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Courtesy of Getty Images Magenta Therapeutics has suspended the development of its clinical programs and initiated a strategic review of business alternatives after a patient's death halted a Phase I/II trial. The Massachusetts biotech paused a dose-escalation study of its lead asset, MGTA-117, in acute myeloid leukemia on Jan. 26th after a patient suffered respiratory failure and cardiac arrest. The death was deemed possibly related to the study drug. The trial hold was voluntary but by the recommendations of a safety Cohort Review Committee. Magenta reported the incident to the FDA as a Suspected Unexpected Serious Adverse Reaction. As of Sept. 30th, 2022, Magenta still had cash, cash equivalents and marketable securities amounting to $128.3 million. The company revealed in its third-quarter financial results, posted November 2022. At the time, Magenta expected its cash runway to extend through the middle of 2024. As part of its business review, the company will assess the feasibility of an acquisition, merger, business combination or other similar transactions. Though Magenta made no assurances that the review would lead to an attractive business option, the company’s shares rose 47% post-market trading Thursday. Suspended Stem Cell Programs Magenta's pipeline is focused on stem cell transplantation. The company was developing novel antibody-drug conjugates to enable either mobilization and collection, wherein stem cells are extracted from a patient’s or donor’s bone marrow, or conditioning, which involves the removal of stem cells from the recipient’s bone marrow. While ADCs have long been known to be effective against specific cancers, Magenta has pioneered its use in stem cell transplantation. MGTA-117 was tested as a conditioning agent. The candidate targeted the CD117 receptor and was designed to selectively deplete cells bearing this protein, thereby reducing or eliminating the need for chemotherapy. CD117 is a cell surface-bound protein enriched in hematopoietic stem cells and leukemia cells, making it a good conditioning target for many blood disorders. Magenta was also developing a second investigational conditioning agent, a CD45-targeted ADC. This candidate was in preclinical studies and had recently completed dose-ranging toxicology assessments with no unexpected findings. MGTA-145, an agonist of the CXCR2 protein, was designed to be used with plerixafor, a CXCR4 antagonist, to target complementary pathways to improve the process of stem cells being released into the bloodstream. The candidate was in two Phase II trials.

CAMBRIDGE, Mass., Dec. 12, 2022 (GLOBE NEWSWIRE) -- Magenta Therapeutics (Nasdaq: MGTA), a clinical-stage biotechnology company developing novel medicines designed to bring the curative power of stem cell transplant to more patients, highlights updated clinical data from the ongoing MGTA-117 Phase 1/2 dose-escalation clinical trial made in an oral presentation today at the American Society of Hematology 2022 Annual (ASH) Meeting in New Orleans and provides program updates across the portfolio. “We have shown that a single dose of MGTA-117 binds target cells, depletes target cells, clears the body quickly as designed, and does so with a favorable tolerability profile in our ongoing Phase 1/2 clinical trial. We believe that these positive clinical data establishes proof-of-mechanism, and that we have reached an active dose. Target cell depletion is a critical measurement of success for MGTA-117, and we are encouraged by the levels of depletion we have observed in both the blood and the bone marrow of relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. We are excited about our planned next steps to take MGTA-117 into transplant-eligible AML and MDS patients as well as into patients who are receiving gene therapy. We are thankful to all of the patients and families who have participated in our trial to date as well as our investigators and the clinical site staff, all of whom have contributed greatly to the advancement of MGTA-117 for patients,” said Jason Gardner, President and Chief Executive Officer of Magenta Therapeutics. “Together with the progress we are making on CD45-ADC and MGTA-145, we are pleased with the momentum across our portfolio and the multiple anticipated inflection points for Magenta in the coming year.” MGTA-117 Clinical Data and Continued Development MGTA-117 is Magenta’s most advanced targeted conditioning product candidate designed to deplete CD117-expressing target cells in the blood and/or bone marrow prior to a patient undergoing stem cell transplant or receiving an ex vivo gene therapy product. MGTA-117 is an anti-CD117 antibody conjugated to an amanitin payload. CD117, also known as c-Kit receptor, is highly expressed on hematopoietic stem cells, progenitor cells and cancer blast cells. Current Phase 1/2 Patient Population and Potential Significance for Clinical Development The ongoing Phase 1/2 clinical trial is in relapsed/refractory (R/R) AML and MDS. These patients are deemed ineligible for transplant due to active disease characterized by high numbers of cancer blast cells present in the bone marrow and in the bloodstream. Over 80% of patients with AML and MDS express the CD117 receptor on the surface of their cancer cells. In these patients, CD117+ target cells are a combination of cancer blast cells in the blood and bone marrow and non-malignant stem and progenitor cells in the bone marrow. MGTA-117 is designed to target all of these cells, and clinical evidence of depletion in this patient population provides valuable support that MGTA-117 will robustly deplete target cells in the proposed next phase of development in (i) transplant-eligible AML and MDS patients who have significantly lower numbers of cancer blast cells and (ii) gene therapy patients who have no cancer blast cells. Therefore, Magenta expects MGTA-117 to bind and deplete target cells in the bone marrow in these patient populations, and potentially achieve greater levels of depletion, at the same dose levels studied in R/R AML and MDS patients. MGTA-117 Proof-of-Mechanism and Potential Active Dose Participants Dosed & Available Data. As of December 1, 2022, a total of 15 participants have been dosed with MGTA-117 in Cohorts 1, 2 and 3. All dosed participants contributed data in whole or in part to the preliminary data set depending on an individual’s availability for collecting assessments. Eleven of the 15 dosed participants completed the dose-limiting toxicity safety observation period of 21 days. None of the four participant discontinuations were deemed to be related to MGTA-117. Target Cell Binding. MGTA-117 bound to CD117-expressing target cells within 15 minutes after dosing in all participants as measured by a receptor occupancy (RO) assay. RO increased with higher dose levels of MGTA-117. The percentage of occupied CD117 receptors was greater, and the receptor occupancy was more durable at the higher dose levels of Cohorts 2 and 3 as compared to Cohort 1 as expected. Target Cell Depletion. Depletion in Blood and Bone Marrow. MGTA-117 showed greater depletion of target cancer blast cells in the blood of participants in Cohorts 2 and 3 compared to Cohort 1. In addition, three out of the four participants in Cohort 3 for whom paired bone marrow samples were collected at baseline and post-dosing had depletion of cancer blast cells in both blood and bone marrow. This matched depletion response in the blood and bone marrow provides evidence of an active dose and dose-dependent depletion of CD117-expressing cells. Two Transplant-Ineligible Participants Became Transplant-Eligible. Participants entering the clinical trial were considered ineligible for stem cell transplant and had active and persistent AML/MDS after receiving one or more anti-leukemic therapies. One relapsed/refractory MDS participant in Cohort 3 had a reduction of bone marrow cancer blast cells to a level that enabled the participant to become eligible for transplant. This is the trial’s second participant who became eligible for transplant after a single dose of MGTA-117. The first participant, from Cohort 1, had relapsed/refractory AML and was previously disclosed. Clearance. MGTA-117 was shown to be rapidly cleared from the body as expected. No MGTA-117 was detectable in the blood 48 hours after dosing in Cohorts 1 and 2, and over 95% of MGTA-117 was cleared in the blood 48 hours after dosing at the higher dose level of Cohort 3. Rapid clearance of MGTA-117 was engineered into the molecule to ensure avoidance of depleting newly transplanted donor cells in allogeneic transplant or, in the case of gene therapy, of autologous gene-modified cells. In addition, the MGTA-117 ADC was shown to be stable in blood over time in all participants, and no free payload was detectable in the blood of any participants at any time point. Tolerability. MGTA-117 was well-tolerated in all participants. No serious adverse events were deemed to be related to MGTA-117, and no dose-limiting toxicities were observed. Treatment-related adverse events deemed to be related to MGTA-117 were low-grade liver enzyme elevations, low-grade fever, and grade 3 and grade 4 leukopenia in two participants who had baseline grade 2 and grade 3 leukopenia, respectively. All instances of observed liver enzyme elevations were low-grade, transient and resolved without intervention, as expected. Continued Trial Progress and Data Expectations. The Phase 1/2 clinical trial is currently enrolling in Cohort 4 (0.13 mg/kg) and Magenta anticipates presenting aggregate clinical data from the clinical trial, including Cohort 4, at a scientific conference in Q1 2023. MGTA-117 Regulatory Engagement and Clinical Development Next Steps in Transplant-Eligible AML/MDS and Autologous Gene Therapy As previously disclosed, Magenta has initiated formal engagements with regulatory agencies to transition MGTA-117 into a transplant-eligible AML and MDS patient population. Magenta also plans to engage regulators in H1 2023 for the purposes of initiating a MGTA-117 clinical trial in autologous ex vivo gene therapy. Transplant-Eligible AML and MDS. Magenta anticipates that MGTA-117’s pharmacokinetics (PK), pharmacodynamics (PD) and tolerability in Cohorts 1-3 will support alignment with regulatory authorities to study MGTA-117 in AML and MDS transplant-eligible patients. Importantly, the proposed study design in the transplant setting will allow for the measurement of depletion of CD117-expressing cells in the bone marrow after a single dose of MGTA-117 prior to reduced-intensity conditioning (RIC) and the ensuing allogeneic transplant. By depleting residual cancer blast cells prior to a standard RIC regimen, MGTA-117 has the potential to boost disease control prior to transplant and improve disease outcomes post-transplant. These potential positive outcomes could address the current significant unmet need associated with RIC-conditioning where AML and MDS patients relapse at a rate of 40%-50% within six months post-transplant1. Pending regulatory alignment, Magenta plans to share additional details of the proposed transplant-eligible MGTA-117 study design in Q1 2023. Gene Therapy. Magenta expects to use the clinical data package from the ongoing Phase 1/2 trial, together with supporting insights from PK/PD modeling, to engage with regulators on a potential MGTA-117 clinical trial in autologous ex vivo gene therapy. In a gene therapy clinical trial, Magenta anticipates dosing patients with MGTA-117 to deplete stem and progenitor cells before the patient receives an infusion of gene-modified stem cells, with a goal of replacing the current standard-of-care conditioning that relies on high doses of chemotherapeutic agents such as busulfan, which is known to be carcinogenic. Magenta anticipates sharing more details in 2023 as development plans progress in collaboration with gene therapy partners. Magenta has existing clinical collaborations with gene therapy companies and anticipates entering into additional collaborations as MGTA-117 development advances. CD45-ADC IND-Enabling Plans Magenta’s CD45-ADC is a second targeted conditioning ADC, designed to selectively target and deplete both stem cells and immune cells, and is intended to replace the use of chemotherapy-based conditioning prior to stem cell transplant in patients with blood cancers and autoimmune diseases. As previously disclosed, Good Manufacturing Practice (GMP) manufacturing and other investigative new drug application (IND)-enabling activities are ongoing for the CD45-ADC program. A Good Laboratory Practice (GLP) toxicology study is expected to be completed in H2 2023. Magenta anticipates regulatory interactions prior to filing an IND and anticipates providing further details on the CD45-ADC program in 2023, including molecule design, key preclinical data, and timelines to IND. MGTA-145 Phase 2 Progress Magenta is developing MGTA-145, in combination with plerixafor, to improve the process by which stem cells are released out of the bone marrow and into the bloodstream, known as stem cell mobilization. The mobilized cells are then collected and available for transplant. This is the first step for patients and is required for the majority of transplants and stem cell gene therapies. Magenta, in partnership with bluebird bio, is enrolling patients in a Phase 2 clinical trial evaluating the ability of MGTA-145 in combination with plerixafor to mobilize stem cells for collection in patients with sickle cell disease. Due to enrollment delays at the clinical sites that are unrelated to MGTA-145, Magenta anticipates disclosing clinical data in H1 2023. Conference Call Information: Magenta will host a conference call and webcast at 8:30 a.m. Eastern Time / 7:30 a.m. Central Time tomorrow, Tuesday, December 13, 2022 to review the MGTA-117 data presented at the 2022 ASH Annual Meeting. To access the conference call, please register online at https://register.vevent.com/register/BI872661cff05d4191a7bb100830aae147. Upon registering, each participant will be provided with call details and a conference ID. The live webcast of the call and slide deck may be accessed at https://edge.media-server.com/mmc/p/hk2eojv2, or by visiting the Investors & Media section of the company's website at https://investor.magentatx.com. A replay of the webcast will be available shortly after the conclusion of the call and will be archived on the Events & Presentations page. 1 Scott, Journal of Clinical Oncology 2017. https://pubmed.ncbi.nlm.nih.gov/28380315/ About Magenta Therapeutics Magenta Therapeutics is a clinical-stage biotechnology company developing medicines designed to bring the curative power of stem cell transplant to more patients with blood cancers, genetic diseases and autoimmune diseases. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise to revolutionize blood and immune reset to allow more patients to take advantage of the curative potential of stem cell transplant and potentially improve eligibility for future gene therapies. Magenta is based in Cambridge, Mass. For more information, please visit www.magentatx.com. Follow Magenta on Twitter: @magentatx