A Phase 2, Open-Label Study to Evaluate the Efficacy and Safety of Mgta-145 in Combination with Plerixafor for the Mobilization of Hematopoietic Stem Cells in Patients with Sickle Cell Anemia

Background: In sickle cell anemia (SCA), a point mutation in the β-globin gene results in abnormal hemoglobin prone to polymerization under hypoxic conditions. Erythrocytes become sickle-shaped and rigid, leading to painful vaso-occlusion, ischemic tissue damage, and endothelial dysfunction. Despite significant, life-threatening risks, allogeneic hematopoietic cell transplant (allo-HCT) is the only cure for SCA. Results of autologous HCT, using the addition of a non-sickling, post-transcriptional gene silencing or gene editing to increase fetal hemoglobin, are promising and suggest an alternative option for those who lack a suitable donor. Procuring hematopoietic stem and progenitor cells (HSPCs) is challenging in patients with SCA, as granulocyte colony-stimulating factor is contraindicated due to severe adverse effects. Peripheral blood mobilization with Plerixafor (Mozobil®, Genzyme) has recently been shown to be safe and effective in SCA. While mobilization with plerixafor allows collection of an HSPC product, many SCA patients require ≥2 cycles of multiday plerixafor doses and apheresis to collect sufficient quantities of HSCs for genetic manipulation. Reports suggest 30% of patients experience vaso-occlusive events (VOEs) of grade ≥3 during and after apheresis; therefore, a considerable unmet need exists for agents that augment stem cell (SC) yields and reduce apheresis time. MGTA-145 is an agonist of cell-surface chemokine receptor 2 (CXCR2) under development for the mobilization of CD34⁺ cells in combination with plerixafor. MGTA-145 binds to CXCR2, resulting in HSC release, which when given with plerixafor, increases mobilization of HSCs. Preclinical studies in animal models and clinical trials in healthy subjects and patients with multiple myeloma demonstrated that MGTA-145 with plerixafor results in more rapid and robust mobilization of CD34⁺ cells, including primitive HSC populations, compared to plerixafor alone.

Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 1 or 2 doses of MGTA-145 combined with plerixafor for the mobilization of HSCs in individuals with SCA.

Study Design and Methods: This phase 2, open-label, 2-part study (NCT05445128) will enroll approximately 10-14 adults ages 18-35 years with SCA, at 3 sites in the US. Participants must have a documented diagnosis of SCA, have a hydroxyurea washout period, and have adequate white blood cell counts and cardiopulmonary, renal, and liver function. Key exclusion criteria include history of VOE requiring a visit to a healthcare facility within 30 days of screening, poorly controlled healthcare conditions, including but not limited to cardiopulmonary or hepatorenal events ≤6 months prior to screening, and cerebrovascular accident or retinal infarct ≤2 years prior to screening. In the 1st cohort of Part A, subjects will receive a single 0.24 mg/kg subcutaneous dose of plerixafor followed by a single 0.03 mg/kg IV dose of MGTA-145, with apheresis occurring within approximately 30-45 minutes of MGTA-145 dosing. After a 1-week follow-up visit and an Independent Data Monitoring Committee (DMC) review, the 2nd cohort with additional subjects may be enrolled and given plerixafor and a 0.03 or 0.015 mg/kg or lower dose of MGTA-145 (FIGURE). Following a 1-week follow-up visit and a 2nd DMC review, patients will be enrolled in Part B and will receive, on 2 consecutive days, plerixafor and the same dose of MGTA-145 as the 2nd Part A cohort, followed by apheresis on each dosing day. The primary endpoint is total yield of CD34⁺ cells (CD34⁺ cells/kg). Safety outcomes include incidence of treatment-emergent adverse events (TEAEs), drug-related TEAEs, Grade ≥3 TEAEs, treatment-emergent serious adverse events, and TEAEs leading to study drug discontinuation. Core exploratory endpoints include characterization of the phenotype and function of cells collected by apheresis and assessment of the gene-modifying potential of mobilized CD34⁺ cells. The results of this trial will establish if MGTA-145 with plerixafor will rapidly and safely mobilize robust numbers of high-quality SCs for HSCT in SCA.

Sharma:Medexus Inc: Consultancy; CRISPR Therapeutics: Research Funding; Vindico Medical Education: Honoraria; Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research collaboration; Vertex Pharmaceuticals/CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Other; Novartis: Other: Other. Manis:Terumo BCT Inc: Speakers Bureau. Williams:Novartis: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beam Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Emerging Therapy Solutions: Consultancy, Membership on an entity's Board of Directors or advisory committees; Skyline Therapeutics (formerly Geneception): Membership on an entity's Board of Directors or advisory committees; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees. Efuni:Magenta Therapeutics: Current Employment. Lee:Magenta Therapeutics: Current Employment. Conlin:Magenta Therapeutics: Current Employment; Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rose:Magenta Therapeutics: Current Employment. Humphrey:Magenta Therapeutics: Current Employment; Cyteir Therapeutics: Membership on an entity's Board of Directors or advisory committees. Bertelsen:Magenta Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company; Janssen Pharmaceuticals: Current equity holder in private company; Abbvie Pharmaceuticals: Current equity holder in private company. Henry:Magenta Therapeutics: Current Employment. Li:Magenta Therapeutics: Current Employment. Pardy:Magenta Therapeutics: Current Employment; Kadmon Corporation: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Santos:Magenta Therapeutics: Current Employment. Zdybowicz:Magenta Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.