Boston-based Magenta Therapeutics confirmed that the U.S. Food and Drug Administration (FDA) has approved the Investigational New Drug (IND) application for MGTA-117 in Acute myeloid leukemia and Myelodysplastic syndromes (MDS).

The investigational agent is the company’s lead targeted conditioning antibody-drug conjugate (ADC) designed to selectively deplete hematopoietic stem cells (HSCs) from patients prior to transplant or HSC-based gene therapy to reduce the need for high-dose or high-intensity chemotherapeutic agents or, in the case of gene therapy applications, to potentially eliminate the need for chemotherapeutic agents altogether,

The company expects to open the Phase 1/2 clinical trial in Q4 2021 to evaluate its MGTA-117 antibody-drug conjugate (ADC) targeted conditioning program n patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes .

“We are very pleased that our collaboration with the FDA has resulted in the clearance of the MGTA-117 IND. We have addressed the FDA’s request for a bioassay to be incorporated into the clinical trial protocol,” said Jason Gardner, D.Phil., President and Chief Executive Officer, Magenta Therapeutics.

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To prepare patients prior to transplantation of allogeneic hemopoietic stem cells (HSCT) they are treated with so-called conditioning regimens. Today, conditioning relies on the use of systemic chemotherapy agents and radiation, which include high-dose total-body irradiation and/or high-dose chemotherapy. The purpose of the conditioning regimen is to remove and reduce the tumor burden in patients with neoplastic disease and suppress the recipient’s immune system, in order to allow engraftment of stem cells.[1]

These current conditioning regimens, which for most patients with leukemia/lymphoma conditioning include either cyclophosphamide (CY) 120 mg/kg and total body irradiation (TBI) (10–15 Gy) (referred to as CY-TBI) or busulfan (BU) 16 mg/kg p.o. and CY 120 mg/kg, (referred to as BU-CY), present a tradeoff between superior long-term efficacy of high-intensity and toxic regimens (myeloablative conditioning) or improved safety and tolerability with lower efficacy (reduced intensity conditioning).[2]

A novel approach
Magenta is developing a suite of novel antibody-drug conjugates or ADCs for conditioning, to replace these toxic, non-targeted conditioning agents with specific and targeted agents with better safety and efficacy profiles.

The company’s targeted conditioning programs is designed to selectively eliminate stem cells and/or immune cells from a patient prior to transplant or gene therapy and to be far less toxic than the current radiation and chemotherapy-based treatments.

Curative potential
While ADCs are an established treatment for certain cancers, this is the first time that ADC technology is being developed for stem cell transplantation.

These programs have 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.

Magenta’s MGTA-117 is designed to selectively deplete stem cells from patients prior to transplant or HSC-based gene therapy to reduce the need for high-dose or high-intensity chemotherapeutic agents or, in the case of gene therapy applications, to potentially eliminate the need for chemotherapeutic agents altogether.

MGTA-117 is an anti-human CD117(c-kit)-targeted antibody conjugated to amanitin, an RNA polymerase II inhibitor, and engineered for a short half-life (t1/2) to enable rapid ADC clearance prior to HSCT.

Conjugated to amanitin, MGTA-117 robustly depletes both CD117+ HSPCs and leukemic blasts.  In preclinical studies, MGTA-117 has a t1/2 of 91 hours in humanized NSG (hNSG) mice compared to the parental wild type (WT) Ab with a t1/2 of 217 hours in human FCRN mice. Via optimization of the linker-toxin moiety, the maximum tolerated dose (MTD) in C57BL/6 mice was improved 17-fold compared to previous generations of the ADC.

The investigational agent’s target, CD117, is highly expressed on hematopoietic stem and progenitor cells (HSPC) and in ~80% of patient cells with AML and MDS, making it an ideal target for conditioning across broad sets of diseases, including certain blood cancers, hemoglobinopathies (sickle cell disease and beta-thalassemia), and inherited metabolic disorders.[3]

The targeted and optimized approach offered by MGTA-117 not only broadens the therapeutic window across preclinical models but also provides the dual benefit of effective conditioning for HSCT and reduction of target-expressing tumor cells.

“Improving conditioning treatments is essential for broadening patient access to the curative potential of stem cell transplant and gene therapies. We have designed MGTA-117 specifically to replace toxic radiation and chemotherapy-based conditioning agents used in current medical practice. [Our] program holds significant potential for patients across several disease areas,” Gardner noted.

The multi-center, open-label Phase 1/2 clinical trial with single-dose escalating cohorts will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MGTA-117 as a single agent in relapsed/refractory AML and MDS patients.

Magenta will continue to engage with the FDA to transition the trial to the intended primary target population of hematopoietic stem cell transplant-eligible AML and MDS patients. In addition, Magenta has planned gene therapy clinical trial collaborations with AVROBIO and Beam Therapeutics to evaluate the potential utility of MGTA-117 for conditioning gene therapy patients without the use of non-selective busulfan or other toxic chemotherapies.

[1] Vriesendorp HM. Aims of conditioning. Exp Hematol. 2003 Oct;31(10):844-54. doi: 10.1016/s0301-472x(03)00229-7. PMID: 14550799.
[2] Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N, Goodell BW, Hickman RO, Lerner KG, Neiman PE, Sale GE, Sanders JE, Singer J, Stevens M, Storb R, Weiden PL. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977 Apr;49(4):511-33. PMID: 14751.
[3] Lanieri L, Lamothe TL, Miske1 O, McDonough SM, Sarma1 GN, Bhattarai P, Latimer K, Dushime J, et al.A Single Dose of a Novel Anti-Human CD117-Amanitin Antibody Drug Conjugate (ADC) Engineered for a Short Half-Life Provides Dual Conditioning and Anti-Leukemic Activity and Extends Survival Compared to Standard of Care in Multiple Preclinical Models of Acute Myeloid Leukemia (AML). Abstract #1044. Presented during the 62nd annual meeting of the American Society of Hematology, held December 5 – 8, 2020. [Abstract]

Featured Image: Doctor explaining clinical trial to patient. Courtesy: © 2019 – 2021. Fotolia/Adobe Used with permission.

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