A plethora of presentations

Magenta Therapeutics presents new research at the Transplant and Cellular Therapy Annual Meeting

Mel J. Yeates
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CAMBRIDGE, Mass.—Magenta Therapeutics has announced data from its newest clinical development candidate for conditioning, MGTA-117, at the recent Transplant and Cellular Therapy (TCT) Annual Meeting in Orlando, Florida. Magenta also noted additional results with a tool CD117-ADC molecule.
Magenta’s portfolio of novel therapeutics will reportedly allow patients to benefit through a more precise stem cell transplant process. This portfolio includes targeted, disease-modifying antibody drug conjugates (ADCs) like MGTA-117 which are designed to precisely and rapidly remove the disease-causing cells in the body, and enable immune system reset and long-term engraftment without the need for chemotherapy or radiation.
“There is a significant opportunity to allow more patients to benefit from immune reset through stem cell transplant with novel, targeted medicines for conditioning. We are excited to present the first results from our MGTA-117 clinical candidate for targeted patient preparation for stem cell transplant or gene therapy,” said John Davis, M.D., M.P.H., chief medical officer, Magenta Therapeutics. “These new data highlight the potency, safety and broad pre-clinical therapeutic index of 30 fold of MGTA-117.”
“We believe that MGTA-117 is the optimal agent for depleting stem cells to enable safe immune reset, and we look forward to moving this product candidate into the clinic, with initial clinical data expected in 2021. The additional impressive results with the tool CD117-ADC in the NIH gene therapy study provide further validation of the safety and potency of the ADC approach and underscore Magenta’s leadership in the field of conditioning,” continued Davis.
MGTA-117, a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, is an ADC developed for patients undergoing immune reset through either autologous or allogeneic stem cell transplant. MGTA-117 precisely depletes hematopoietic stem and progenitor cells. MGTA-117 was developed under a partnership with Heidelberg Pharma that grants Magenta exclusive worldwide development and marketing rights for ADCs targeting CD117 and using an amanitin payload.
Magenta presented the new data in a talk called “A Non-Genotoxic Anti-CD117 Antibody Drug Conjugate (ADC) Designed for Patient Conditioning Prior to Stem Cell Transplant and HSC-Based Gene Therapy Has a Broad Therapeutic Window across Species.” The presentation demonstrated that MGTA-117 potently depleted stem and progenitor cells with an improved therapeutic index over prior molecules.
The results with MGTA-117 build on additional data presented at TCT with a tool CD117-ADC molecule. This study, entitled “A Single Dose of CD117 Antibody Drug Conjugate Enables Autologous Gene-Modified Hematopoietic Stem Cell Transplant (Gene Therapy) in Nonhuman Primates,” showed the first-ever successful transplant of gene-modified cells in non-human primates using a tool CD117-targeted, single-agent ADC, without the use of chemotherapy or radiation. These data were awarded Best Oral Abstract by TCT.
Magenta is scaling up manufacturing of MGTA-117 and completing IND-enabling studies in 2020. The company intends to move this new product candidate into the clinic with initial clinical data in 2021.
Magenta also announced at the TCT meeting the completion of dosing in its Phase 1 trial of stem cell mobilization therapy clinical candidate MGTA-145, as well as updated clinical data from the trial in a presentation titled “Phase 1 Clinical Study of MGTA-145 in Combination with Plerixafor Shows Rapid Single-Day Mobilization and Collection of CD34+ HSCs without G-CSF.”
Mobilized peripheral blood is used for most of the 65,000 stem cell transplants performed every year across the U.S. and Europe. The current standard of care, G-CSF, requires at least five days of dosing and is associated with significant side effects — including bone pain that often requires narcotics. Patients with autoimmune diseases or sickle cell disease can have severe side effects, including potentially fatal complications.
Magenta is developing MGTA-145 as a new first-line standard of care for stem cell mobilization in a broad range of diseases, including autoimmune diseases, blood cancers and genetic diseases. MGTA-145, a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism of stem cell mobilization.
“Current options for stem cell mobilization for transplant are inefficient and cannot be used in all patients,” stated John DiPersio, M.D., Ph.D., professor of Medicine and chief of the Oncology Division at Washington University School of Medicine, in St. Louis, Missouri. “MGTA-145 is a novel medicine developed as a completely new standard of care for first-line stem cell mobilization for all patients and donors. The data presented at TCT show safe and robust mobilization of sufficient cells for transplant in hours with MGTA-145 and plerixafor, compared to the typical five or more days of dosing required for G-CSF. Additionally, we saw rapid engraftment of the cells collected in the Phase 1 study in humanized mouse models.”
Magenta’s Phase 1 trial achieved all primary and secondary endpoints. The company plans to move the MGTA-145 program into multiple Phase 2 studies in 2020. The studies will include both allogeneic and autologous transplant settings across multiple diseases, and will evaluate mobilization and collection of high-quality cells, and engraftment of the cells after transplant.
In addition, Magenta Therapeutics reported updated clinical data from Phase 2 trials of MGTA-456 at the TCT meeting, in a presentation called “MGTA-456 Cell Therapy in Inherited Metabolic Disease Yields Rapid and Durable Long-Term Improvement of Disease-Specific Outcomes in a Phase 2 Trial.”
MGTA-456 is designed to provide a high dose of hematopoietic stem cells (HSCs) that are well matched to the patient to enable safe immune and blood system rebuild in patients with inherited metabolic disorders, and remission in patients with blood cancers. Magenta is currently developing MGTA-456 in an ongoing Phase 2 study in patients with inherited metabolic disorders, including cerebral adrenoleukodystrophy, mucopolysaccharidosis type IH (Hurler syndrome), metachromatic leukodystrophy or globoid cell leukodystrophy (Krabbe disease). Investigators at the University of Minnesota are also studying the cryopreserved formulation of MGTA-456 in a Phase 2 clinical trial in patients with high-risk blood cancers.
“The clinical demonstration of rapid and durable resolution of disease in patients with inherited metabolic disorders is very compelling; it’s particularly encouraging as these results are not seen with currently available treatments, nor with gene therapies under investigation. Data from the University of Minnesota study in blood cancers add to the body of safety and engraftment data for MGTA-456, and, importantly, validate the introduction of cryopreserved 456 product into the Phase 2 study of inherited metabolic disorders, crucial for the establishment of multi-center trials, as well as eventual global patient access,” Davis noted.
Magenta intends to complete enrollment in the Phase 2 in 2020 and to continue dialogue with the U.S. Food and Drug Administration on the design of a registration-enabling study. The company also intends to have discussions with the European Medicines Agency for development in Europe.
In a separate presentation, John Wagner, M.D., from University of Minnesota, presented results from a Phase 2 trial of MGTA-456 in patients with high-risk hematologic malignancies. All patients treated to date in this Phase 2 trial successfully engrafted, with rapid neutrophil recovery. Kevin Goncalves, Ph.D., Magenta Therapeutics, also presented preclinical data demonstrating rapid and durable resolution of CNS, peripheral and skeletal abnormalities associated with IMDs in a Hurler mouse model following a high dose of CD34+ stem cells. This supports the hypothesis that a higher dose of CD34+ cells, such as MGTA-456, is linked to earlier engraftment and disease impact, and suggests that MGTA-456 may have impact on the disease in the periphery and skeleton.

Mel J. Yeates

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