Clinical-stage biotech Magenta Therapeutics confirmed that latest participant dosed at the Cohort 3 level (0.08 mg/kg) in the ongoing MGTA-117 Phase 1/2 Dose-Escalation Clinical Trial in relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) experienced a Grade 5 Serious Adverse Event (SAE) (respiratory failure and cardiac arrest resulting in death) deemed to be possibly related to MGTA-117.
The available information has been reported to the U.S. Food and Drug Administration (FDA) as a Suspected Unexpected Serious Adverse Reaction (SUSAR). After consultation with the trial’s safety Cohort Review Committee and with the highest regard for patient safety, Magenta Therapeutics said that it had voluntarily paused dosing in the clinical trial and is working to evaluate the totality of available data and determine next steps for the development of MGTA-117.
Hematopoietic stem cell transplant (HSCT) is a highly effective and potentially curative treatment for malignant and nonmalignant blood disorders, including relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
This treatment option requires patients to first receive a high dose of chemotherapy which is followed by an infusion of stem cells from a healthy donor’s bone marrow to helps form new blood cells to fight off the cancer long-term.
A crucial step in the hematopoietic stem cell transplantation (HSCT) process is called preparative ‘conditioning.’ This process involves removing a patient’s stem cells from the bone marrow before infusion of the new stem cells in the transplant.
The current approach to preparative myeloid conditioning prior to hematopoietic stem cell transplantation (HSCT) present a tradeoff between superior long-term efficacy of high-intensity radiation and non-targeted and non-selective toxic chemotherapy-based treatments regimens, known as myeloablative conditioning, or improved safety and tolerability with lower efficacy, referred to as reduced intensity conditioning. *
To change this approach, Magenta Therapeutics is developing MGTA-117, a novel, targeted and less toxic conditioning approach.
MGTA-117 is an anti-CD117 (c-KIT) antibody-drug conjugate (ADC) targeting the CD117 receptor conjugated with a stable linker to an amanitin payload.
CD117 is highly expressed on the cell surface of HSCs and leukemia cells, making it an ideal target for conditioning across broad sets of diseases, including certain hematological malignancies, hemoglobinopathies, such as sickle cell disease and beta-thalassemia, and inherited metabolic disorders.
Upon binding to CD117, the ADC is rapidly internalized, undergoing lysosomal degradation and intracellular release of the amanitin payload. This leads to apoptosis of quiescent and cycling cells. MGTA-117 is rapidly cleared from blood via selective binding and internalization of CD117. In addition, the antibody component of the ADC is an antagonist of the natural ligand for CD117 (stem cell factor), providing a dual mechanism of target cell depletion.
MGTA-117 is engineered to to rapidly clear from the bloodstream to ensure avoidance of depleting newly transplanted donor cells in allogeneic transplant or, in the case of gene therapy, of autologous gene-modified cells.
The investigational approach, which is far less toxic and with potentially better safety and efficacy profiles compared to current strategies, is designed to selectively eliminate stem cells and/or immune cells from a patient prior to transplant or gene therapy.
Based on preclinical studies, this technology has the potential to spare patients from the collateral damage to all organs that results from systemic high dose/high intensity chemotherapy conditioning and expand the number of patients eligible for the curative power of blood and immune reset through stem cell transplant. 
MGTA-117 is investigated in a phase 1/2 clinical study (NCT05223699). This study is designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and potential anti-leukemic activity and to establish the minimum safe and biologically-effective dose of a single dose of MGTA-117 in participants with relapsed/refractory (R/R) CD117+ acute myeloid leukemia (AML) and participants with myelodysplastic syndrome with excessive blasts (MDS-EB).
The paused phase 1/2 clinical trial in relapsed/refractory (R/R) AML and MDS included patients that 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.
Based on preclinical studies researchers MGTA-117 binds 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.
On December 1, 2022, Magenta Therapeutics reported that a total of 15 participants had 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. The four patient discontinuations were deemed to be related to MGTA-117.
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 originally expected.
Later in December 2022 Magenta Therapeutics reported that, per the clinical trial protocol for the MGTA-117 Phase 1/2 Dose Escalation Clinical Trial in relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), it has stopped dosing participants at the Cohort 4 dosing level (0.13 mg/kg) and plans to dose additional participants at the Cohort 3 dosing level (0.08 mg/kg).
As presented at the 2022 American Society of Hematology (ASH) Annual Meeting on December 12, 2022, no DLTs were observed in the fifteen participants dosed in the first three Cohorts in the clinical trial. 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.
At that time, three participants had been dosed in Cohort 4, and dose-limiting toxicities (DLTs) were observed in the second and third dosed participants. The first participant completed the 21-day DLT observation period with no DLTs. Subsequent to Magenta Therapeutics earlier presentation on December 13, 2022, a second dosed participant in Cohort 4 experienced a Grade 4 Serious Adverse Event (SAE) (respiratory) considered possibly related to MGTA-117. This Serious Adverse Event was later determined to be a DLT and a Suspected Unexpected Serious Adverse Reaction (SUSAR) due to lung involvement. This participant also experienced Grade 4 aspartate transaminase (AST) and Grade 3 alanine transaminase (ALT) elevations without clinically significant changes in bilirubin, gamma glutamyl transferase or alkaline phosphatase.
In the phase 1/2 study, MGTA-117 was shown to be rapidly cleared from the body as expected and MGTA-117 was no longer detectable in the blood 48 hours after dosing in Cohorts 1 and 2. The results also showed that over 95% of the investigational agent was cleared in the blood 48 hours after dosing at the higher dose level of Cohort 3.
In the study MGTA-117 was shown to be stable in blood over time in all participants. In addition, the investigators did not detect free payload in the blood of any participants at any time point.
Overall, MGTA-117 was well-tolerated in all participants without serious adverse events related to MGTA-117 or observed dose-limiting toxicities. The observed treatment-related adverse events 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 was expected.
Reporting adverse events
On December 15, 2022, Magenta Therapeutics received a report of a respiratory Serious Adverse Event (SAE) for the third dosed participant. This SAE was subsequently determined to be the second DLT in Cohort 4, thereby triggering pre-specified stopping rules for further dosing in Cohort 4. Following these reports, clinical trial sites reported that the first participant with a DLT has demonstrated improved respiratory status and AST/ALT enzyme levels, and the second participant with a DLT had improved respiratory status.
Ongoing Business (update)
Following the confirmation of the Suspected Unexpected Serious Adverse Reaction, Magenta Therapeutics’ management team said that it had completed a review of its business, including the status of its programs, resources, and capabilities and made the determination to halt further development of its programs and conduct a comprehensive review of strategic alternatives focused on maximizing shareholder value.
As part of this review process, Magenta Therapeutic will explore potential strategic alternatives that may include an acquisition, merger, business combination, or other transaction.
On February 6, the Board of Directors of Magenta Therapeutic approved a restructuring plan to reduce the company’s operations to preserve financial resources, resulting in a reduction of it’s workforce by up to 56 positions, or approximately 84%, to be substantially completed by February 17, 2023. As a result of the plan, Magenta Therapeutic expects to incur estimated severance and related costs of US $5.4 million by the end of February 2023.
In late November 2022, Magenta Therapeutic revealed in its third-quarter financial results, expected its cash runway to extend through the middle of 2024. At that time, the company’s cash equivalents and marketable securities were approximately US $128.3 million. In their filing with the US Securities and Exchange Commission on February 7, Magenta Therapeutics, announced that as of December 31, 2022, the company’s cash, cash equivalents and marketable securities were reduced to approximately US $112 million.
This article was updated on February 10, 2023.
* Note: According to the Center for International Blood & Marrow Transplantation Research (CIBMTR) the most commonly used conditioning regimens for myeloablative and reduced intensity/non-myeloablative conditioning in patients with AML or MDS/MPN. Of the myeloablative regimens, 43% were busulfan + fludarabine +/- others, TBI +/- others category were used in 21%. Amongst reduced intensity/non-myeloablative regimens 35% were fludarabine + melphalan +/- others, TBI +/- others were used in 34%. Myeloablative conditioning regimen: regimens with total body irradiation doses of ≥500 cGY, single fractionated doses of ≥800 cGY, busulfan doses of >9mg/kg oral or Bu >= 7.2 mg/kg IV, or melphalan doses of >150 mg/m2 given as single agents or in combination with other drugs. Reduced-intensity conditioning/Non-myeloablative regimen: regimens with lower doses of total body irradiation, fractionated radiation therapy, busulfan, and melphalan than those used to define a myeloablative conditioning regimen.
Study of MGTA-117 in Patients With Adult Acute Myeloid Leukemia (AML) and Myelodysplasia-Excess Blasts (MDS-EB)
 Bertelsen K, Lanieri L, Palchaudhuri R, Olson L. The Pharmacokinetic and Pharmacodynamic Characterization of Mgta-117, an Anti-CD117-Amanitin Antibody-Drug Conjugate for Targeted Conditioning Prior to Transplant, in Nonhuman Primates (Abstract #4592; Session: 701). Presented during the 64th American Society of Hematology Annual Meeting and Exposition held December 10 – 13, 2022 in New Orleans, Louisiana.
 Westervelt P, Kebriaei P, Juckett M, Artz AS, Chan O, McCarthy PL, Farag SS, Singh AK, Stein E, Humphrey J, Baeder W, Lee JH, Occhiuti A, Tang J, Santos D, Bertelsen K, Mahender B, Henry N, Rose S. Mgta-117, an Anti-CD117 Antibody-Drug Conjugated with Amanitin, in Participants with Relapsed/Refractory Adult Acute Myeloid Leukemia (AML) and Myelodysplasia with Excess Blasts (MDS-EB): Safety, Pharmacokinetics and Pharmacodynamics Initial Findings from a Phase 1/2 Study (Abstract #874; Session 721). Presented during the 64th American Society of Hematology Annual Meeting and Exposition held December 10 – 13, 2022 in New Orleans, Louisiana.
 Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2009;15(12):1628–1633. doi: 10.1016/j.bbmt.2009.07.004.
 Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2009;15(3):367–369. doi: 10.1016/j.bbmt.2008.12.497.
Featured image: Georgetown University Hospital, Washington, D.C. (Dec. 04, 2002) Surgeon Dr. Hans Janovich performs a bone marrow harvest operation on Aviation Electronics Technician 1st Class Michael Griffioen. The procedure consists of inserting a large-gauge syringe into an area of the hip and extracting the bone marrow. It is transfused into the recipient, and helps to recreate and replenish T-cells and the white and red blood cells killed while undergoing chemotherapy. Griffioen is assigned to the Pre-commissioning Unit Ronald Reagan (CVN 76) and was matched with an anonymous cancer patient through the Department of Defense Marrow Donor Program. Photo courtesy: © 2002 US Navy / U.S. Navy photo by Photographers Mate 2nd Class Chad McNeeley. File# 021204-N-0696M-180. Public domain.