Magenta Therapeutics Presents New Data from Phase 2 Study of MGTA-456 Cell Therapy in Patients with Inherited Metabolic Disorders
– All five patients with inherited metabolic disorders (IMDs) treated with MGTA-456 in ongoing Phase 2 study met the primary endpoint of successful engraftment –
– Patients with cerebral adrenoleukodystrophy (cALD) showed resolution of brain inflammation on MRI as early as one month post-treatment –
– Patients with Hurler’s syndrome showed increase in corrected enzyme and decrease in disease-related metabolites –
MGTA-456 is a cell therapy providing a high dose of hematopoietic stem
cells that are well-matched to the patient, administered through a
transplant procedure. The ongoing Phase 2 study in inherited metabolic
disorders aims to enroll 12 patients with cerebral adrenoleukodystrophy
(cALD), metachromatic leukodystrophy or globoid cell leukodystrophy, and
previously also enrolled patients with Hurler’s syndrome. The primary
endpoint of the study is engraftment after transplantation and the
secondary endpoint is transplant-related safety and tolerability. Early
data from this Phase 2 study were highlighted in a poster presentation
“Inherited metabolic disorders are rare and often fatal diseases. The
only disease-modifying treatment option is bone marrow transplant, which
can be challenging for patients without a matched sibling donor.
MGTA-456 is a cell therapy with a high dose of stem cells that are well
matched to the patient and may represent a promising treatment option
for these patients,” said
Preliminary Phase 2 Results Demonstrate Engraftment with Minimal Neutropenia with MGTA-456, a CD34+ Expanded Cord Blood Product in Patients Transplanted for Inherited Metabolic Disorders, Abstract #3467
Key results, as of
- Five patients treated and evaluable: two with cALD, three with Hurler’s syndrome
Five of five patients treated with MGTA-456 met the primary endpoint
of successful engraftment by day 42 following the transplant procedure.
- In recent historical cohorts of patients undergoing regular cord blood transplantation with identical pre-transplant conditioning, up to 32% did not engraft at comparable time points.
The patients treated with MGTA-456 had minimal neutropenia, lasting
for a median of 1 day.
- In the historical cohort, neutropenia lasted for a median of 8 days.
- The two patients with cALD showed resolution/reduction of gadolinium enhancement on MRI, an indicator of brain inflammation, by day 28 post-transplant. Resolution of gadolinium enhancement is correlated with long-term disease benefit in patients with cALD.
- Patients with Hurler’s syndrome showed an increase in blood leukocyte Idua enzyme, the enzyme that is deficient in untreated patients with Hurler’s syndrome, suggesting that transplant with MGTA-456 is beginning to affect the disease in these patients.
- Patients with Hurler’s syndrome showed a marked decline in urine total glycosaminoglycan (GAG) levels, which is correlated with improved long-term disease outcomes.
- Two treatment-related adverse events were observed: one grade 1 vomiting and one grade 3 nausea, both of which were transient.
Preclinical Data, MGTA-456 Stem Cell Expansion Program
MGTA-456, A First-in-Class Cell Therapy Produced from a Single Cord Blood Unit, Enables A Reduced Intensity Conditioning Regimen and Enhances Speed and Level of Human Microglia Engraftment in the Brains of NSG Mice, Abstract #115
Key results presented by
- NSG mice were transplanted with MGTA-456 or unexpanded cord blood after being conditioned with total body irradiation or either high- or low-dose busulfan, and engraftment of microglial cells in the brain was measured.
- In sublethally-irradiated animals, MGTA-456 led to an 11-fold increase in hematopoietic engraftment and a 24-fold increase in microglial engraftment in the brain (p<0.001, n=8 mice) relative to standard of care, with histology consistent with engrafting microglia in the brain.
- In busulfan-conditioned animals, MGTA-456 led to a 25-fold increase in hematopoietic engraftment and a 60-fold increase in microglial engraftment in the brain relative to standard of care (p<0.001, n=8 mice).
- MGTA-456 led to faster microglial engraftment: a 28-fold increase in microglial engraftment was demonstrated as early as 2 weeks post-transplant with MGTA-456 (p<0.001, n=8 mice). The number of engrafting hematopoietic cells in the periphery correlated with number of engrafting microglia in the brain (p<0.0001).
- Subpopulations of MGTA-456 were evaluated to determine the source of microglial engraftment. Only CD34+CD90+ cells, but not CD34+CD90- or CD34- cells, led to brain engraftment, consistent with the subpopulation of cells that result in hematopoietic engraftment following transplant of unexpanded cells (Radtke et al., Sci Trans Med 2017 and Goncalves et al., Blood 2017 130:659).
- These data demonstrate that microglial engraftment is faster and greater in recipients of MGTA-456 even after lower dose busulfan conditioning, that microglial engraftment correlates with peripheral blood recovery, and that microglia cells are derived from CD34+CD90+ cells.
“Inherited metabolic disorders are characterized by defective enzyme
function in the brains of patients, and engraftment of microglial cells
in the brain after transplant is crucial for successful correction of
the disease,” said
MGTA-456 Contains Large Numbers of Expanded Cord Blood (CB) CD34+CD90+ Hematopoietic Stem Cells (HSC) Which Confer All Engraftment Activity and Correlate with Accelerated Neutrophil Recovery after Myeloablative Conditioning in Patients with Hematologic Malignancy, Abstract #2083
Key results, presented by
- To date 41 patients have been treated with MGTA-456 (36 with blood cancers; 5 with inherited metabolic disorders), and all have engrafted at a significantly faster rate than what was seen in historical controls.
- Magenta scientists sought to fully characterize the expanded CD34+ cell fraction of MGTA-456 phenotypically and functionally and identify the cell population that correlates with time to neutrophil recovery.
- MGTA-456 was found to contain large doses of CD34+CD90+ hematopoietic stem cells and progenitors, which are responsible for engraftment in mouse models.
- The dose of CD34+CD90+ cells was also found to have the strongest correlation with faster time to neutrophil recovery in patients.
- Of the 36 patients with blood cancers treated with MGTA-456, 100% of patients engrafted in a median of 14 days, with 67 percent overall survival at 2 years in this high-risk disease setting.
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Manisha Pai, Vice President, Communications & Investor Relations