manufacturers, or establishing manufacturing capabilities, for both clinical and commercial supplies of our product candidates;

 

    developing and implementing marketing and reimbursement strategies;

 

    establishing sales, marketing and distribution capabilities and launching commercial sales of our products, if and when approved, whether alone or in collaboration with others;

 

    acceptance of our products, if and when approved, by patients, the medical community and third-party payors;

 

    effectively competing with other therapies;

 

    obtaining and maintaining third-party coverage and adequate reimbursement;

 

    protecting and enforcing our rights in our intellectual property portfolio; and

 

    maintaining a continued acceptable safety profile of the products following approval.

A change in the outcome of any of these variables with respect to the development of any of our product candidates would significantly change the costs and timing associated with the development of that product candidate. We may never succeed in obtaining regulatory approval for any of our product candidates.

 

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Research and development activities are central to our business model. Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We expect research and development costs to increase significantly for the foreseeable future as our product candidate development programs progress. However, we do not believe that it is possible at this time to accurately project total program-specific expenses through commercialization. There are numerous factors associated with the successful commercialization of any of our product candidates, including future trial design and various regulatory requirements, many of which cannot be determined with accuracy at this time based on our stage of development. Additionally, future commercial and regulatory factors beyond our control will impact our clinical development programs and plans.

General and Administrative Expenses

General and administrative expenses consist primarily of salaries and related costs, and stock-based compensation, for personnel in executive, finance and administrative functions. General and administrative expenses also include direct and allocated facility-related costs as well as professional fees for legal, patent, consulting, accounting and audit services.

We anticipate that our general and administrative expenses will increase in the future as we increase our headcount to support our continued research activities and development of our product candidates. We also anticipate that we will incur increased accounting, audit, legal, regulatory, compliance, and director and officer insurance costs as well as investor and public relations expenses associated with operating as a public company.

Other Income (Expense)

Interest Expense. Interest expense consisted of interest accrued on convertible promissory notes, all of which notes and accrued interest were converted into redeemable convertible preferred stock in November 2016.

Interest and Other Income, Net. Interest and other income, net, consists of interest income and insignificant amounts of miscellaneous income and expense unrelated to our core operations.

Income Taxes

Since our inception, we have not recorded any U.S. federal or state income tax benefits for the net losses we have incurred in each year or for our earned research and development tax credits, due to our uncertainty of realizing a benefit from those items. As of December 31, 2017, we had federal and state net operating loss carryforwards of $18.7 million and $19.3 million, respectively, which begin to expire in 2035. As of December 31, 2017, we also had federal and state research and development tax credit carryforwards of $1.0 million and $0.4 million, respectively, which begin to expire in 2035 and 2030, respectively.

On December 22, 2017, the Tax Cuts and Jobs Act, or TCJA, was signed into United States law. The TCJA includes a number of changes to existing tax law, including, among other things, a permanent reduction in the federal corporate income tax rate from 35% to 21%, effective as of January 1, 2018, as well as limitation of the deduction for net operating losses to 80% of annual taxable income and elimination of net operating loss carrybacks, in each case, for losses arising in taxable years beginning after December 31, 2017 (though any such net operating losses may be carried forward indefinitely). The tax rate change resulted in (i) a reduction in the gross amount of our deferred tax assets as of December 31, 2017, without an impact on the net amount of our deferred tax assets, which are recorded with a full valuation allowance, and (ii) no income tax expense or benefit being recognized as of the enactment date of the TCJA.

Critical Accounting Policies and Significant Judgments and Estimates

Our financial statements are prepared in accordance with generally accepted accounting principles in the United States, or GAAP. The preparation of our financial statements and related disclosures requires us to make

 

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estimates and judgments that affect the reported amounts of assets, liabilities, costs and expenses, and the disclosure of contingent assets and liabilities in our financial statements. We base our estimates on historical experience, known trends and events and various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. We evaluate our estimates and assumptions on an ongoing basis. Our actual results may differ from these estimates under different assumptions or conditions.

While our significant accounting policies are described in more detail in Note 2 to our financial statements appearing at the end of this prospectus, we believe that the following accounting policies are those most critical to the judgments and estimates used in the preparation of our financial statements.

Accrued Research and Development Expenses

As part of the process of preparing our financial statements, we are required to estimate our accrued research and development expenses. This process involves reviewing open contracts and purchase orders, communicating with our applicable personnel to identify services that have been performed on our behalf and estimating the level of service performed and the associated cost incurred for the service when we have not yet been invoiced or otherwise notified of actual costs. The majority of our service providers invoice us in arrears for services performed, on a pre-determined schedule or when contractual milestones are met; however, some require advance payments. We make estimates of our accrued expenses as of each balance sheet date in the financial statements based on facts and circumstances known to us at that time. We periodically confirm the accuracy of the estimates with the service providers and make adjustments if necessary. Examples of estimated accrued research and development expenses include fees paid to:

 

    vendors in connection with the preclinical development activities;

 

    CROs in connection with preclinical and clinical trials;

 

    CMOs in connection with the production of preclinical and clinical trial materials; and

 

    investigative sites in connection with clinical trials.

We base our expenses related to preclinical studies and clinical trials on our estimates of the services received and efforts expended pursuant to quotes and contracts with multiple research institutions and CROs that conduct and manage preclinical studies and clinical trials on our behalf. The financial terms of these agreements are subject to negotiation, vary from contract to contract and may result in uneven payment flows. There may be instances in which payments made to our vendors will exceed the level of services provided and result in a prepayment of the expense. In accruing service fees, we estimate the time period over which services will be performed and the level of effort to be expended in each period. If the actual timing of the performance of services or the level of effort varies from the estimate, we adjust the accrual or prepaid expense accordingly. Although we do not expect our estimates to be materially different from amounts actually incurred, our understanding of the status and timing of services performed relative to the actual status and timing of services performed may vary and may result in reporting amounts that are too high or too low in any particular period. To date, there have not been any material adjustments to our prior estimates of accrued research and development expenses.

Determination of Fair Value of Common and Preferred Stock

As there has been no public market for our common stock to date, the estimated fair value of our common stock has been determined by our board of directors as of the date of each award grant, with input from management, considering our most recently available third-party valuations of common stock and our board of directors’ assessment of additional objective and subjective factors that it believed were relevant and which may have changed from the date of the most recent valuation through the date of the grant. These third-party valuations were performed in accordance with the guidance outlined in the American Institute of Certified Public

 

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Accountants’ Accounting and Valuation Guide, Valuation of Privately-Held-Company Equity Securities Issued as Compensation. Our common stock valuations were prepared using either an option pricing method, or OPM, or a hybrid method, both of which used market approaches to estimate our enterprise value. The OPM treats common stock and preferred stock as call options on the total equity value of a company, with exercise prices based on the value thresholds at which the allocation among the various holders of a company’s securities changes. Under this method, the common stock has value only if the funds available for distribution to stockholders exceeded the value of the preferred stock liquidation preferences at the time of the liquidity event, such as a strategic sale or a merger. A discount for lack of marketability of the common stock is then applied to arrive at an indication of value for the common stock. The hybrid method is a probability-weighted expected return method, or PWERM, where the equity value in one or more scenarios is calculated using an OPM. The PWERM is a scenario-based methodology that estimates the fair value of common stock based upon an analysis of future values for the company, assuming various outcomes. The common stock value is based on the probability-weighted present value of expected future investment returns considering each of the possible outcomes available as well as the rights of each class of stock. The future value of the common stock under each outcome is discounted back to the valuation date at an appropriate risk-adjusted discount rate and probability weighted to arrive at an indication of value for the common stock. These third-party valuations were performed at various dates, which resulted in valuations of our common stock of $4.84 per share as of April 30, 2017, $7.71 per share as of December 31, 2017 and $9.49 per share as of April 2, 2018. In addition to considering the results of these third-party valuations, our board of directors considered various objective and subjective factors to determine the fair value of our common stock as of each grant date, which may be at a date later than the most recent third-party valuation date, including:

 

    the prices at which we sold shares of preferred stock and the superior rights and preferences of the preferred stock relative to our common stock at the time of each grant;

 

    the progress of our research and development programs, including the status of preclinical studies and clinical trials for our product candidates;

 

    our stage of development and commercialization and our business strategy;

 

    external market conditions affecting the biotechnology industry, and trends within the biotechnology industry;

 

    our financial position, including cash on hand, and our historical and forecasted performance and operating results;

 

    the lack of an active public market for our common stock and our preferred stock;

 

    the likelihood of achieving a liquidity event, such as an initial public offering, or IPO, or a sale of our company in light of prevailing market conditions; and

 

    the analysis of IPOs and the market performance of similar companies in the biopharmaceutical industry.

The assumptions underlying these valuations represent management’s best estimates, which involve inherent uncertainties and the application of management judgment. As a result, if factors or expected outcomes change and we use significantly different assumptions or estimates, our stock-based compensation expense could be materially different.

Following the closing of this offering, the fair value of our common stock will be determined based on the quoted market price of our common stock.

We estimated the fair value of our Series A redeemable convertible preferred stock, or Series A preferred stock, and Series B redeemable convertible preferred stock, or Series B preferred stock, as of April 30, 2017 to be $2.71 per share and $3.88 per share, respectively, using the OPM valuation method and other relevant factors as described above.

 

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Common and Preferred Stock Issued for Licenses

When common and preferred stock are issued in exchange for a license, we determine the fair value of the common and preferred stock granted as either the fair value of the consideration received or the fair value of the equity instruments issued. For the common and preferred stock issued for licenses during the years ended December 31, 2016 and 2017, we determined the expense based on the fair value of the stock issued as it was more readily determinable.

Stock-Based Compensation

We measure all stock options and other stock-based awards granted to employees and directors based on the fair value on the date of the grant and recognize compensation expense of those awards over the requisite service period, which is generally the vesting period of the respective award. Generally, we issue stock options and restricted stock awards, or RSAs, with service-based vesting conditions and record the expense for these awards using the straight-line method. We have historically granted stock options with exercise prices equivalent to the fair value of our common stock as of the date of the grant. We estimate the fair value of each stock option award using the Black-Scholes option-pricing model, which uses as inputs the fair value of our common stock and assumptions we make for the volatility of our common stock, the expected term of our stock options, the risk-free interest rate for a period that approximates the expected term of our stock options and our expected dividend yield and the then-current fair value of common stock for restricted stock.

We measure the fair value of stock-based awards granted to non-employees on the date at which the related service is complete. Compensation expense is recognized over the period during which services are rendered by such non-employee consultants until completed. At the end of each financial reporting period prior to completion of the service, the fair value of these awards is re-measured using the then-current fair value of our common stock and updated assumption inputs in the Black-Scholes option-pricing model for options and the then-current fair value of our common stock for restricted stock.

We do not estimate and apply a forfeiture rate as we have elected to account for forfeitures as they occur.

Grants of Stock-Based Awards

The following table sets forth by grant date the number of shares of restricted stock and shares subject to options granted between January 1, 2017 and June 7, 2018, the per share exercise price of the options, the fair value of common stock per share on each grant date, and the per share estimated fair value of the award:

 

Grant Date

   Type of
Award
   Number
of Shares
Subject
to Award
     Per
Share

Exercise
Price of
Options
     Fair
Value of
Common
Stock
per
Share on
Grant
Date
     Per Share
Estimated
Fair
Value of
Award
 

March 31, 2017

   RSA      218,654        —        $ 4.84      $ 4.84  

September 28, 2017

   Option      522,822      $ 4.84      $ 4.84      $ 3.31  

October 7, 2017

   Option      4,837      $ 4.84      $ 4.84      $ 3.26  

November 30, 2017

   Option      96,747      $ 4.84      $ 4.84      $ 3.29  

January 31, 2018

   Option      762,171      $ 7.71      $ 7.71      $ 5.30  

April 26, 2018

   Option      459,576      $ 9.49      $ 9.49      $ 6.83  

May 9, 2018

   Option      912,664      $ 9.49      $ 9.49      $ 6.59  

May 12, 2018

   Option      551,473      $ 9.49      $ 9.49      $ 6.59  

 

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Results of Operations

Comparison of the Three Months Ended March 31, 2017 and 2018

The following table summarizes our results of operations for the three months ended March 31, 2017 and 2018:

     Three Months
Ended March 31,
        
     2017      2018      Change  
     (in thousands)  

Revenue

   $ —        $ —        $ —    
  

 

 

    

 

 

    

 

 

 

Operating expenses:

        

Research and development

     3,322        7,849        4,527  

General and administrative

     1,489        3,457        1,968  
  

 

 

    

 

 

    

 

 

 

Total operating expenses

     4,811        11,306        6,495  
  

 

 

    

 

 

    

 

 

 

Loss from operations

     (4,811      (11,306      (6,495
  

 

 

    

 

 

    

 

 

 

Other income (expense):

        

Interest and other income, net

     —          145        145  
  

 

 

    

 

 

    

 

 

 

Total other income (expense), net

     —          145        145  
  

 

 

    

 

 

    

 

 

 

Net loss

   $ (4,811    $ (11,161    $ (6,350
  

 

 

    

 

 

    

 

 

 

Research and Development Expenses

 

     Three Months
Ended March 31,
        
     2017      2018      Change  
     (in thousands)  

Direct research and development expenses by program:

        

Conditioning

   $ 1,208      $ 2,797      $ 1,589  

Mobilization

     319        437        118  

Expansion

     156        866        710  

GvHD

     —          228        228  

Unallocated expenses:

        

Personnel related (including stock-based compensation)

     806        1,918        1,112  

Consultant fees

     311        775        464  

Facility related and other

     522        828        306  
  

 

 

    

 

 

    

 

 

 

Total research and development expenses

   $ 3,322      $ 7,849      $ 4,527  
  

 

 

    

 

 

    

 

 

 

Expenses related to our conditioning program increased primarily as a result of costs incurred in connection with our collaboration agreement with Heidelberg Pharma Research GmbH for an upfront technology access fee, research exclusivity fees and payments for research support related to our drug discovery efforts, primarily lead optimization. Conditioning program costs also increased due to our ongoing proof of mechanism non-human primate study. Expenses related to our expansion program increased primarily due to clinical trial costs incurred for our MGTA-456 Phase II study for inherited metabolic diseases, which we initiated in December 2017, and preparation for planned additional clinical trials in indications beyond inherited metabolic diseases. The increase in spending related to our GvHD program was due to costs related to our drug discovery efforts, primarily target validation.

The increase in personnel-related costs included in unallocated expenses was due to an increase in headcount in our research and development function. Personnel-related costs for the three months ended March 31, 2017 and

 

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2018 included stock-based compensation expense of $0.1 million and $0.2 million, respectively. The increase in consultant fees was primarily due to an increase in stock-based compensation from $0.2 million for the three months ended March 31, 2017 to $0.7 million for the three months ended March 31, 2018. The increase in facility related and other costs was primarily due to rent expense under our lease agreement for our Cambridge, Massachusetts facility, which we entered into in February 2017, as well as higher costs related to laboratory supplies and equipment.

General and Administrative Expenses

 

     Three Months
Ended March 31,
        
     2017      2018      Change  
     (in thousands)  

Personnel related (including stock-based compensation)

   $ 570      $ 1,814      $ 1,244  

Professional and consultant fees

     676        1,149        473  

Facility related and other

     243        494        251  
  

 

 

    

 

 

    

 

 

 

Total general and administrative expenses

   $ 1,489      $ 3,457      $ 1,968  
  

 

 

    

 

 

    

 

 

 

The increase in personnel-related costs was primarily a result of an increase in headcount. Personnel-related costs for the three months ended March 31, 2017 and 2018 included stock-based compensation expense of $0.1 million and $0.5 million, respectively. The increase in professional and consultant fees was primarily due to an increase in legal and patent costs related to our ongoing business activities and preparations to operate as a public company. The increase in facility related and other costs was primarily due to higher facility and other costs related to our Cambridge, Massachusetts facility lease, which we entered into in February 2017, as well as our growth.

Other Income (Expense)

There was no interest and other income, net for the three months ended March 31, 2017. There was $0.1 million interest and other income, net for the three months ended March 31, 2018 primarily related to interest income earned on our invested cash balances.

Comparison of the Years Ended December 31, 2016 and 2017

The following table summarizes our results of operations for the years ended December 31, 2016 and 2017:

 

     Year Ended         
     December 31,         
     2016      2017      Change  
     (in thousands)  

Revenue

   $ —        $ —        $ —    
  

 

 

    

 

 

    

 

 

 

Operating expenses:

        

Research and development

     5,782        27,899        22,117  

General and administrative

     3,486        7,828        4,342  
  

 

 

    

 

 

    

 

 

 

Total operating expenses

     9,268        35,727        26,459  
  

 

 

    

 

 

    

 

 

 

Loss from operations

     (9,268      (35,727      (26,459
  

 

 

    

 

 

    

 

 

 

Other income (expense):

        

Interest expense

     (163      —          163  

Interest and other income, net

     —          236        236  
  

 

 

    

 

 

    

 

 

 

Total other income (expense), net

     (163      236        399  
  

 

 

    

 

 

    

 

 

 

Net loss

   $ (9,431    $ (35,491    $ (26,060
  

 

 

    

 

 

    

 

 

 

 

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Research and Development Expenses

 

     Year Ended
December 31,
        
     2016      2017      Change  
     (in thousands)  

Direct external research and development expenses by program:

        

Conditioning

   $ 303      $ 6,259      $ 5,956  

Mobilization

     431        1,416        985  

Expansion

     13        11,045        11,032  

Unallocated expenses:

        

Personnel related (including stock-based compensation)

     1,527        4,384        2,857  

Consultant fees

     1,442        2,364        922  

Facility related and other

     2,066        2,431        365  
  

 

 

    

 

 

    

 

 

 

Total research and development expenses

   $ 5,782      $ 27,899      $ 22,117  
  

 

 

    

 

 

    

 

 

 

Expenses related to our conditioning program increased primarily as a result of our drug discovery efforts for target validation, lead identification and lead optimization. The increase in our mobilization program was due to an increase in preclinical costs for toxicology studies and manufacturing to support our Investigational New Drug, or IND, enabling studies. Expenses related to our expansion program increased primarily due to the cost of in-licensing technology of $9.3 million for the rights to MGTA-456 under a license agreement with Novartis. The cost of in-licensing technology was a result of the issuance of preferred stock to Novartis which was recorded at the fair value of the preferred stock issued. Expansion program costs also increased due to clinical trial costs incurred in preparation for our MGTA-456 Phase II study for inherited metabolic diseases, which we initiated in December 2017.

The increase in personnel-related costs included in unallocated expenses was due to an increase in headcount in our research and development function. Personnel-related costs for the years ended December 31, 2016 and 2017 included stock-based compensation expense of $0.1 million and $0.3 million, respectively. The increase in consultant fees was primarily due to an increase in stock-based compensation from $0.4 million for the year ended December 31, 2016 to $1.3 million for the year ended December 31, 2017. The increase in facility-related and other costs included in unallocated expenses was primarily due to rent expense under our lease agreement for our Cambridge, Massachusetts facility, which we entered into in February 2017.

General and Administrative Expenses

 

     Year Ended
December 31,
        
     2016      2017      Change  
     (in thousands)  

Personnel related (including stock-based compensation)

   $ 1,205      $ 3,369      $ 2,164  

Professional and consultant fees

     1,942        3,217        1,275  

Facility related and other

     339        1,242        903  
  

 

 

    

 

 

    

 

 

 

Total general and administrative expenses

   $ 3,486      $ 7,828      $ 4,342  
  

 

 

    

 

 

    

 

 

 

The increase in personnel-related costs was primarily a result of an increase in headcount. Personnel-related costs for the years ended December 31, 2016 and 2017 included stock-based compensation expense of $0.2 million and $0.6 million, respectively. The increase in professional and consultant fees was primarily due to an increase in legal, audit and recruiting fees related to ongoing business activities and our preparations to operate as a public

 

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company as well as an increase of $0.4 million related to market research activities. The increase in facility-related and other costs was primarily due to rent expense under our lease agreement for our Cambridge, Massachusetts facility, which we entered into in February 2017.

Other Income (Expense)

Interest expense was $0.2 million for the year ended December 31, 2016. There was no interest expense for the year ended December 31, 2017. The decrease of $0.2 million in interest expense was due to the conversion of outstanding convertible notes into redeemable convertible preferred stock in November 2016.

There was no other income or expense for the year ended December 31, 2016. There was $0.2 million other income, net for the year ended December 31, 2017 primarily related to interest income earned on our invested cash balances.

Liquidity and Capital Resources

Since our inception, we have incurred significant operating losses. We have not yet commercialized any of our product candidates and we do not expect to generate revenue from sales of any product candidates for several years, if at all. To date, we have funded our operations primarily with proceeds from the sales of redeemable convertible preferred stock and issuance of convertible notes. Through March 31, 2018, we had received net proceeds of $82.7 million from sales of our redeemable convertible preferred stock (including proceeds from convertible notes, which converted into redeemable convertible preferred stock in November 2016). As of March 31, 2018, we had cash and cash equivalents of $41.5 million. In April 2018, we received gross proceeds of $52.3 million from the sale of Series C preferred stock.

Cash Flows

The following table summarizes our sources and uses of cash for each of the periods presented:

 

     Year Ended
December 31,
    Three Months
Ended March 31,
 
     2016     2017     2017     2018  
     (in thousands)  

Cash used in operating activities

   $ (6,529   $ (22,263   $ (4,030   $ (9,604

Cash used in investing activities

     (169     (2,334     (731     (161

Cash provided by (used in) financing activities

     10,711       71,486       6,214       (175
  

 

 

   

 

 

   

 

 

   

 

 

 

Net increase (decrease) in cash and cash equivalents

   $ 4,013     $ 46,889     $ 1,453     $ (9,940
  

 

 

   

 

 

   

 

 

   

 

 

 

Operating Activities

During the three months ended March 31, 2018, operating activities used $9.6 million of cash, primarily resulting from our net loss of $11.2 million, partially offset by non-cash charges of $1.6 million.

During the three months ended March 31, 2017, operating activities used $4.0 million of cash, primarily resulting from our net loss of $4.8 million, partially offset by non-cash charges of $0.3 million and cash provided by changes in our operating assets and liabilities of $0.4 million. Net cash provided by changes in our operating assets and liabilities for the three months ended March 31, 2017 consisted primarily of a $0.5 million increase in accounts payable and accrued expenses partially offset by an increase of $0.1 million in prepaid expenses and other current assets.

During the year ended December 31, 2017, operating activities used $22.3 million of cash, primarily resulting from our net loss of $35.5 million, partially offset by non-cash charges of $11.9 million and cash provided by

 

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changes in our operating assets and liabilities of $1.3 million. Net cash provided by changes in our operating assets and liabilities for the year ended December 31, 2017 consisted primarily of a $2.2 million increase in accounts payable and accrued expenses, partially offset by an increase of $0.9 million in prepaid expenses and other current assets.

During the year ended December 31, 2016, operating activities used $6.5 million of cash, primarily resulting from our net loss of $9.4 million, partially offset by non-cash charges of $1.3 million and cash provided by changes in our operating assets and liabilities of $1.6 million. Net cash provided by changes in our operating assets and liabilities for the year ended December 31, 2016 consisted primarily of a $1.6 million increase in accounts payable and accrued expenses.

Changes in accounts payable, accrued expenses and prepaid expenses in both periods were generally due to growth in our business and the timing of vendor invoicing and payments.

Investing Activities

During the three months ended March 31, 2018 and 2017, we used $0.2 million and $0.6 million, respectively, to purchase property and equipment. During the three months ended March 31, 2017, we increased our restricted cash by $0.2 million to secure a letter of credit related to a lease agreement.

During the years ended December 31, 2017 and 2016, we used $2.2 million and $0.1 million, respectively, to purchase property and equipment.

Financing Activities

During the three months ended March 31, 2018, net cash used by financing activities was $0.2 million, consisting primarily of payments of initial public offering costs.

During the three months ended March 31, 2017, net cash provided by financing activities was $6.2 million, consisting primarily of $6.3 million of the remaining proceeds received in January 2017 from the sale of Series A redeemable convertible preferred stock that we recorded as other receivable as of December 31, 2016.

During the year ended December 31, 2017, net cash provided by financing activities was $71.5 million, consisting primarily of $6.3 million of the remaining proceeds received in January 2017 from the sale of Series A preferred stock that we recorded as other receivable as of December 31, 2016, $15.4 million of proceeds from the sale of additional shares of Series A preferred stock and $49.8 million of net proceeds received from the sale of Series B preferred stock.

During the year ended December 31, 2016, net cash provided by financing activities was $10.7 million, consisting primarily of proceeds of $6.5 million from the sale of convertible promissory notes and net proceeds of $4.2 million from the sale of Series A preferred stock that we received in 2016.

Funding Requirements

We expect our expenses to increase substantially in connection with our ongoing activities, particularly as we advance the preclinical activities and clinical trials for our product candidates in development. In addition, upon the closing of this offering, we expect to incur additional costs associated with operating as a public company. The timing and amount of our operating expenditures will depend largely on:

 

    the initiation, progress, timing, costs and results of current and future preclinical studies and clinical trials for our product candidates;

 

    the clinical development plans we establish for these product candidates;

 

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    the number and characteristics of product candidates that we develop or may in-license;

 

    the terms of any collaboration agreements we may choose to conclude;

 

    the outcome, timing and cost of meeting and maintaining compliance with regulatory requirements established by the FDA, the EMA and other comparable foreign regulatory authorities;

 

    the cost of filing, prosecuting, defending and enforcing our patent claims and other intellectual property rights;

 

    the cost of defending intellectual property disputes, including patent infringement actions brought by third parties against us;

 

    the effect of existing or new competing technological and market developments;

 

    the cost and timing of completion of commercial-scale outsourced manufacturing activities; and

 

    the cost of establishing sales, marketing and distribution capabilities for any product candidates for which we may receive regulatory approval in regions where we choose to commercialize our products on our own.

As of March 31, 2018, we had cash and cash equivalents of $41.5 million. In April 2018, we received gross proceeds of $52.3 million from the sale of our Series C preferred stock. We believe that the net proceeds from this offering, together with our existing cash and cash equivalents, will enable us to fund our operating expenses and capital expenditure requirements through at least the first quarter of 2020. We have based these estimates on assumptions that may prove to be wrong, and we could utilize our available capital resources sooner than we expect. Because of the numerous risks and uncertainties associated with research, development and commercialization of pharmaceutical product candidates, we are unable to estimate the exact amount of our working capital requirements. Our future funding requirements will depend on and could increase significantly as a result of many factors, including those listed above.

Without giving effect to the anticipated net proceeds from this offering, we expect that our existing cash and cash equivalents of $41.5 million as of March 31, 2018, together with the gross proceeds of $52.3 million from the sale of Series C preferred stock in April 2018, will be sufficient to fund our operating expenses and capital expenditure requirements through 12 months from the issuance date of our financial statements.

Until such time, if ever, as we can generate substantial product revenue, we expect to finance our operations through a combination of equity financings, debt financings, collaborations with other companies or other strategic transactions. We do not currently have any committed external source of funds. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as a common stockholder. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making acquisitions or capital expenditures or declaring dividends. If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings or other arrangements when needed, we may be required to delay, limit, reduce or terminate our research, product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

 

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Contractual Obligations and Commitments

The following table summarizes our contractual obligations as of December 31, 2017 and the effects that such obligations are expected to have on our liquidity and cash flows in future periods:

 

     Payments Due By Period  
     Total      Less Than
1 Year
     1 to 3 Years      4 to 5 Years      More Than
5 Years
 
     (in thousands)  

Operating lease commitments(1)

   $ 612      $ 612      $ —        $ —        $ —    
  

 

 

    

 

 

    

 

 

    

 

 

    

 

 

 

Total

   $ 612      $ 612      $ —        $ —        $ —    
  

 

 

    

 

 

    

 

 

    

 

 

    

 

 

 

 

(1) Reflects payments due for our sublease of office and laboratory space in Cambridge, Massachusetts under an operating lease agreement that expires in August 2018. In May 2018, we entered into a sublease for up to approximately 69,000 square feet of office and laboratory space in Cambridge, Massachusetts. The term of the lease commences in June 2018 and expires in February 2028. Over the lease term, we are obligated to pay $59.2 million in rental payments. Such payments are not reflected in the table.

We enter into contracts in the normal course of business with CROs, CMOs and other third parties for clinical trials, preclinical research studies and testing and manufacturing services. These contracts are cancelable by us upon prior written notice. Payments due upon cancellation consist only of payments for services provided or expenses incurred, including noncancelable obligations of our service providers, up to the date of cancellation. These payments are not included in the preceding table as the amount and timing of such payments are not known.

We have also entered into license and collaboration agreements with third parties, which are in the normal course of business. We have not included future payments under these agreements in the table of contractual obligations above since obligations under these agreements are contingent upon future events such as our achievement of specified development, regulatory, and commercial milestones, or royalties on net product sales. As of December 31, 2017, we were unable to estimate the timing or likelihood of achieving these milestones or generating future product sales.

Off-Balance Sheet Arrangements

We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined in the rules and regulations of the Securities and Exchange Commission.

Recently Issued and Adopted Accounting Pronouncements

A description of recently issued accounting pronouncements that may potentially impact our financial position and results of operations is disclosed in Note 2 to our financial statements appearing at the end of this prospectus.

Quantitative and Qualitative Disclosures about Market Risks

We are exposed to market risk related to changes in interest rates. Our primary exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest rates, particularly because our cash equivalents are in the form of a money market fund, which is primarily invested in short-term U.S. Treasury obligations. However, because of the short-term nature of the investments in our portfolio, an immediate 10% change in market interest rates would not have a material impact on the fair market value of our investment portfolio or on our financial position or results of operations.

We are not currently exposed to significant market risk related to changes in foreign currency exchange rates; however, we have contracted with and may continue to contract with foreign vendors that are located in Europe. Our operations may be subject to fluctuations in foreign currency exchange rates in the future.

 

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Inflation generally affects us by increasing our cost of labor. We do not believe that inflation had a material effect on our business, financial condition or results of operations during the years ended December 31, 2016 and 2017.

Emerging Growth Company Status

We are an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. Under the JOBS Act, emerging growth companies can delay adopting new or revised accounting standards issued subsequent to the enactment of the JOBS Act until such time as those standards apply to private companies. We have elected not to “opt out” of such extended transition period, which means that when a standard is issued or revised and it has different application dates for public or private companies, we will adopt the new or revised standard at the time private companies adopt the new or revised standard and will do so until such time that we either (1) irrevocably elect to “opt out” of such extended transition period or (2) no longer qualify as an emerging growth company.

We are in the process of evaluating the benefits of relying on other exemptions and reduced reporting requirements under the JOBS Act. Subject to certain conditions, as an emerging growth company, we may rely on certain of these exemptions, including without limitation, providing an auditor’s attestation report on our system of internal controls over financial reporting pursuant to Section 404(b) of the Sarbanes-Oxley Act. We would cease to be an emerging growth company upon the earliest of: (1) the last day of the fiscal year ending after the fifth anniversary of our initial public offering; (2) the last day of the fiscal year in which we have more than $1.07 billion in annual revenue; (3) the last day of the fiscal year in which we qualify as a “large accelerated filer,” with at least $700.0 million of equity securities held by non-affiliates as of the prior June 30th; or (4) the issuance, in any three-year period, by our company of more than $1.0 billion in non-convertible debt securities held by non-affiliates.

 

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BUSINESS

Overview

For more than 50 years, doctors and patients have had difficult conversations about bone marrow transplant: the procedure can save patients’ lives and cure them of disease, but the risk of toxicity and even mortality is often a significant deterrent. At Magenta, we believe we can refocus that conversation on the cure and enable many more patients with devastating diseases such as severe autoimmune diseases, including multiple sclerosis; blood cancers, including leukemia; and genetic diseases such as sickle cell disease to benefit from advances in transplant medicine.

We are a clinical-stage biotechnology company developing novel medicines to bring the curative power of bone marrow transplant to more patients.

Transplant is a well-established and often curative medical procedure, and emerging data on stem cell gene therapy, which is bone marrow transplant using gene-modified stem cells, suggest the potential for meaningful benefit with this newer form of transplant. Bone marrow transplant and stem cell gene therapies use the same widely-adopted decades-old transplant process. As it exists today, bone marrow transplant is a large market opportunity, and improvements to the current approaches could extend bone marrow transplant to more patients. The ability to treat patients with a bone marrow transplant is limited by the challenge of obtaining sufficient cells to perform the procedure, the inherent morbidity and mortality of current methods used to prepare patients for transplant, and complications following transplant.

At Magenta, we believe we are uniquely positioned to overcome these challenges and to lead a new era in transplant medicine. Our portfolio of product candidates includes biologics, small molecules and a cell therapy designed to address deficiencies in existing approaches and extend the curative power of bone marrow transplant to more patients across many diseases. Currently, only a fraction of eligible patients with these diseases receive a transplant because the risks and challenges outweigh the potential for a cure. These include diseases where bone marrow transplant is a standard of care (e.g., blood cancers such as acute myelogenous leukemia, myelodysplastic syndromes, multiple myeloma, and non-Hodgkin lymphoma), diseases where transplant is performed but limited in use (e.g., hemoglobinopathies such as sickle cell disease and beta-thalassemia), and autoimmune diseases. Emerging clinical data suggest that bone marrow transplant may represent a breakthrough approach with curative potential for patients with severe autoimmune diseases. For example, recent results from multiple clinical trials show that patients with autoimmune diseases, including multiple sclerosis and scleroderma, can be cured with a transplant. However, based on our epidemiology analyses, currently only approximately 1 to 2% of eligible patients with multiple sclerosis or scleroderma in the United States and Europe receive a bone marrow transplant.

To address the major unmet medical needs in the existing bone marrow transplant process, we are developing a stem cell biology discovery platform and comprehensive portfolio of novel therapeutics. Our programs will improve stem cell dose (expansion), stem cell collection (mobilization), patient preparation for transplant (conditioning) and potential post-transplant complications, to address key limitations of the bone marrow transplant process to allow more patients to benefit. Within our expansion program, MGTA-456, our most advanced clinical product candidate, is a cell therapy that has achieved clinical proof of concept in 36 patients with blood cancers and is now being studied in patients with fatal inherited metabolic diseases. MGTA-456 is an expanded cord blood product, and has the potential to allow more patients to have a better chance for a successful stem cell transplant. Within our mobilization program, MGTA-145 is focused on enabling physicians to more easily harvest a greater number of blood stem cells, known as hematopoietic stem cells or HSCs, from patients and donors to improve patient outcomes. Our targeted transplant conditioning programs, which prepare the patient for transplant, are designed to selectively remove stem and/or immune cells from a patient prior to transplant, and to be far less toxic than the decades-old radiation and chemotherapy-based approaches which are still the only available options. Our post-transplant complications program is designed to target the donor immune cells within the patient that cause Graft vs. Host Disease, or GvHD, which can be a fatal complication of transplant.

 

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We intend to become a fully integrated discovery, development and commercial company in the field of transplant medicine. We believe that our product portfolio will offer significant commercial synergies. We are developing our products so that they can each be used individually or in combination with each other. As a result, our portfolio could be utilized in a manner tailored to the patient’s disease, such that a patient may receive more than one Magenta therapy as part of their individual transplant journey.

Our goal is to have three clinical programs moving forward in multiple indications by 2020, with a rapidly advancing portfolio and sustainable platform.

Background on Bone Marrow Transplant

Bone marrow is the tissue inside the bones where HSCs are located. HSCs produce all of the cells in the blood and immune systems, including: T cells and B cells to fight infections; red blood cells to carry oxygen; and platelets to control bleeding. The bone marrow is highly active, and gives rise to billions of new cells every day. However, abnormal functioning of the system can lead to serious and sometimes fatal blood and immune diseases. The aim of bone marrow transplant, also called HSC transplant or stem cell transplant, is to replace the diseased blood and immune cells with new stem cells that will produce new blood and immune cells, thereby effectively resetting the blood and immune systems to a healthy state. Bone marrow transplant is a well-established procedure with curative intent, rooted in decades of clinical experience.

Starting from the first procedure in 1956, more than 1 million patients with blood cancers and genetic diseases worldwide have undergone a bone marrow transplant, and currently approximately 65,000 patients undergo the procedure annually. Bone marrow transplant serves as the standard of care in many blood cancers, such as leukemias, lymphomas and multiple myeloma; and for rare genetic diseases such as Hurler’s syndrome and is the only curative option for sickle cell disease.

However, bone marrow transplant is a complex procedure that carries significant risks, including serious complications such as infection, secondary cancers and even patient death. A majority of patients who could significantly benefit from or be cured by a transplant do not receive one primarily because of the toxicity and risks associated with the procedure. For example, primarily because of these risks, approximately two out of three eligible patients suffering from acute myeloid leukemia do not receive a transplant despite it being the standard of care. For debilitating but non-life-threatening diseases, such as sickle cell disease and multiple sclerosis, even fewer patients are offered and receive a transplant because the risks of the current transplant procedure often outweigh the potential benefits. There is a clear need to improve the safety and efficacy of transplant so that we can refocus the patient and physician conversation and bring the curative power of transplant to more patients.

Bone Marrow Transplant: The Process and Challenges

A bone marrow transplant procedure utilizes a number of integrated steps, which we highlight below: stem cell sourcing and collection, patient conditioning and stem cell infusion and engraftment. All transplants are categorized as either autologous or allogeneic, depending on the source of cells for the transplant. In an autologous transplant, used for conditions such as multiple myeloma, non-Hodgkin’s lymphoma and autoimmune diseases, the patient’s own stem cells are used. This is also the case for stem cell gene therapy. In an allogeneic transplant, used for conditions such as acute leukemia and genetic diseases, patients receive cells from a stem cell donor or umbilical cord blood.

Step 1: Stem Cell Sourcing and Collection

Once the patient and physician agree that bone marrow transplant is the best treatment option, first the source of stem cells must be identified and then the cells are collected. There are three sources of stem cells for transplant:

 

    extraction from the bone marrow, which requires a procedure performed under general anesthesia where cells are withdrawn directly from the bone marrow with needle aspirates;

 

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    mobilization into the peripheral blood, which requires several days of injections of a drug or combination of drugs to mobilize the cells, or move them from the bone marrow into the bloodstream, where they are then collected through a process called apheresis; and

 

    harvesting from umbilical cord blood units, which are stored in cord blood banks.

In the case of stem cell gene therapy, once the cells are collected from the patient, they are then modified to either insert a functioning gene or correct a defective gene.

Challenges

Finding a matched donor: For patients requiring an allogeneic transplant, the preferred source of stem cells is a donor from their family who has a well-matched immune system. For patients without a matched, related donor, the second option is a matched, unrelated donor identified through the bone marrow donor registry. Although there are more than 25 million registered bone marrow donors worldwide, nearly half of all patients are unable to find a matched donor. For patients without a matched donor, other options include mismatched donors, who can either be unrelated or related; however, transplant outcomes are not optimal with these donor types. For patients without a matched, related donor, umbilical cord blood also provides a potential source of stem cells. However, despite the utility of this approach, there are significant challenges with umbilical cord blood transplant. Even when patients find matched cord blood units, transplants are severely limited because there are often too few stem cells in the cord blood unit. Although more than 712,000 units are available in the worldwide cord blood inventory, current cell dose requirements mean that fewer than approximately 4% of these units contain enough stem cells for use in adult patients. Because so few units are suitable for use in adult patients, the patient is less likely to find a closely matched cord blood unit, leading to less than optimal transplant outcomes.

Stem cell collection: It is critical that physicians obtain enough stem cells for the transplant, whether from a patient or a donor, as higher cell doses are closely correlated to better patient outcomes. In some cases, multiple invasive bone marrow harvests are needed to obtain an adequate number of stem cells. The autologous transplant field has moved away from bone marrow harvest to stem cell mobilization in recent years due to the difficulty of the procedure for both patients and physicians. In the case of stem cell mobilization, current treatments involve repeated injections and are often associated with bone pain, nausea, headache, and fatigue. Another challenge associated with current mobilization approaches is the difficulty of predicting whether mobilization will be successful, especially in heavily treated blood cancer patients. In fact, most patients require multiple days of apheresis and some patients require more than one mobilization procedure to obtain a sufficient number of cells for transplant. Additionally, mobilization failure rates for autologous transplants are as high as 40%. Given that mobilized peripheral blood is the predominant source of stem cells for transplant, there is a need for better HSC mobilization agents.

Step 2: Conditioning

Once sufficient cells have been obtained, the patient is then conditioned for transplant using systemic, toxic chemotherapy and/or radiation. Depending on the disease and type of transplant, the conditioning treatment is intended to remove or deplete:

 

    existing stem cells in the bone marrow to provide space for the incoming stem cells;

 

    immune cells (T cells and B cells) to prevent rejection of the incoming cells or remove disease-causing autoimmune cells; and/or

 

    cancer cells to prevent disease relapse in patients with blood cancers.

Challenges

Conditioning toxicity: Bone marrow transplant conditioning is very burdensome and risky for both pediatric and adult patients. Conditioning treatments today are typically non-targeted and involve systemic, toxic

 

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chemotherapy and/or radiation. Most of these genotoxic chemotherapy agents, including derivatives of mustard gas, were discovered more than 50 years ago, and were never intended for bone marrow transplant conditioning. The current treatments eradicate the stem and immune cells and diseased cells but also indiscriminately damage DNA and kill normal, healthy cells in the body, which can lead to severe infections, organ failure, infertility, secondary cancers and even death. Nearly all transplant patients experience complications as a result of current conditioning treatments, and conditioning toxicity is responsible for up to 35% of mortality following allogeneic transplants. The side effects and mortality risk of conditioning are among the major barriers preventing bone marrow transplants from being performed more widely in other diseases where they may be curative. Efforts to reduce chemotherapy doses have met with some success, but the most commonly used conditioning regimens all involve the use of genotoxic agents.

Step 3: Stem Cell Infusion and Engraftment

Once conditioning is complete, the stem cells are infused into the patient via the bloodstream. The cells travel to the bone marrow and engraft there, meaning they lodge in the bone marrow and begin to make new blood and immune cells. Once the bone marrow has made enough blood cells – particularly white blood cells to fight infection – which typically takes several weeks, the patient can be discharged from the hospital. There are instances where the stem cells do not engraft or are rejected by the patient’s body, leading to prolonged hospitalization and the need for an additional transplant. Outcomes of additional transplants are typically very poor.

Challenges

Transplant rejection: A major complication of stem cell transplant is when the infused stem cells are rejected by the patient’s body. Rejection is a particular problem where stem cell doses are low, for example with cord blood transplants.

Delayed engraftment: Depending on the dose of stem cells infused, engraftment can take between two to six weeks. During this period, patients are required to be in specialized isolation rooms at the hospital and are susceptible to infections.

Graft vs. Host Disease: GvHD is a reaction that commonly develops after an allogeneic bone marrow transplant and is a result of the donor immune cells recognizing the patient’s cells as foreign and attacking them. Acute GvHD typically occurs within weeks of a patient receiving a bone marrow transplant and can severely damage the skin, liver, and gastrointestinal system. GvHD accounts for approximately 10% of deaths following allogeneic transplant.

 

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Transplant Patient Journey

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Our Solutions

We are applying our expertise in stem cell biology and biotherapeutics discovery to bring innovative, modern medicines to the transplant field through our programs, specifically designed to address each of the key challenges of the bone marrow transplant journey for patients:

 

    Stem cell source and engraftment challenges (expansion programs): Our stem cell expansion programs are focused on generating higher cell doses, which have been shown to improve the speed and success of engraftment in bone marrow transplant. Through the cord blood expansion process, our MGTA-456 product candidate also has the potential to allow more patients to access better matched cord blood units that were previously not available due to low cell dose. Our AHR antagonist, E478, uses the same mechanism applied to make MGTA-456 to expand gene-modified HSCs for gene therapy and genome editing.

 

    Stem cell mobilization (mobilization program): Our stem cell mobilization program is focused on enabling physicians to more easily collect larger numbers of high-quality HSCs from patients and donors to yield higher cell doses for transplant.

 

    Conditioning toxicity (targeted conditioning programs): Our targeted transplant conditioning programs are designed to selectively eliminate stem and/or immune cells from a patient prior to transplant, and to be far less toxic than the current radiation and chemotherapy-based treatments. These programs focus on developing targeted products that deplete specific cell types, with an approach that is tailored to the patient’s disease and designed to be less toxic than the current chemotherapy-based treatments.

 

    GvHD (post-transplant complications program): Our post-transplant program is designed to target the donor immune cells within the patient that cause GvHD, potentially reducing the occurrence of GvHD without sacrificing the benefits of an allogeneic transplant, broadening access to the curative potential of transplant.

Our Current Programs

We are developing a pipeline of small molecules; biologics, including antibody drug conjugates; and a cell therapy, which we believe can meaningfully improve and expand curative bone marrow transplant options for many more patients with autoimmune diseases, blood cancers and genetic diseases. Our portfolio of novel

 

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medicines for transplant has the potential to allow more patients with debilitating or life-threatening diseases to access a one-time, transformative bone marrow transplant with better outcomes, less toxicity risk and less mortality risk. We are developing our product candidates so that they can each be used individually or in combination with each other, such that a patient may receive more than one Magenta therapy as part of their individual transplant journey. In addition to our first set of clinical and preclinical product candidates, we are in the process of identifying several other potential candidates from our discovery programs as shown in the below chart. The first of the two charts below summarizes our current preclinical development programs, where product candidates have not yet been identified. The second chart highlights the status of our IND-enabling-stage and clinical-stage product candidates. Our goal is to have three distinct clinical programs in multiple indications by 2020 with a series of data read-outs.

Our Preclinical Development Programs

 

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* To be developed in partnership for E478-expanded gene therapies
** Development candidate to be identified

Our IND-Enabling and Clinical-Stage Product Candidates

 

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C100, C200, C300: targeted antibody-drug conjugates for conditioning

We are developing a suite of novel antibody-drug conjugates, or ADCs, for transplant conditioning, a step in the transplant process that is still dominated by the use of systemic chemotherapy agents and radiation. We are seeking to replace these non-targeted toxic conditioning agents with targeted ADCs. These drugs are designed for transplant and specifically deplete only the cell types required to be eliminated in order to perform a successful transplant. Certain ADCs are currently used to treat cancer by directing a toxin to specific cells using antibodies. Our programs are adapting this clinically validated modality for conditioning patients for bone marrow transplant.

 

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All of our conditioning programs share an ADC platform but differ in the targeted cell types. The C100 program targets HSCs, immune cells, and disease-causing cells, the C200 program targets HSCs and disease-causing cells and the C300 program targets only immune cells. This is achieved by tuning the antibodies to specific cellular markers or receptors that are expressed on the particular cell types.

 

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Our most advanced conditioning program, C200, is designed to specifically deplete HSCs and disease-causing cells. Our lead ADC product candidate targets CD117, also known as c-Kit, which is highly expressed on HSCs and leukemia cells, making it an ideal target for conditioning across broad sets of diseases. This includes blood cancers as well as hemoglobinopathies like sickle cell disease and beta-thalassemia, with potential applicability in both bone marrow transplant and stem cell gene therapy. At the American Society of Hematology, or ASH, annual meeting in December 2017, we presented data showing that a single dose of CD117-ADC depleted more than 90% of human HSCs in the bone marrow of humanized NSG (immunodeficient) mice and was well tolerated over the entire 21-day study. Preliminary data suggest that a single dose of CD117-ADC is also effective at significantly reducing tumor burden and conferring survival benefits in mice challenged with CD117-expressing acute myelogenous leukemia cells. Our antibodies are designed to also recognize the target antigen in non-human primates, which gives us the opportunity to evaluate efficacy and safety in non-human primates prior to conducting human clinical trials. We are currently studying CD117-ADC in non-human primates and expect to submit primate proof of concept data for presentation at a medical meeting in late 2018.

The second conditioning program in our portfolio is C100, under which we are developing ADCs that specifically deplete host HSCs and immune cells. Within our C100 program, our lead target is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune systems. We are currently in the lead identification stage for this program and intend to declare a development candidate in 2019. We plan to develop C100 for use in patients with CD45-expressing leukemias and lymphomas, followed by patients with autoimmune diseases such as multiple sclerosis and scleroderma.

Our third ADC-based conditioning program, C300, targets T cells, a type of immune cell. T cell depletion is currently performed with highly toxic, non-specific drugs which can lead to immune deficiency, infections and other complications including secondary autoimmune reactions. We are pursuing targets expressed on the surfaces of T cells with the goal of offering a safer and more optimized targeted conditioning approach through T cell depletion before CAR T therapy for blood cancers, prevention of stem cell rejection prior to allogeneic bone marrow transplant or achievement of immune system reset before autologous bone marrow transplant in autoimmune disease patients.

MGTA-145: CXCR2 agonist combined with plerixafor for HSC mobilization

MGTA-145 is a novel stem cell mobilization product candidate that was developed based on our understanding of the physiological mechanisms that control stem cell mobilization. The goal of MGTA-145 is to achieve high levels of stem cell mobilization in patients and donors in order to replace the current standard of care, a drug known as granulocyte colony-stimulating factor, or G-CSF. G-CSF is a glycoprotein that mobilizes stem cells indirectly and comes with limitations that include a prolonged treatment period of up to one week of injections, lack of efficacy in some patients, and significant bone pain. MGTA-145 is a CXCR2 agonist protein that activates neutrophils to release proteases that cause the release of HSCs into the blood. This novel mechanism of

 

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action is complementary to that of plerixafor, another commonly used mobilization agent marketed by Sanofi. Plerixafor acts as a small molecule CXCR4 antagonist, blocking a pathway that otherwise plays an essential role in attracting and retaining HSCs in the bone marrow. The combination of MGTA-145 and plerixafor leads to a synergistic, robust and rapid stem cell mobilization, which was highlighted in recent data we presented at the ASH annual meeting in December 2017. Based on these results, we have initiated IND-enabling studies of MGTA-145 in combination with plerixafor and expect to file an Investigational New Drug Application, or IND, with the U.S. Food and Drug Administration, or FDA, for this product candidate in 2019. We plan to develop MGTA-145 for mobilization first in patients with multiple myeloma and non-Hodgkin lymphoma, followed by healthy donors for allogeneic transplant. We plan to further investigate MGTA-145 in patient populations where G-CSF can exacerbate the disease, such as autoimmune diseases, and patient populations where G-CSF is contra-indicated, such as sickle cell disease.

MGTA-456: aryl hydrocarbon receptor (AHR) antagonist expanded stem cells

Our most advanced product candidate, MGTA-456, is a novel proprietary allogeneic stem cell therapy that was developed based on our understanding of the mechanisms that control stem cell growth. The goal of MGTA-456 is to extend the use of cord blood transplant to more patients by generating a higher stem cell dose. This is done by expanding a single umbilical cord blood unit ex vivo with a small molecule AHR antagonist. AHR antagonism is a novel, well-studied and clinically validated pathway that controls the self-renewal and differentiation of human HSCs. We have applied this technology to increase the number of HSCs present in an umbilical cord blood unit to extend the use of umbilical cord blood as a stem cell source for transplant. In addition, MGTA-456 also has the potential to improve overall survival by allowing more patients to have access to better matched cord blood units, which is associated with better outcomes and lower rates of post-transplant complications.

MGTA-456 has achieved human proof-of-concept in a Phase I/II study in patients with blood cancers. Data from the study showed that the median expansion of stem cells from the original cord blood unit was 330-fold, and all 36 patients treated with MGTA-456 in the study successfully achieved engraftment of these expanded stem cells. The rapid and robust engraftment of MGTA-456 in patients with blood cancers suggests that MGTA-456 may also improve engraftment in other patients in whom engraftment failure is a potential problem. For example, a group of diseases where cord blood transplant is increasingly used is inherited metabolic diseases, which typically affect infants and young children. Although transplant can be curative in these diseases, between approximately 20 to 30% of patients with inherited metabolic diseases treated with transplant experience engraftment failure, resulting in severe complications, including death. We believe the high number of HSCs present in MGTA-456 should speed engraftment, reduce or eliminate engraftment failure and improve patient outcomes.

We have initiated a Phase II study of MGTA-456 in patients with inherited metabolic diseases and intend to explore other debilitating diseases where we believe MGTA-456 could bring transformative benefit to patients. We expect to report initial data from our Phase II study in late 2018. If the results from this trial are favorable, we plan to initiate a Phase III trial in 2019. We also intend to initiate a Phase II study of MGTA-456 in patients with sickle cell disease in early 2019. On April 11, 2018, we received orphan drug designation from the FDA for MGTA-456 for the enhancement of cell engraftment in patients receiving bone marrow transplant.

We are the sponsor of the IND for MGTA-456 in inherited metabolic diseases. The IND was originally filed by Novartis International Pharmaceutical Ltd., or Novartis, on November 6, 2015 and formally transferred to us on July 25, 2017. The IND is active and up to date with reporting requirements, such as annual reports.

We obtained the rights to MGTA-456 through an April 2017 license agreement with Novartis granting us the sole worldwide rights to research, develop and commercialize certain AHR antagonist compounds specifically for the expansion of cord blood-derived non-gene-edited/-modified HSCs. See “Licenses and Collaborations” section.

 

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E478: AHR antagonist for expansion of gene-modified stem cells

E478 is a novel and proprietary small molecule AHR antagonist that was developed to increase the number of gene-modified HSCs ex vivo for stem cell based-gene therapy. Gene therapy, or bone marrow transplant with gene-modified or genome-edited cells, is a promising treatment approach for several diseases. However, this approach is significantly limited by the inability to generate a sufficient dose of gene-modified HSCs that retain the ability to engraft in patients as well as the cost and complexity of manufacturing viral vectors for gene modification of cells. These constraints could limit the commercial viability of this approach. E478 uses the same clinically validated mechanism as MGTA-456 to expand gene-modified HSCs. In addition to addressing cell dose limitations, the ability to expand long-term repopulating HSCs ex vivo has the potential to reduce manufacturing costs for these therapies by requiring less viral vector for gene modification of the stem cells. At the ASH annual meeting in December 2017, we presented data showing that culturing gene-modified human HSCs with E478 increased the number of gene-modified stem cells that retained engraftment ability in preclinical models. We are developing E478 specifically to partner with gene therapy and genome editing companies. E478 would be integrated into our potential partners’ cell-based products leading to a newly defined cell therapy.

G100: ADC program for prevention of acute GvHD

We are developing a unique approach to preventing acute GvHD, a major complication and a leading cause of death in allogeneic transplantation. GvHD occurs when alloreactive T cells in the donor stem cell graft recognize the patient as foreign and attack their tissues. Current treatments for acute GvHD prevention include the prophylactic use of non-specific immune suppressive agents. The use of high doses of non-specific immune suppressive agents for GvHD treatment is correlated with an increased risk of infection and poor immune function, and despite the use of these powerful immune suppressive agents, approximately 50 to 80% of allogeneic transplant patients will experience acute GvHD. Our G100 program is designed to selectively eliminate only the components of the graft that cause acute GvHD, specifically the alloreactive T cells. This ADC therapy is intended to be dosed in vivo at the time of transplant. By specifically targeting the alloreactive T cells that arise shortly after transplant, this therapy should spare the remainder of the patient’s immune system to allow immune recovery and protection from infections.

Our Strategy

Our mission and our culture are centered around the goal of enabling more patients with severe or life-threatening diseases to have access to the transformative benefit of a bone marrow transplant. We intend to provide physicians with a tailored, multi-product treatment regimen based on the disease setting and the individual needs of each patient. Our strategic priorities are as follows:

Bring the curative power of bone marrow transplant to all patients who can benefit by advancing an integrated product portfolio: We believe we are the only company that is committed to addressing the major limitations and challenges of bone marrow transplant to revolutionize this entire field of medicine. Our product engine is generating a comprehensive portfolio of therapies to optimize the bone marrow transplant process. Our initial focus is on inherited genetic diseases, blood cancers and autoimmune diseases, and we also plan to address other diseases for which transplant could represent a one-time, curative treatment.

Build on our deep expertise in stem cell biology to lead a new era in transplant medicine: We have assembled a group of world leaders and pioneers in the fields of stem cell biology, biotherapeutics and transplant medicine. With this team, we are converting recent scientific breakthroughs into a product engine for bone marrow transplant therapies.

Create a fully integrated patient-focused biotechnology company: We are building a fully integrated biotechnology company with end-to-end capabilities in research, development and commercialization, and we believe the broad and synergistic nature of our portfolio will allow us to address many of the significant limitations of bone marrow transplant.

 

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Commercialize our therapeutics to bring tailored transplant solutions to physicians and patients: We are developing our portfolio of products so that they can be used individually or in combination with each other, such that a patient may receive more than one Magenta therapy as part of their individual patient journey. Our commercial model centers around hospital-based prescribers, and this is consistent across all of the products in our portfolio. Bone marrow transplants are performed in a few hundred accredited medical centers in the U.S. and Europe, with more than half of the U.S. procedures performed at the top 20% of transplant centers. We believe the synergies among our programs and the well-defined structure of the current bone marrow transplant provider network will allow us to commercialize all of our own therapeutics in the U.S. and Europe through a focused, targeted commercial organization.

Leverage our most advanced product candidate, MGTA-456, as a clinical catalyst and commercial beachhead for our portfolio: We obtained the rights to MGTA-456, a clinical program currently in Phase II studies, through an April 2017 license agreement with Novartis. In addition to its potential to bring meaningful clinical benefit to patients, MGTA-456 provides strategic value to Magenta by allowing us to accelerate the build-out of our clinical development infrastructure and footprint and to establish key customer relationships that will be important for future commercialization of our products.

Continue to integrate our innovative collaboration with Be The Match with our science, medicine and business approaches: Be The Match is a leading patient-focused bone marrow transplant organization in the U.S. Because of our shared patient focus, we and Be The Match have established a broad, first-of-its-kind collaboration. This collaboration positions us as a partner with high-priority access to many services that will continue to enable us to establish relationships across transplant centers and with key transplant physicians. Through our partnership, we access clinical strategy support; clinical development operational support, including a unique cell supply platform that is very well established at Be The Match and which will also enable our commercialization efforts across several programs. We also have access to the Be The Match payer and policy group to support our pricing and reimbursement plans across the portfolio.

Strategically collaborate to realize the full potential of our portfolio: We currently retain 100% of the commercial rights for our products. We will evaluate additional collaborations to:

 

    maximize the patient impact of our portfolio by partnering to enable cell therapies, including stem cell-based gene therapies, genome editing and CAR T therapy;

 

    build relationships with partners to access complementary expertise and capabilities to bring our therapies as quickly as possible to all patients who can benefit; and

 

    opportunistically bring in preclinical or clinical assets that fit with our integrated portfolio.

 

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The chart below illustrates the synergistic nature of our portfolio of products, with examples of how our products could be used in combination to create disease-tailored solutions for patients.

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Background on Our Current Programs

 

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Conditioning Programs

Unmet need

For patients undergoing bone marrow transplant, the toxicity and mortality associated with current conditioning protocols are significant challenges and prevent more patients from benefitting from a life-saving and potentially curative transplant procedure. In many diseases, physicians have needed to use the most aggressive conditioning regimens to generate the best efficacy outcomes for transplant.

Conditioning treatments today are typically non-targeted and involve high doses of radiation and/or toxic chemotherapy. These chemotherapy agents, including derivatives of mustard gas, were discovered more than 50 years ago and were never intended for bone marrow transplant conditioning. The current treatments eradicate the stem and immune cells and diseased cells but also indiscriminately damage the DNA and kill normal, healthy cells in the body. These conditioning regimens can cause nausea and vomiting, mucositis, alopecia, acute and long term lung injury and liver toxicity, serious infections, organ failure, secondary cancers and even death. Nearly all transplant patients experience complications as a result of current conditioning treatments, and conditioning toxicity is responsible for up to 35% of mortality following allogeneic transplants.

Emerging clinical data have shown that we are now at a stage where autoimmune disease can be cured with a transplant, with recent data in multiple sclerosis and scleroderma. However, the toxicity of the required conditioning regimens has historically led many physicians to conclude that the risks of transplant in these patient populations far outweigh the benefits. A pair of comprehensive reviews published in 2017 in Nature journals summarized the clinical transplant results in multiple sclerosis and broader rheumatic autoimmune diseases. The main conclusions from this combined experience in over 3000 patients during the past 20 years were that the therapeutic benefit of stem cell transplant is significant across multiple studies in severe autoimmune diseases: Relapsing remitting multiple sclerosis, or RRMS, (five Phase II trials) and systemic sclerosis (two Phase II trials and two randomized trials) have the most clinical evidence using stringent disease

 

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endpoints. When compared to the standard of care in RRMS, certain studies have shown that the proportion of patients with clinical benefit at two years appears to be double that of the next best treatment. Another study showed complete long-term suppression of all inflammatory activity in a cohort of patients with active and progressing multiple sclerosis who received a bone marrow transplant. Given bone marrow transplant’s ability to durably eliminate relapses and disease activity in multiple sclerosis patients, we believe a safer transplant procedure would be a viable option for those patients with highly active disease beyond what therapeutics can manage. However, currently only approximately 1 to 2% of eligible patients with multiple sclerosis and scleroderma in the U.S. and Europe receive a bone marrow transplant primarily because the risk of the procedure outweighs the benefits of a potential cure. We believe we can significantly expand the number of autoimmune patients who can benefit from transplant.

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Timeline of clinical relapses. Each line represents a patient treated in the study. The lines continue until the latest follow-up assessment, death (cross), or censoring because the patient received a conventional, experimental, or unproven treatment (star). The lines begin at diagnosis of multiple sclerosis, inverted triangles denote a clinical relapse.

Our solution

We are developing a suite of novel ADCs for transplant conditioning. We are seeking to replace the current non-targeted toxic conditioning agents with targeted ADCs designed for transplant that specifically deplete only the cell types required to be eliminated in order to perform a successful transplant. While ADCs are an established treatment for certain cancers, we believe this is the first time that ADC technology has been harnessed for transplant medicine. These programs have the potential to expand the curative power of transplant beyond the eligible patient populations to patients who cannot tolerate current conditioning regimens, and to patients with autoimmune diseases, such as multiple sclerosis, where the current risk-benefit of transplant is not considered favorable due to the toxicity of the existing conditioning regimens.

ADCs are a technology developed over the past 20 years where a monoclonal antibody specific for a cell surface protein is coupled to a drug. The ADC binds the receptor on the target cell, is internalized and degraded to release the drug into the target cell. Coupling the drug to the antibody increases the specificity of drug delivery to the target cell, reducing systemic exposure and increasing the safety and efficacy compared to delivering the drug alone or the antibody without the drug attached. Today most ADCs are directed toward treating cancer cells expressing specific target receptors enriched on tumor cells. Our programs build on this clinically validated modality and adapt it for conditioning patients for bone marrow transplant.

 

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Targeted conditioning is more specific compared to traditional conditioning. Traditional conditioning is performed with total body irradiation and chemotherapy which eliminates all hematopoietic cells and nonspecifically damages other organs. Targeted conditioning with an antibody drug conjugate specifically eliminates the hematopoietic stem cells while sparing the immune system and avoiding systemic side effects.

In our development of ADCs for use in conditioning, we are optimizing for several key parameters:

 

    First, the antibody must specifically target a receptor that is expressed on the cells of interest, but not on other cell types.

 

    Second, to comply with typical bone marrow transplant conditioning timelines, the antibody must have suitable efficacy to ensure that the ADC is able to kill the target cells rapidly, in days rather than weeks or months.

 

    Third, the antibody clearance needs to be accelerated so that it is eliminated by the time the transplanted cells are infused into the patient, typically within a week of starting conditioning. This requirement stems from the fact that the target receptor is expressed on cells present in the patient but also on the similar cell types in the transplanted cells.

 

    Finally, the linker-drug must be able to kill non-dividing cells as most HSC and immune cells are not actively dividing. The ADC linker must be chosen to minimize damage to non-target cells.

We are addressing each of these requirements through careful selection of the appropriate target receptor as well as antibody properties, including binding site, affinity, half-life and linker toxin.

We are developing three distinct programs for bone marrow conditioning that specifically deplete the particular cells that need to be removed to make room for the incoming cells. These programs share a common platform but differ in the cell types targeted: The C100 program targets HSCs, immune cells and disease-causing cells, the C200 program targets HSCs and disease-causing cells and the C300 program targets only immune cells. The lead antigen targets for C100 and C200 and potential applications for each program are listed in the table below.

 

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C200 program

Our most advanced conditioning program, C200, is designed to specifically deplete HSCs and disease-causing cells. Our lead ADC product candidate targets CD117, also known as c-Kit, which is expressed on HSCs, making it an ideal target for conditioning across broad sets of diseases. This includes blood cancers, hemoglobinopathies (sickle cell and beta-thalassemia), and inherited metabolic diseases, with potential applicability in both bone marrow transplant and HSC based gene therapy.

We are currently evaluating several key parameters to develop and optimize our CD117-ADCs for the C200 program. This includes investigating different toxins, methods of attaching the toxin to the antibody, the number of toxin molecules per antibody and modifications to the antibody that impact binding site and target affinity, half-life and interactions with other antibody binding proteins. The antibody components of our ADCs are designed to also recognize the target antigen in humans and non-human primates and deliver the toxin to target cells. This selectivity provides the opportunity to evaluate and optimize the efficacy and safety during preclinical studies in both mice bearing a human immune system and non-human primates prior to conducting human clinical trials. We are currently studying probe CD117-ADC molecules in mice and non-human primates and have seen encouraging preliminary data. The results using these probe CD117-ADCs are establishing proof of mechanism for the ability of CD117-ADC to selectively deplete HSCs, provide an early look at safety and tolerability and establish these critical preclinical mouse and non-human primate models to guide the further development of our C200 program.

Preclinical pharmacology studies

To investigate the potential of CD117-ADC to kill human HSCs in vivo, we performed studies using immunodeficient NSG mice that have been engrafted with human HSCs, a commonly used preclinical model to study human HSC biology. At the joint annual meetings of the American Society of Bone Marrow Transplant and the Center for International Blood and Marrow Transplant Research, or CIBMTR, and collectively, Tandem, in February 2018, we presented data showing that a single dose of CD117-ADC can deplete human HSCs in vivo. For this experiment, human engrafted mice were treated with a single dose ranging from 0.03 to 1 mg/kg of body weight of CD117-ADC or a variant of CD117-ADC modified to have a reduced half-life. Controls included mice that were untreated or treated with 1 mg/kg of an Isotype-ADC or unconjugated CD117 antibody. Analysis of human cell numbers in the blood of these mice showed a marked and stable reduction of HSC-derived CD33+ myeloid cells in mice treated with either variant of the CD117-ADC at doses of 0.1 mg/kg or higher, while lymphoid cells, including T cells, were unaffected. We believe this reflects the specificity of the CD117 antibody for HSCs and the rapid turnover of human CD33+ cells in this system due to engulfment by mouse-derived phagocytes and the lack of CD117 expression on lymphoid cells. The depletion of CD33+ myeloid cells was an on-target, toxin-dependent effect because the effect was not observed with the Isotype-ADC or unconjugated CD117 antibody. To confirm that the CD117-ADC can deplete human HSCs, the mice were euthanized three weeks after treatment and HSCs were enumerated in the bone marrow by flow cytometry. This analysis showed that both variants of CD117-ADC eliminated more than 95% of human CD34+ cells, at doses of 0.1 mg/kg or higher, while unconjugated CD117 antibody or Isotype-ADC had no impact on CD34+ numbers.

 

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CD117-ADC selectively depletes human HSCs in humanized NSG mice. (A) Schematic of the in vivo model. CD117-ADC or controls were dosed on day 0. Peripheral blood mononuclear cells (PBMCs) and bone marrow were collected on day 21 and examined by flow cytometry. (B) The absolute number of CD34+ cells in the bone marrow of CD117-ADC or control treated mice. (C) Percent of human myeloid, T cells, and B cells present in the peripheral blood of CD117-ADC or control treated mice, expressed as a percent of that cell population prior to treatment (normalized to baseline).

Based on these positive findings in humanized mice, we have commenced a series of studies designed to evaluate key parameters of our C200-ADCs in non-human primates with the intent of optimizing the final development candidate across these parameters.

 

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The initial study tested the ability of a probe CD117-ADC to deplete HSCs in non-human primates. This proof-of-mechanism study was designed as a single-dose escalation study to determine at what dose, if any, CD117-ADC would result in HSC depletion. According to the study design, successful HSC depletion with the ADC was expected to cause hematopoietic failure as it was not planned for these animals to undergo a subsequent bone marrow transplant to replenish the depleted HSCs.

The study showed significant (>95%) dose-dependent HSC depletion in the bone marrow six days after treatment with the probe CD117-ADC at doses greater than 0.3 mg/kg. In contrast, treatment with an unconjugated CD117 antibody or a control ADC not targeted to CD117 did not have a significant impact on HSC numbers in the bone marrow.

Hematopoietic Stem and Progenitor

Cell Number in Bone Marrow at Day 6

 

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HSC numbers in the bone marrow six days following a single dose of CD117-ADC or unconjugated CD117 antibody (CD117) or non-targeted ADC (IgG1-ADC). The dots represent individual animals and the bars represent the mean for each group. The percent of HSC depletion relative to control animals treated with phosphate buffered saline (PBS) is noted. Statistical significance was determined using analysis of variance (ANOVA). ANOVA is a collection of statistical models and their associated procedures (such as “variation” among and between groups) used to analyze the differences among group means. p-value is a conventional statistical method for measuring the statistical significance of experimental results. A p-value of less than 0.05 is generally considered to represent statistical significance, meaning that there is a less than five percent likelihood that the observed results occurred by chance.

In addition, this first study was designed to provide preliminary safety data to guide the development of our ADC platform. The preliminary findings revealed transient dose-dependent elevation of liver enzymes in the groups treated with a non-targeted ADC and the highest doses of CD117-ADC. In addition, of the 12 non-human primates treated with the probe CD117-ADC, one treated at the highest dose level was euthanized after receiving scheduled pain medication before a planned bone marrow aspiration. Moreover, one non-human primate treated with CD117-ADC in each of the two highest dose groups showed the anticipated signs of bone marrow failure resulting from HSC depletion and was euthanized prior to the end of the study.

 

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We next initiated a second dose-escalation study in non-human primates, with a CD117-ADC probe compound engineered to have a shorter half-life and a lower number of drugs per antibody (two, compared with the average of four with the probe compound used in the previous study). This ongoing study is intended to achieve HSC depletion with short half-life antibodies, identify the maximum tolerated dose of the probe and evaluate HSC depletion based on multi-dosing regimens.

The first phase of the study was a single-dose escalation, and three dose levels were tested. The two lower doses achieved substantial HSC depletion and were well tolerated. At the highest of the three dose levels tested, one of the three non-human primates experienced a decrease in body temperature and showed elevated liver enzymes; this animal was subsequently euthanized. The other animals in this dose group remain on study. The second multi-dosing phase of the study is continuing as designed. Preliminary data demonstrated that the first multi-dose was well tolerated, and it achieved significant depletion of target cells in the blood and in the bone marrow.

We believe these studies are the first to show that a probe CD117-ADC can deplete HSCs in non-human primates. These data validate the non-human primate as a suitable model for efficacy and tolerability to guide the further development of our other ADCs in the C200 program.

We expect to submit non-human primate data on our C200 program, including the results of the studies described above, for presentation at future medical meetings.

 

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Anti-tumor activity of CD117-ADC

In addition to its expressions on HSCs, CD117 is also frequently overexpressed on tumor cells in patients with acute myeloid leukemia and myelodysplastic syndromes. Thus, the CD117-ADC has the potential to reduce tumor burden in patients with CD117-expressing tumors. In data presented at the joint annual meetings of the American Society of Bone Marrow Transplant and the Center for International Blood and Marrow Transplant Research, or CIBMTR, and collectively, Tandem, in February 2018, we showed that CD117-ADC was effective at killing human HSCs cultured in vitro and was also highly potent at killing the human acute myeloid leukemia cell line Kasumi-1. To extend these data, we also assessed the ability of CD117-ADC to reduce tumor burden and confer a survival benefit in mice bearing Kasumi-1 cells. For this study, mice were inoculated with a lethal dose of the Kasumi-1 cells and left either untreated or treated with CD117-ADC or unconjugated CD117 antibody seven days after tumor inoculation. Tumor-bearing mice treated with a single dose of CD117-ADC showed significantly improved survival compared to mice left untreated or those treated with unconjugated CD117 antibody. Treatment at 42 days after tumor inoculation, a time when untreated mice are showing overt signs of tumor toxicity, also led to improved survival with CD117-ADC, compared to mice that were untreated or treated with unconjugated CD117 antibody. These data suggest that CD117-ADC may have utility to treat leukemias through a direct cytotoxic effect on CD117-expressing tumors.

 

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CD117-ADC effectively depletes human leukemic cells in NSG mice. (A) Schematic of in vivo leukemia model. Kasumi-1 cells were injected into NSG mice to serve as human cell line model of acute myeloid leukemia. A single injection of 0.3 mg/kg anti-CD117 ADC or anti-CD117 antibody occurred on (B) day 7 or (C) day 42 to assess the impact of tumor burden on efficacy. Survival curves of mice after tumor injection are shown.

The targeted conditioning and potential for disease control offered by CD117-ADC may extend bone marrow transplant to additional leukemia patients and improve outcomes. This is especially important as acute myeloid leukemia and myelodysplastic syndromes represent areas of high medical need. Current treatment for patients with high-risk acute myeloid leukemia or myelodysplastic syndromes involves chemotherapy to induce disease remission followed by allogeneic bone marrow transplant. However, many patients are unable to achieve disease remission using current chemotherapy agents, rendering them ineligible for allogeneic transplant. Moreover, in the approximately 35% of eligible patients with acute myeloid leukemia and myelodysplastic syndrome that do receive a transplant, outcomes remain suboptimal with only 50% survival five years after transplant. In addition, many patients have co-morbidities such as increased age or decreased organ function that necessitate the use of a reduced intensity of conditioning which leads to higher rates of disease relapse. Because acute myeloid leukemia and myelodysplastic syndromes are increasingly seen in older patients, many patients are often deemed too frail to undergo a transplant, leaving them with limited treatment options. The anti-leukemia activity of CD117-ADC has the potential to reduce disease burden and improve outcomes for patients with CD117 expressing tumors, and allow relapsed/refractory patients with CD117-expressing tumors to have access to a bone marrow transplant.

Clinical development plans

Given the ability of CD117-ADC to deplete HSCs and CD117-expressing leukemia cells shown in our preclinical data, we intend to pursue a development plan for patients with acute myeloid leukemia and myelodysplastic syndromes. Once we have established a safe and effective dose in that study, we plan to explore multiple indications, including elderly patients with acute myeloid leukemia or myelodysplastic syndromes who are too frail to tolerate current conditioning protocols. The study would be designed to focus on single dose rising efficacy and safety. The studies’ endpoints may include safety/tolerability, HSC depletion, and relapse prevention.

Approximately 47,000 patients in the U.S. and Europe are diagnosed with acute myeloid leukemia every year. Of those patients, about 60% achieve remission with chemotherapy agents and are eligible for transplant. However, of these, only approximately 30 to 40% actually receive a transplant. This is largely due to the toxicity risk associated with current conditioning protocols. We believe our conditioning agents would allow more patients to achieve remission and become eligible for transplant.

Approximately 34,300 patients in the U.S. and Europe are diagnosed with myelodysplastic syndromes every year. Of those patients, about 30% are eligible for transplant based on high risk disease. However, of these patients, only approximately 16 to 40% actually receive a transplant. This is largely due to the toxicity risk associated with current conditioning protocols. We believe our conditioning agents would allow more patients to achieve remission and become eligible for transplant.

We will also explore CD117-ADC in patients with non-malignant diseases, such as sickle cell disease, including those who are undergoing transplant with gene-modified stem cells.

C100 program

Other ADC-based conditioning programs in our portfolio include C100, a conditioning program with a profile that specifically depletes host HSCs and immune cells. Within our C100 program, our lead target is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune system. We are currently in the lead identification stage for this program and intend to declare a development candidate in 2019.

 

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C100-targeting HSC and immune cells

For many applications of HSC transplant, it is important to eliminate both immune cells and HSCs in the patient prior to transplant. This is especially important in the allogeneic setting where host immune cells can elicit an immune-mediated rejection of the incoming foreign stem cells. In addition, immune cell depletion is a key feature of the use of autologous transplant for the treatment of severe autoimmune disease. In this case, the goal is to eliminate the pathogenic auto-reactive immune cells that perpetuate the underlying autoimmune disease. Lastly, for patients with tumors expressing CD45, there may also be a direct anti-tumor effect providing additional therapeutic benefit. For these reasons, we are developing therapeutics that simultaneously target both HSCs and immune cells.

Pioneering work from Magenta founding scientists demonstrates that HSCs can be successfully targeted using a CD45-ADC to facilitate syngeneic transplant and allow for transplant-mediated cure of a mouse model of sickle cell disease. Importantly, CD45-ADC-treated mice show greatly reduced levels of organ damage and faster immune cell reconstitution and infection control compared to mice conditioned using radiation.

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Source: Palchaudhuri et. al., Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nature (2016).

CD45–SAP has potent cell-depletion activity and enables efficient donor-cell engraftment. (A) CD45–SAP depletes HSCs in C57BL/6 mice whereas non-biotinylated CD45 antibody in the presence of streptavidin– SAP does not. Data represent mean ± s.d. (n = 5 mice/group, one of two independent experiments shown). HSCs were assessed by flow cytometry (Lin-cKit+Sca1+CD48-CD150+). (B) Long-term assessment of peripheral blood chimerism following CD45.2 GFP cell transplantation 8 days post CD45–SAP conditioning; all data points significant vs. control (P < 0.05). Data represent mean ± s.d. (n = 5 mice/group, assayed individually).

To translate these initial mouse studies into human therapeutics, we have deployed our biotherapeutics and stem cell biology platforms to discover and develop anti-human CD45 ADCs. These platforms include antibody discovery campaigns to identify high-affinity antibodies able to bind to human CD45 protein and cell lines expressing CD45. Conjugation of these candidate antibodies to select toxins and testing in functional killing assays in cell lines expressing CD45 and human HSCs growing in vitro is used to select lead antibodies for characterization in vivo. We anticipate nominating a development candidate for the C100 program in 2019.

Clinical development plans

We expect to conduct our initial clinical trials in patients with lymphomas and leukemias. Once we have established a safe and effective dose, we intend to begin testing C100 product candidate(s) in autoimmune diseases, such as multiple sclerosis and scleroderma. The study would be designed to focus on single dose rising efficacy and safety. The studies’ endpoints may include safety/tolerability, HSC depletion, immune cell depletion and relapse prevention.

 

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There are approximately 72,000 cases of non-Hodgkin lymphoma diagnosed in the U.S. each year, of which approximately 6,500 are eligible for transplant; and in Europe there are approximately 95,000 new cases of non-Hodgkin lymphoma each year, with 8,500 eligible for transplant. Of these patients, approximately 60 to 80% receive a transplant. Approximately 47,000 patients in the U.S. and Europe are diagnosed with acute myelogenous leukemia every year. Of those patients, about 60% achieve remission with chemotherapy agents and are eligible for transplant. However, of these, only approximately 30 to 40% actually receive a transplant. This is largely due to the toxicity risk associated with current conditioning protocols. We believe our conditioning agents would allow more patients to achieve remission and become eligible for transplant.

Multiple sclerosis is diagnosed in approximately 15,000 patients in the U.S. and 32,000 patients in Europe annually. To assess eligibility in this population, we focused on the patients with active relapsing-remitting disease and relapsing secondary progressive multiple sclerosis patients who are not adequately treated by current therapies. This population represents approximately 45,000 multiple sclerosis patients who switch therapies each year in the U.S., and we believe that a greater population of patients switch therapies each year in Europe. Many of these patients switch because their current therapy does not adequately control disease activity such as relapses. Given bone marrow transplant’s ability to durably eliminate relapses and disease activity in multiple sclerosis patients, we believe a safer transplant procedure would be a viable option for those patients with highly active disease beyond what therapeutics can manage. Currently approximately 1 to 2% of eligible multiple sclerosis patients in the U.S. and Europe receive a bone marrow transplant because the risk of the process outweighs the benefits of a potential cure, and we believe we can significantly expand this number.

Scleroderma, a chronic connective tissue disease that is characterized by thickening of the skin, is diagnosed in approximately 6,600 patients in the U.S. and 10,900 patients in Europe annually. Approximately 35% (2,300 patients in U.S., 3,800 patients in Europe) of scleroderma patients suffer from diffuse cutaneous disease and are therefore eligible for bone marrow transplant. Currently, approximately 1% or less of eligible scleroderma patients in the U.S. and Europe receive a bone marrow transplant, though the recent inclusion of bone marrow transplant in the European League Against Rheumatism, or EULAR, treatment guidelines for scleroderma may increase this number. With this increased acceptance of bone marrow transplant as a treatment option for scleroderma and the opportunity for a safer transplant procedure through targeted conditioning, we believe transplant could become a new standard of care for patients with severe scleroderma, who have no other therapeutic options available.

C300 program

Our third ADC-based conditioning program, C300, targets T cells. T cell depletion is currently performed with highly toxic non-specific drugs, which can lead to immune deficiency, infections and other complications, including secondary autoimmune reactions. We are pursuing targets expressed on the surface of T cells with the goal of offering a safer and more optimized conditioning approach to prevent transplant rejection prior to allogeneic bone marrow transplant, achieve immune system depletion before autologous bone marrow transplant in autoimmune disease patients or condition patients prior to infusion of CAR T therapy for blood cancers,.

Stem cell mobilization program

Unmet need

Successful stem cell transplantation requires collection of HSCs in both sufficient number and quality to allow for robust engraftment, recovery of blood cells, and lifelong maintenance of the hematopoietic system. Higher cell doses are associated with better outcomes in bone marrow transplant.

Current methods for stem cell collection include a bone marrow harvest, a procedure performed under general anesthesia, or mobilization of stem cells from the bone marrow to blood, where they are then collected through a process called apheresis. The autologous transplant field has moved away from bone marrow harvest in recent years, due to the difficulty of the procedure for both patients and physicians, and there is a need for better HSC mobilization agents for apheresis.

 

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The predominant source of HSCs for adult transplant is mobilized peripheral blood that is acquired by apheresis, or collection of donor or patient blood after several days of injections of G-CSF. G-CSF mobilizes stem cells indirectly, requiring repeated daily injections, and is often associated with bone pain, nausea, headache, and fatigue. The multi-day regimen can take up to a week and side effects can be disruptive for both patients having their cells collected for autologous transplants and for healthy volunteers donating their cells for allogeneic transplants. It is difficult to predict whether mobilization will be successful, especially in heavily treated blood cancer patients. In fact, most patients require multiple apheresis sessions and some patients require more than one stem cell collection procedure to obtain a sufficient number of cells for transplant. Mobilization failure rates are as high as 35% in patients with multiple myeloma or non-Hodgkin lymphoma. For patients who are unable to mobilize sufficient numbers of stem cells with G-CSF, physicians are then required to retreat with G-CSF and add another drug, called plerixafor. Plerixafor acts as a small molecule CXCR4 antagonist, blocking a pathway that otherwise plays an essential role in attracting and retaining HSCs in the bone marrow. It is approved for use in combination with G-CSF for patients who fail to achieve sufficient mobilization of stem cells with G-CSF alone. It can mobilize stem cells as a single agent but not to sufficient levels to be used as a standalone agent. In addition, G-CSF is also contra-indicated in some patient populations, such as patients with sickle cell disease, and it can exacerbate autoimmune diseases.

Our solution

MGTA-145 is a novel stem cell mobilization product candidate that was developed based on our understanding of the physiological mechanisms that control stem cell mobilization. The goal of MGTA-145 is to achieve high levels of stem cell mobilization in patients and donors in order to offer a rapid and robust mobilization option that does not require the use of G-CSF, which is the current standard of care. MGTA-145 is a CXCR2 agonist protein that activates neutrophils to release proteases that cause the release of HSCs into the blood. This novel mechanism of action is complementary to that of plerixafor. Preclinical data have shown that the synergistic combination of MGTA-145 and plerixafor leads to robust and rapid stem cell mobilization. Further, these mobilized stem cells outperform stem cells mobilized by G-CSF in mouse transplant models.

Mechanism of action

CXCR2 is a chemokine receptor expressed on the surface of neutrophils. Binding of MGTA-145 to the receptor results in neutrophil activation. Published data from Magenta founders and scientists show that a key event for mobilization of stem cells is the MGTA-145-mediated release of proteases from activated neutrophils, which together with the actions of the CXCR4 antagonist, plerixafor, results in the rapid release of HSCs from the bone marrow into the blood. Blocking CXCR4 using plerixafor and activating neutrophils with MGTA-145 together produce an effective and synergistic untethering and release of HSCs from bone marrow into the blood, resulting in rapid and robust mobilization of HSCs.

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The goal of MGTA-145 is to enable single day mobilization of high numbers of HSCs. Mobilized peripheral blood stem cells are currently the predominant source of HSCs for both autologous and allogeneic transplantation. The most common clinical HSCs mobilization protocol is five days of G-CSF. This regimen requires daily injections, has been associated with bone pain and often results in unpredictably low yields. MGTA-145, in combination with plerixafor, provides a rapid mobilization method that only requires a single treatment and has robust and predictable kinetics. The stem cells mobilized with this combination contain a higher frequency of HSCs compared to those mobilized with G-CSF, which could significantly improve transplant outcomes over the current standard of care.

Preclinical development

Research from Magenta scientific collaborators from Harvard and Massachusetts General Hospital published in Cell in December 2017 demonstrates that a single administration of MGTA-145, in combination with plerixafor, resulted in rapid mobilization of robust numbers of HSCs from the bone marrow and into the blood. The cells were then harvested for transplant in mouse models. Notably, HSCs mobilized with MGTA-145 and plerixafor and subsequently transplanted into mouse models resulted in faster engraftment and higher levels of donor cells, two important factors for the success of a transplant, compared to cells obtained with the current mobilization standard of care, G-CSF.

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The combination of MGTA-145 and plerixafor rapidly mobilizes mouse HSCs. Blood was assessed at various time points after administration of plerixafor (5mg/kg), MGTA-145 (2.5mg/kg) or MGTA-145 plus plerixafor combination given simultaneously. Mean ± the standard error of the mean (SEM) from n = 4 BALB/c mice/group/time point. *p < 0.01 versus MGTA-145 or plerixafor ANOVA. (Ref: Hoggatt et al., 2018, Cell 172, 1–14)

 

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In studies in non-human primates, we showed that a single administration of MGTA-145, in combination with plerixafor, induces robust mobilization of a transplantable dose of CD34+CD90+CD45RA- HSCs within four hours of administration. CD34+CD90+CD45RA- cells are highly enriched for HSCs and are important for long-term engraftment and hematopoietic reconstitution, both of which influence patient outcomes. These data were presented at the ASH annual meeting in December 2017.

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CD34+ cells mobilized in response to MGTA-145 + plerixafor contain a high fraction of primitive CD34+CD90+CD45RA- stem cells. The absolute numbers of CD34+CD90+CD45RA- HSCs in whole blood for each treatment group is shown. Data are expressed as mean ± SEM and represent five animals per group. Dotted line represents level of mobilization required to achieve transplantable dose.

Taken together, these data suggest that MGTA-145 with plerixafor offers a more robust, safer and more practical alternative to G-CSF for mobilization of stem cells for use in autologous and allogeneic transplant.

Clinical development plan

Based on the results presented at the ASH annual meeting in December 2017, we have initiated IND-enabling studies of MGTA-145 in combination with plerixafor and expect to file an IND with the FDA for this product candidate in 2019. We plan to develop MGTA-145 for mobilization first in patients with multiple myeloma and non-Hodgkin lymphoma, followed by healthy donors for allogeneic transplant.

There are approximately 30,000 cases of multiple myeloma diagnosed in the U.S. each year, of which approximately 15,000 are eligible for transplant; and in Europe there are approximately 40,000 cases diagnosed each year, with 20,000 eligible for transplant. There are approximately 72,000 cases of non-Hodgkin lymphoma diagnosed in the U.S. each year, of which approximately 7,200 are eligible for transplant; and in Europe there are approximately 95,000 new cases of non-Hodgkin lymphoma each year, with 9,500 eligible for transplant.

In the U.S. approximately 65% of stem cell donors donated through peripheral blood mobilization in 2016. In Europe, 73% of all donors donated through peripheral blood mobilization. The number of patients requiring mobilization may increase as safer transplant conditioning protocols, such as the ones we are developing, increase the number of patients eligible for transplant, including patients with autoimmune or sickle cell disease.

We plan to further investigate MGTA-145 in patient populations where G-CSF can exacerbate the disease, such as autoimmune diseases, and patient populations where G-CSF is contra-indicated, such as sickle cell disease.

 

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Stem cell expansion program: cord blood

Unmet need

Bone marrow transplant is a life-saving procedure with curative potential; however, up to half of the approximately 23,000 patients requiring an allogeneic bone marrow transplant will not find a suitable donor within their families or among the registered bone marrow donors. In addition, long search times for unrelated donors and their frequent unavailability represent a major challenge, particularly for patients with diseases that can progress rapidly, such as high-risk acute leukemia and certain inherited metabolic diseases. Because of the urgency for these patients to undergo transplant, there is a need for new options, and the ability to find a well-matched stem cell donor with sufficient cells remains one of the most significant hurdles in bone marrow transplant.

Challenges in finding a matched donor

The probability of finding a matched donor is influenced by the complexity and frequency of the patient’s human leukocyte antigen, or HLA, type in the population and among the 25 million registered bone marrow donors. The HLA is a group of highly variable proteins involved in immune recognition, present on nearly all cells. Differences in HLA genes between the stem cell donor and the patient can result in severe complications, including GvHD, where the donor T cells in the transplant cells attack the patient, or rejection, where the patient T cells attack the donor stem cells, leading to transplant rejection. In bone marrow transplant, donors and patients are typically matched for both copies of four key HLA genes, or eight “loci”, with the best results occurring when donor and patient are matched at all eight loci. Patients transplanted with bone marrow stem cells matched at seven of eight loci have inferior outcomes compared to those who matched at eight of eight loci, with an 8% reduction in the probability of survival five years after transplant. Thus, bone marrow transplant is not commonly performed with mismatched bone marrow grafts. The probability of finding a well matched eight of eight donor differs widely depending on the patient’s HLA type, which is reflective of their ethnicity. Caucasian patients of western European descent have an approximately 75% probability of identifying an eight of eight matched donor, while patients of African descent have an approximately 16% probability, with other ethnic groups having an intermediate probability.

Opportunities and challenges related to cord blood transplant

For patients who do not have a well-matched donor, umbilical cord blood provides a potential source of suitably matched stem cells. However, despite the proven utility of cord blood transplant, significant challenges remain.

First, even when a patient has a matched cord blood unit, transplants are often not performed because there are too few stem cells in the cord blood unit. Cord blood units are currently selected based on a minimum cell dose threshold per kilogram of patient body weight, with the best HLA match unit selected from among those large enough for use. Since stem cell dose is based on the number of stem cells per kilogram of patient body weight, cord blood is more commonly used in smaller pediatric patients than in adults. Although more than 712,000 frozen cord blood units are available in the worldwide cord blood inventory, current cell dose requirements mean that less than approximately 4% of these units are suitable for use in adult patients. The low number of units available for use in adults negatively impacts the ability to identify a well-matched cord blood unit because the searchable pool of adequately sized units is drastically limited.

Currently an adult Caucasian patient in the U.S. has an approximately 40% chance of finding a seven of eight matched cord blood unit, and an adult patient of African descent has only an approximately 5% chance.

Secondly, even when a cord blood unit of adequate size is identified, engraftment can be slow and there is an increased risk of life-threatening infections and transplant failure compared to other stem cell sources. These complications result from the low number of stem cells present in cord blood units, since the speed and probability of engraftment are positively correlated with the number of stem cells in the graft. Thus, the higher

 

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the number of stem cells, the faster the engraftment and the lower the likelihood that the patient will experience transplant failure.

The ability to expand HSCs in cord blood has the potential to address the challenge of low cell doses typically obtained from cord blood, and thereby:

 

    increase the available pool of cord blood units, allowing more patients to obtain better matched cord blood units; and

 

    improve the speed and probability of engraftment in patients, resulting in improved transplant outcomes.

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Wagner et al, Blood 2002; 1611-8

Increase in CD34 cell dose improves engraftment and speed of hematopoietic recovery. Cumulative incidence of neutrophil engraftment after unrelated donor cord blood unit transplantation (n = 102): effect of CD34 cell dose (× 105/kg of recipient body weight).

Our solution

MGTA-456, is a novel allogeneic stem cell therapy, produced by expanding a single umbilical cord blood unit ex vivo with a proprietary small molecule aryl hydrocarbon receptor, or AHR, antagonist.

Blockade of AHR is a novel, well-studied and clinically validated pathway that controls the self-renewal and differentiation of human HSCs. Growing human HSCs in the laboratory with growth factors leads to cell division; however, this is accompanied by differentiation of the cells into more mature cell types, resulting in the loss of HSCs. Magenta scientists discovered that growth factor treatment activates the AHR pathway, which leads to differentiation and loss of HSCs. Including an AHR antagonist during HSC culture blocks the AHR pathway, thereby inhibiting differentiation and leading to an increase in the number of HSCs.

 

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Schematic showing the impact of AHR antagonist on stem expansion culture. Purple cells represent HSCs and blue cells represent differentiated, non-HSCs.

The ability to expand HSCs ex vivo using an AHR antagonist has the potential to address many of the current challenges of cord blood transplant. Since the speed and probability of engraftment are increased with the number of HSCs within the cord blood unit, increasing the dose of stem cells is predicted to speed engraftment and immune reconstitution, reduce the probability of engraftment failure, and allow the use of cord blood in adult patients. In addition, MGTA-456 also has the potential to improve overall survival by allowing more patients to have access to better HLA-matched cord blood units, which is associated with better outcomes and lower rates of post-transplant complications.

We obtained the rights to MGTA-456 through an April 2017 license agreement with Novartis granting us the sole worldwide rights to research, develop and commercialize certain AHR antagonist compounds specifically for the expansion of cord blood-derived non-gene-edited/-modified HSCs.

Clinical history of MGTA-456

The goal of the first clinical study was to determine if MGTA-456 was safe and could provide more rapid and complete engraftment, and if the engraftment was able to supply long-term (longer than one year) hematopoietic recovery. If MGTA-456 was shown to be a reliable source of engraftable long term HSCs in the double cord blood transplant setting, the product would next be tested as the sole source of HSCs in the single cord blood transplant setting.

Initial first-in-human studies: double blood cord transplant

Initial clinical testing of MGTA-456 was done by Novartis between 2012 and 2016 in adult (n=15) and pediatric (n=3) patients with blood cancers conditioned with a myeloablative protocol, which means near-complete elimination of stem cells in the bone marrow. The study focused on the simultaneous transplant of two cord blood units, or double cord blood transplant, where one unit was expanded using the AHR antagonist to produce MGTA-456 and the other unit was unmanipulated. A second study commenced in 2014 and ended in 2016. Both studies were completed at the University of Minnesota.

The first clinical study was a first-in-human, single-arm, single-center, open-label, proof-of concept study to evaluate the safety and tolerability of infusing MGTA-456 in patients with blood cancers. In this study, a total of 31 patients (mean age 32 years) were enrolled and 27 were infused with MGTA-456. These 18 patients were treated with double unit cord blood transplant, or DUCBT, until sufficient data were available to support a single UCB transplant, of which 9 patients were eligible, with an acceptable benefit-risk. Primary endpoints of the study were lack of infusional toxicity and absence of excess graft failure, secondary endpoints were time to neutrophil

 

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recovery, incidence of neutrophil recovery within 42 days, incidence of platelet recovery within six months, frequency of expanded unit predominance at day 100 (DUCBT recipients only), incidence of transplant related mortality within 100 days and one year, incidence of acute GvHD within 100 days, incidence of chronic GvHD within one year, incidence of relapse within one year and overall survival and disease free survival within one year.

The second clinical study for MGTA-456 was a single-arm, open-label study to evaluate the safety and tolerability of infusing MGTA-456 in patients with blood cancers undergoing UCB transplantation using a non-myeloablative conditioning regimen. MGTA-456 was used as the only source of HSC in SUCBT. Patients between the ages of 18-70 years eligible for UCB transplant were enrolled into this study. Of the nine patients enrolled in the study, two had diagnoses of acute leukemia, three had myelodysplastic syndromes, one had non-Hodgkin’s lymphoma, one had multiple myeloma, one had chronic lymphocytic leukemia, and one had myeloproliferative disease. The study’s primary endpoint was absence of excess graft failure at day 42, secondary endpoints of incidence of neutrophil recovery within 42 days, incidence of transplant related mortality within 100 days and one year and overall survival and disease free survival within one year.

In these clinical studies, no study stopping rules were met. Specifically, no infusional toxicity that prohibited administration of the product and no primary graft failure were observed in any patient. All transplanted patients achieved neutrophil engraftment with a median of 14 days in the first clinical study and seven days in the second clinical study.

In the first clinical study, a total of 14 of 27 patients died, including three after the one-year study completion visit. There were five deaths in the second clinical study, including one after the end of the study. None of the deaths in either study were suspected to be related to the investigational product administered in the studies. Collectively, there were five serious adverse events suspected to be related to MGTA-456 in four patients. Of these serious adverse events, events of febrile neutropenia and hypotension occurred in one patient, with three other patients each reporting an event of pre-engraftment syndrome. All patients from the aforementioned studies were eligible to participate in the ongoing five-year follow-up study. No study-stopping rules were met and all patients engrafted, including those transplanted following non-myeloablative conditioning.

In December 2015, prior to our license of MGTA-456 from Novartis, the FDA imposed a partial clinical hold on the cryopreserved part of the protocol covered by the IND application for MGTA-456 until Novartis demonstrated comparability between the fresh and cryopreserved product. This partial clinical hold was later removed by the FDA in June 2016.

These first-in-human studies used the double cord blood approach primarily for patient safety, to provide a source of HSCs in case the manufacturing process used to produce MGTA-456 led to HSC loss. The simultaneous use of two cord blood units was originally used as a procedure to increase the number of HSCs in adult cord blood transplantation. In this model, immune-mediated rejection of one cord blood unit by the T cells present in the competing unit results in a single unit “winning” and providing long-term engraftment in more than 90% of patients. Clinical trials of double cord blood transplant have shown that while T cells dictate which cord wins, the time to neutrophil engraftment of the winning cord blood is determined by how many HSCs are present in the cord blood unit that wins, with the larger of the two cord blood units winning two-thirds of the time.

 

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For these initial studies, two units were obtained that were matched to the patient and each other, and the smaller of the two units was expanded for 15 days using an AHR antagonist to produce MGTA-456. On the day of transplant, patients received the unmanipulated cord blood unit, followed by MGTA-456 and the previously cryopreserved CD34-depleted fraction matched to MGTA-456. Since MGTA-456 was produced from the smaller unit, the expectation was that one-third of the patients would engraft with MGTA-456, rather than with the unmanipulated cord blood unit.

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Schematic of the first in human clinical trial for MGTA-456. On day -15 the smaller umbilical cord blood (UCB) unit is thawed and the CD34+ cells are selected and expanded in the presence of an AHR antagonist. On day -7 to day -1 the patient is conditioned with fludarabine (FLU), cyclophosphamide (CY), and total body irradiation (TBI). On day 0, the larger, unmanipulated UCB unit is infused followed by the expanded CD34+ cells. The following day (day 1), the CD34-fraction is infused.

 

 

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Demographics of patients treated with MGTA-456 and historical and concurrent controls treated with the same conditioning protocol with single or double unmanipulated cord blood units at the clinical site. The trial based the patient inclusion/exclusion criteria on historical and concurrent controls. Patient demographics were comparable.

A total of 18 patients were treated and all patients successfully engrafted neutrophils (absolute neutrophil count greater than 500 per mL of blood for three days) with a median time to engraftment of 14.5 days – significantly faster than the 26 days seen in historical and concurrent cord blood transplant recipients treated at the same site with the same myeloablative conditioning protocol. There were no early or late engraftment failures in patients

 

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treated with MGTA-456, which represented a marked improvement compared to 17% engraftment failure in the control cohort.

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Rate and incidence of neutrophil recovery in recipients of MGTA-456 compared to historical controls (double cord blood transplant)

Of the 18 patients treated in the double cord blood study, the MGTA-456 product predominated in 12 patients and the unmanipulated unit in six. Since MGTA-456 was produced from the smaller unit, the expectation was that only one-third of the patients would engraft with MGTA-456. Patients who engrafted with MGTA-456 recovered neutrophils by 10.5 days, while those who engrafted with the unmanipulated cord blood unit engrafted in 23 days, similar to historical and concurrent controls transplanted with unmanipulated cord blood.

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Rate and incidence of neutrophil recovery in patients engrafted with MGTA-456 compared to patients engrafted with unmanipulated cord blood units and historical and concurrent control patients

These published studies demonstrate that MGTA-456 results in rapid and durable engraftment when used in the double cord blood transplant protocol with myeloablative conditioning.

Use of MGTA-456 as a sole stem cell source: single cord blood transplant

Additional clinical trials were undertaken to investigate the ability of MGTA-456 to act as a stand-alone source of stem cells without a second cord blood unit under a range of conditioning protocols. In data presented at the ASH annual meeting in December 2017 from a Phase I/II study, single cord blood units were expanded for 18 additional adult and adolescent patients with blood cancers. Nine patients underwent a myeloablative conditioning regimen before transplant, and the other nine patients received non-myeloablative conditioning.

 

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Patient demographics were similar between MGTA-456 and the control cohorts, except patients in the myeloablative study treated with MGTA-456 were heavier and patients in the non-myeloablative study were older and had a higher risk disease status. These traits suggest more challenging patient populations to treat.

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Demographics of patients in which MGTA-456 was tested as a sole stem cell source (myeloablative top, non-myeloablative bottom)

MGTA-456 successfully engrafted in all 18 patients, with rapid time to neutrophil engraftment and immune recovery regardless of conditioning intensity, as compared to historical and concurrent controls transplanted with unmanipulated cord blood using the same myeloablative or non-myeloablative conditioning protocols. For the myeloablative protocol, all patients transplanted with MGTA-456 engrafted with a median time to neutrophil recovery of 14 days, significantly faster than the 26.5 days seen in historical and concurrent controls transplanted with unmanipulated cord blood using the same myeloablative protocol. Engraftment failure was not observed in any of the patients transplanted with MGTA-456, in contrast to the historical controls where 17% of patients failed to engraft. Among patients conditioned with the non-myeloablative protocol, all patients treated with MGTA-456 engrafted with a median time to neutrophil recovery of eight days, which is significantly faster than the 17.5 days observed in historical controls. There were no early engraftment failures among patients treated with MGTA-456, in contrast to the historical controls where 6% of patients failed to engraft. There were no late engraftment failures in any patient treated with MGTA-456, with a median patient follow-up of two years for all studies, supporting the view that MGTA-456 contains HSCs that retain long-term engraftment.

 

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Time to engraftment, as defined by neutrophil recovery, for patients transplanted with MGTA-456 after myeloablative (left) or non-myeloablative (right) conditioning

These studies showed rates of acute GvHD and disease relapse with MGTA-456 and overall survival that were comparable to historical cohorts. These preliminary data suggest that MGTA-456 increases the speed and probability of engraftment while substantially preserving the previously reported benefits of cord blood transplant of low acute GvHD, low relapse and favorable overall survival.

Impact of MGTA-456 on cord blood HLA matching

MGTA-456 allows for expansion of smaller units that would otherwise not be suitable for transplant. This effectively increases the available cord blood inventory for adults from approximately 4% of all units to approximately 80%. Analysis of the current cord blood inventory in collaboration with CIBMTR using the lower starting cell dose threshold for MGTA-456 showed that the ability to identify an optimal cord blood unit matched at seven of eight HLA loci increases for all patients. This is particularly improved for patients of African or Japanese ancestry for whom it is especially difficult to find well matched units. Since better matched units yield superior outcomes, the ability to use these smaller well matched units is anticipated to improve transplant outcomes.

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Cord blood unit availability for an 80kg adult based on current practice compared to availability using MGTA-456 expanded cords

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Impact of lower cell dose threshold for MGTA-456 on the probability of finding a >7/8 allele matched cord blood unit for patients of different ethnicities. Current practice minimum cell dose of 25 million total nucleated cells per kg of body weight.

MGTA-456 manufacturing process

MGTA-456 is manufactured at a GMP-certified contract manufacturing facility, which has produced all batches of MGTA-456 used for clinical trials. The manufacturing process involves selection of CD34+ cells which contain the stem cells, from an umbilical cord blood unit matched to the patient to create a CD34-enriched cell fraction and a CD34-depleted cell fraction. The CD34-depleted fraction is cryopreserved following selection and later thawed and infused at the time of transplant. The CD34-depleted fraction contains immune cells that are important for immune recovery and provide a source of donor T cells that can recognize and kill residual tumor cells in the patient when used in patients with blood cancers. The CD34+ enriched cells are cultured for 15 days with growth factors that promote cell division and the low molecular weight AHR antagonist to produce MGTA-456. While the cells are being cultured, the patient is conditioned for transplant. The MGTA-456 manufacturing process results in a median increase in the number of CD34+ cells of 327-fold (range: 67-fold to 848-fold) across all studies.

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Summary of clinical manufacturing of MGTA-456, CD34+ cell numbers before and after expansion in 36 clinical manufacturing batches

After culture, the cells are washed, characterized, and re-suspended in human serum albumin solution. The cells then undergo quality and release testing. MGTA-456 can then be infused directly into the recipient (“fresh” product) or can be mixed with cryopreservation medium, cryopreserved and infused to the patient after thawing. The ability to cryopreserve MGTA-456 should allow for shipment of the product globally. The manufacturing process takes a total of 15 days from receipt of the cord blood unit to product release. The shelf life of the fresh product is 24 hours after manufacturing. The shelf life of the frozen product is up to 90 days. We are currently working with third-party GMP suppliers for our clinical manufacturing process and with commercial contract manufacturing organizations to develop a process for commercial supply.

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Schematic of the MGTA-456 manufacturing process. The cord blood unit is thawed and the CD34+ cells are selected and expanded in the presence of an AHR antagonist. Following expansion, the CD34+ cells are infused followed by the CD34-depleted fraction. The HSCs migrate to the bone marrow and rebuild the blood system.

The manufacturing process for MGTA-456 does not require genomic manipulation. The small molecule AHR antagonist used in the MGTA-456 manufacturing process is manufactured under GMP conditions from readily available starting materials in reliable and reproducible synthetic processes that do not require specialized equipment in the manufacturing process.

Clinical development plan

The rapid, robust and consistent engraftment of MGTA-456 in patients with blood cancers suggests that MGTA-456 may also improve engraftment in other patients in whom engraftment failure is a problem. For example, one group of diseases where cord blood transplant is curative is inherited metabolic diseases, specifically, Hurler’s syndrome (also referred to as mucopolysaccharidosis-1H or MPS-1H), cerebral adrenoleukodystrophy, metachromatic leukodystrophy and globoid cell leukodystrophy (also referred to as Krabbe disease). Although some of these diseases can be treated with enzyme replacement therapy, this treatment does not halt neurocognitive decline. In contrast, transplant can be curative in these diseases and prevent neurocognitive decline. However, up to 20% of inherited metabolic diseases patients treated with transplant experience engraftment failure, resulting in severe complications, including death. We believe the high number of HSCs present in MGTA-456 will speed engraftment, reduce or eliminate engraftment failure and improve patient outcomes.

 

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According to the National Organization for Rare Disorders, there are currently approximately 270 inherited metabolic diseases patients diagnosed each year in the U.S. and Europe. Allogeneic bone marrow transplant is the standard of care for inherited metabolic diseases patients – approximately 65% of inherited metabolic diseases patients are treated with a bone marrow transplant and many receive a cord blood transplant. Cord blood transplant volumes for these patients are currently increasing, and additional growth is expected with the adoption of newborn screening and earlier diagnosis for cerebral adrenoleukodystrophy.

In December 2017, we initiated a Phase II study of MGTA-456 in patients with inherited metabolic diseases. The Phase II trial is a single-arm, open-label study designed to evaluate the safety and efficacy of MGTA-456 after myeloablative conditioning in 12 patients with inherited metabolic diseases undergoing bone marrow transplant. The primary endpoint of this study is the incidence of neutrophil engraftment by day 42. In February 2018, we treated the first patient with MGTA-456 in our Phase II study in inherited metabolic diseases. This patient successfully met the primary engraftment endpoint and all of the secondary endpoints within the first 100 days post-transplant. However, on June 14, 2018 (day 122 following transplant), this patient was admitted to the hospital for autoimmune cytopenia, a known potential complication of bone marrow transplant in this patient population, which includes severe side effects and the possibility of death. This patient was subsequently transferred to the intensive care unit in critical condition due to these autoimmune cytopenia side effects. The occurrence of autoimmune cytopenia has been considered by the principal investigator overseeing the Phase II study and the chair of our data safety monitoring committee to be unrelated to the use of MGTA-456 specifically. We plan to initiate a pivotal study of MGTA-456 in patients with inherited metabolic diseases in 2020.

We anticipate reporting initial data from this study at a major medical meeting in late 2018, and will continue to provide updates on our studies at major medical meetings. If the results from this trial are favorable, we plan to treat additional patients in a registration-enabling trial focused on transplant endpoints, including engraftment neutrophil and platelet recovery and hospitalization time.

On April 11, 2018, we received orphan drug designation from the FDA for MGTA-456 for the enhancement of cell engraftment in patients receiving bone marrow transplant. In addition, we expect to focus on obtaining regenerative medicine advanced therapy, or RMAT, designation, accelerated approval for inherited metabolic diseases and eventually obtain a broad allogeneic cord label.

We intend to study MGTA-456 in other conditions where we believe it may bring transformative benefit to patients. We intend to continue to explore MGTA-456 in patients with blood cancers who could benefit from a well-matched stem cell transplant with a high dose of cells. We are in discussions with physician groups and regulatory agencies on the ideal endpoints and comparator treatments to enable clinical trial(s), which could lead to registration. We currently expect an investigator-initiated trial to begin in the second half of 2018.

Bone marrow transplant is widely accepted as a curative option for patients with sickle cell disease; however, very few patients are able to find a suitable matched donor or cord blood unit. MGTA-456 may offer the possibility for more patients with sickle cell disease to have access to transplant with high numbers of stem cells from a matched cord blood unit and we intend to initiate a Phase II study in patients with sickle cell disease in early 2019.

Stem cell expansion program: gene-modified HSCs

Unmet need

Bone marrow transplant with gene-modified HSCs, which is referred to as stem cell gene therapy or genome editing, is a promising treatment approach for a number of inherited diseases but is currently limited by the inability to generate a sufficient dose of gene-modified HSCs to achieve clinically meaningful results.

The ability to expand HSCs ex vivo has the potential to improve outcomes with gene therapy or genome editing by increasing the dose of genetically modified stem cells. This has been a long-term goal of the field and has the potential to reduce manufacturing costs for these therapies by requiring less viral vector for gene modification of

 

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the stem cells. Scaling up vector manufacturing in a cost-effective manner has been a significant challenge for HSC-based gene therapy companies and a significant cost driver. Such cost and capacity issues could limit the commercial viability and widespread deployment of gene therapies. This will only be a bigger challenge as more gene therapies enter the marketplace in the coming years.

Our solution

We developed the E478 program in response to an unmet technological need recognized in the field of gene therapy – the challenge of achieving sufficiently high doses of transduced or gene-modified cells. We believe that E478 could represent a key component for unlocking the full value of gene therapy by providing each patient with an optimal dose of gene-modified HSCs for rapid and successful engraftment.

E478 uses the same clinically validated method as MGTA-456, AHR antagonism, to expand HSCs. We are developing E478 specifically to partner with gene therapy and/or genome editing companies to integrate into their manufacturing processes, leading to newly defined cell therapy products.

To demonstrate the utility of E478 for increasing the dose of gene-modified human HSCs that retain engraftment activity, we performed a series of in vitro and in vivo experiments. We cultured human HSCs for 24 hours prior to gene editing using CRISPR/Cas9 or gene insertion using lentiviral vectors. Following gene modification, we cultured the cells in the presence of E478 and cytokines for seven days to increase the dose of gene-modified cells. At the end of the culture, we enumerated the number of gene-modified cells and transplanted them into immune-deficient mice. Twelve weeks following transplantation, we determined the number of gene-modified cells present to allow us measure the number of gene modified human HSC that retain engraftment activity.

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In data we presented at the ASH annual meeting in December 2017, we showed that in vitro culture of HSCs with E478 resulted in up to an 8-fold increase in the number of CD34+ cells, a cell population enriched for human HSCs. Transplant of cells expanded with E478 into immune-deficient mice resulted in a 10-fold increase in the number of human cells that engrafted in vivo compared to cells cultured in the absence of E478. Importantly, the high levels of editing of the expanded cells obtained during the in vitro culture (approximately 80%) were maintained in vivo, demonstrating that the expanded and edited HSCs retain engraftment activity.

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Expansion and transplantation of edited bone marrow CD34+ cells into NSG mice: Bone marrow-derived CD34+ cells were thawed, edited, and expanded for seven days with (magenta bars) or without (gray bars) E478. (A) Fold expansion of CD34+ cells generated over the seven day culture. (B) Human engraftment and (C) editing rates in the bone marrow of mice as determined by flow cytometry at 16 weeks post-transplant.

 

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We next performed similar experiments designed to evaluate the ability of E478 to increase HSC numbers for HSC based gene therapy. In these studies, human CD34+ cells isolated from G-CSF mobilized peripheral blood were cultured with cytokines in the presence or absence of E478 and transduced with lentiviral vectors expressing a green fluorescent protein (GFP) to identify cells that were effectively transduced. Inclusion of E478 increased the number of CD34+ cells and improved the level of human cell engraftment while maintaining high levels of transduction.

 

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Expansion and transplantation of transduced peripheral blood derived CD34+ cells into NSG mice: Peripheral-derived CD34+ cells were thawed, transduced, and expanded for seven days with (magenta bars) or