Hematopoietic stem-cell transplantation, also known as a bone marrow transplant, includes the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood to replicate inside a patient and to produce additional normal, healthy, blood cells.

Using a conditioning regimen before infusion of the new hematopoietic stem cells is necessary to remove the patient’s diseased cells from the patient’s bone marrow. These conditioning regimens generally include chemotherapy or radiation to the entire body. They are designed to “make room” in the patient’s bone marrow for new blood stem cells to grow, helps prevent the patient’s body from rejecting the transplanted cells, and help kill any cancer cells that are in the body.

Current conditioning regimens 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).

Magenta Therapeutics is developing a novel approach designed to bring the curative power of stem cell transplant to more patients. Among the agents the company is developing is MGTA-117, an 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.

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MGTA-117 targets the CD117 receptor, which is highly expressed on the cell surface of HSCs and leukemia cells, making it a promising target for conditioning across broad sets of diseases, including certain blood cancers, hemoglobinopathies (sickle cell disease and beta-thalassemia), and inherited metabolic disorders.

Phase 1/2 Clinical Trial Ongoing
The company is currently conducting a Phase 1/2 dose-escalation clinical trial of MGTA-117 in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB).

“Improving conditioning treatments is essential for broadening patient accessibility 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. This program holds significant potential for patients across several disease areas,” noted Jason Gardner, D.Phil., President and Chief Executive Officer, Magenta Therapeutics.

The clinical trial progressed from Cohort 1 to Cohort 2 after meeting all protocol requirements for dose escalation. In the trial, patients in Cohort 1 had varying degrees of disease burden as measured in part by the percentage of leukemic cells in the bone marrow and the bloodstream. Clinical observations were made from a preliminary data set from Cohort 1 which utilizes the trial’s lowest dose of MGTA-117 (0.02 mg/kg). Three patients with relapsed/refractory adult acute myeloid leukemia (AML) completed the safety evaluation period. A fourth patient with high disease burden did not complete the evaluation period due to disease progression with no drug-related adverse events. Cohort 2 is now open and enrolling and MGTA-117 will be evaluated as a single dose of 0.04 mg/kg.

Early Clinical Observations from Cohort 1.

  • Target Engagement/Binding: Preliminary data from four patients were available for measuring target engagement. In all patients, MGTA-117 was shown to bind CD117+ cells in the blood as measured by a receptor occupancy assay.
  • Cell Depletion: Bone marrow aspirates were obtained for three patients at baseline and post-dosing and provided evidence supportive of biologic activity.
  • Reductions of Erythroid Progenitor Cells in the Bone Marrow: One patient had measurable reductions of CD117+ erythroid progenitor cells in the bone marrow following MGTA-117 administration.
  • Reductions of Blasts in the Bone Marrow: An additional patient had an approximate 83% reduction of blasts in the bone marrow at day 14 post-dosing (from 6% to 1%). The patient proceeded to a conditioning regimen followed by stem cell transplant. The patient’s baseline profile closely resembled that of transplant-eligible AML patients due to relatively low percentages of blasts in the bone marrow and bloodstream. Magenta believes that this outcome provides an encouraging early signal in support of MGTA-117’s planned transition to the transplant-eligible AML patient population.
  • Rapid Drug Clearance: Preliminary data from four patients were available for measuring drug clearance. In all patients, MGTA-117 was deemed to be cleared 48 hours after dosing. Rapid and sufficient clearance of conditioning agents from circulation is a necessary step before stem cell infusion.
  • Favorable Tolerability Profile: For all four patients, no unexpected or serious drug-related adverse events were reported, no dose-limiting toxicities were observed and no drug-related adverse events higher than Grade 1 were reported.

The company anticipates that further data from the current clinical trial showing MGTA-117 at high receptor occupancy levels with well-tolerated cell depletion in the blood and/or bone marrow will be supportive of the planned transition to transplant-eligible patients. Magenta is planning to engage with regulatory authorities prior to amending the clinical trial protocol to evaluate MGTA-117 as a targeted conditioning agent in combination with reduced intensity chemotherapy prior to a stem cell transplant. Simultaneously with the planned clinical trial transition, Magenta expects to initiate clinical collaboration planning with existing and potential gene therapy partners to explore MGTA-117 as a single agent conditioning regimen prior to autologous stem cell gene therapy.

“Our clinical observations from preliminary data indicate that MGTA-117 is functioning as designed by binding to the intended cells with a post-dose reduction of target cells in the bone marrow, clearing the body rapidly and doing so with a favorable tolerability profile. With this level of measurable activity at our lowest dose, we believe we will collect enough information in 2022 from the next 1-2 cohorts to build a data set for communications with regulators for our planned transition to the transplant-eligible AML patient population, including possible proof-of-concept of MGTA-117 in transplant-eligible AML patients and genetic diseases with gene therapy,” Gardner said.

“We are encouraged by these preliminary data. Post-dose reduction of progenitor and tumor blast cell populations in bone marrow suggests biologic activity. We anticipate that dose escalation will lead to further drug activity and enable identification of an appropriate dose for development in patients eligible for transplant,” said Jeff Humphrey, MD, Chief Medical Officer of Magenta Therapeutics.

A second Targeted Condition program
In addition to MGTA-117, Magenta is also developing a second targeted conditioning program called CD45-ADC in combination with plerixafor.[1]

CD45 is broadly expressed on hematopoietic cells and Magenta’s CD45-ADC called MGTA-145, is designed to selectively target and deplete both stem cells and lymphocytes, which would enable patients with blood cancers and autoimmune diseases to avoid the use of chemotherapy prior to stem cell transplant.

MGTA-145 in combination with plerixafor is designed to improve stem cell mobilization from bone marrow into the bloodstream. The collection of peripheral blood stem cells, known as stem cell mobilization, is a common source of stem cells for hematopoietic stem cell transplants and gene therapy applications.

In completed Phase 1 study in healthy volunteers, the investigational drug demonstrated that it can rapidly and reliably mobilize high numbers of functional stem cells in a single day, without the need for G-CSF.  In these trials, MGTA-145 was well tolerated and enabled same-day dosing, and simplified collection of sufficient stem cells for transplant, meeting all primary and secondary endpoints.

MGTA-145 works in combination with plerixafor to harness a physiological mechanism of stem cell mobilization to rapidly and reliably mobilize HSCs for collection and transplant across multiple indications.

Additionally, as shown in preclinical studies, stem cells mobilized with MGTA-145 can be efficiently gene-modified and are able to engraft, potentially allowing for safer and more efficient mobilization for gene therapy approaches to treat sickle cell disease and other genetic diseases.

Ongoing studies
The company is preparing for the initiation of a Phase 2 clinical trial in sickle cell disease (SCD) in collaboration with bluebird bio to evaluate MGTA-145, in combination with plerixafor, for mobilization and collection of stem cells in patients with sickle cell disease. Mobilization and collection are difficult in sickle cell disease, and there is a clear unmet medical need. Initial data from this trial are expected in the second half of 2022.

Clinical trials
Study of MGTA-117 in Patients With Adult Acute Myeloid Leukemia (AML) and Myelodysplasia-Excess Blasts (MDS-EB) – NCT05223699
Study of MGTA-145 and Plerixafor in Patients With Sickle Cell Disease – NCT05445128
MGTA-145 + Plerixafor in the Mobilization of HSCs for Allogeneic Transplant in Hematologic Malignancies – NCT04762875
MGTA-145 + Plerixafor in the Mobilization of Hematopoietic Stem Cells for Autologous Transplantation in Multiple Myeloma – NCT04552743
Study Assessing Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MGTA-145 in Healthy Volunteers as a Single Agent or in Combination With Plerixafor – NCT03932864
Study Assessing PK and Safety of MGTA-145 in Subjects With Normal Estimated GFR and Varying Degrees of Renal Impairment – NCT04154670

Reference
[1] Li C, Goncalves KA, Raskó T, Pande A, Gil S, Liu Z, Izsvák Z, Papayannopoulou T, Davis JC, Kiem HP, Lieber A. Single-dose MGTA-145/plerixafor leads to efficient mobilization and in vivo transduction of HSCs with thalassemia correction in mice. Blood Adv. 2021 Mar 9;5(5):1239-1249. doi: 10.1182/bloodadvances.2020003714. PMID: 33646305; PMCID: PMC7948287.

Featured Image: Clinical trial. Courtesy: © 2010 – 2022 Fotolia/Adobe. Used with permission.

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