Motixafortide for Hematopoietic Stem and Progenitor Cell Mobilization and Collection in Sickle Cell Disease

Background and Significance: Gene therapy for sickle cell disease (SCD) using ex vivo modified autologous hematopoietic stem cells (HSCs) is advancing rapidly, with two cellular products approved in 2023 by the US Food and Drug Administration (FDA) and several others in ongoing clinical trials. All ex vivo modified autologous HSC-based products require peripheral blood (PB) mobilization and collection of patient HSCs, however several complications inherent to SCD may impair HSC collection. These include a stressed and damaged bone marrow niche, myelosuppression by the most commonly used disease modifying agent hydroxyurea (HU), and inability to mobilize with granulocyte colony stimulating factor (G-CSF). Mobilization of HSCs to the PB using the CXCR4 antagonist plerixafor followed by apheresis collection is the current strategy for harvesting HSCs. However, most patients require at least two mobilization cycles to collect the large numbers of HSCs required to manufacture an adequate cellular product. Each collection cycle, consisting of multi-day apheresis, must be separated by at least 2-4 weeks, which complicates manufacturing, increases cost, delays therapy, and increases the probability of adverse events. Moreover, failure to obtain adequate numbers of HSCs can prohibit gene therapy for some patients.

Motixafortide, a novel CXCR4 inhibitor peptide with high affinity CXCR4 receptor occupancy and extended pharmacodynamic effects, was recently FDA approved for mobilizing HSCs in individuals with multiple myeloma. Compared to plerixafor, motixafortide results in higher and more sustained levels of mobilized PB CD34+ cells with minimal adverse effects (Abraham et al. Clin Cancer Res.2017). Similar to plerixafor and in contrast to GCSF, motixafortide causes minimal neutrophil activation that can be dangerous in SCD. Therefore, motixafortide may represent an improved strategy to isolate patient HSCs for gene therapy applications by reducing the required number of mobilization cycles and increasing the proportion of patients for whom adequate numbers of HSCs can be obtained without the additional risk of severe events associated with GCSF.

Study Design and Methods: This is a phase 1 multicenter study (NCT06442761) to investigate the safety and tolerability of a single dose (Part A) or two daily doses (Part B) of motixafortide for HSC mobilization followed by apheresis collection in 12 adult participants with SCD. Participants with severe SCD of any genotype who are >/=18 years of age and willing to undergo mobilization and collection will be eligible. Participants must have adequate organ function, negative infectious disease testing, and be able to hold HU for at least 30 days. Participants with a history of recent acute SCD-related complications requiring medical care, use of an alternative investigational agent, history of an allogeneic bone marrow transplant, or inability to receive red blood cell transfusion will be excluded. If a participant is taking HU, it will be held for 30 days prior to mobilization, and blood transfusions will be recommended to limit the risk of sickle-related complications while HU is on hold. Participants will undergo red cell exchange transfusion to reduce the fraction of sickle hemoglobin near 30% within one week before mobilization. Arm A (N=6) will evaluate single dose motixafortide mobilization (1.25mg/kg) followed by a single apheresis collection. Arm B (N=6) will evaluate daily motixafortide administration (1.25mg/kg) for two days with two consecutive apheresis collections. During mobilization and apheresis, the kinetics of peripheral CD34+ cell mobilization will be analyzed by flow cytometry from blood collected at scheduled timepoints. A portion of mobilized mononuclear cells will be cryopreserved as a back-up product for possible future use by the participant. The statistical design is a modified 3+3 design with a safety review of dose-limiting toxicities after enrolling 3 participants at a time. Due to the small sample size, data related to all objectives will be analyzed and reported descriptively.

Conclusion: HSC mobilization with motixafortide may represent a safe and effective strategy to improve HSC mobilization and collection in individuals with SCD. Information gained by this study may contribute to the medical care, treatment, and advancement of transformative therapy for individuals with SCD.

Leonard:bluebird bio: Consultancy. Sharma:Beam Therapeutics: Other: Clinical Trial site-PI; CRISPR Therapeutics: Other: Clinical Trial site-PI, Research Funding; Novartis: Other: Clinical Trial site-PI; Vertex Pharmaceuticals: Consultancy, Other: Clinical Trial site-PI; Sangamo Therapeutics: Consultancy; Editas Medicine: Consultancy; Medexus Inc.: Consultancy. Rai:Global Blood Therapeutics: Consultancy. Sorani:BioLineRx, Ltd.: Current Employment. Gliko Kabir:BiolineRX: Current Employment, Current equity holder in publicly-traded company. Weiss:Cellarity Inc., Novartis, and Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Immatics: Other: DSMB; Be Biopharma: Consultancy; CARGO: Consultancy; T cell and/or gene therapy for cancer: Other: Patent and patent applications. Kanter:GLG Pharma: Consultancy; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline Rx: Consultancy; Optum United Health: Consultancy; bluebird bio: Consultancy, Research Funding; Guidepoint Global: Consultancy; Novo Nordisk: Consultancy, Research Funding; Sanofi: Consultancy; Affimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; EcoR1: Consultancy; Chiesi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam Tx: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; NIH/NHLBI: Other: Federal Funding; CDC: Other: Federal Funding; Health Resources and Services Administration: Other: Federal Funding; Bausch: Consultancy; Emerging Therapy Solutions: Honoraria; Fulcrum: Consultancy; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Watkins, Lourie, Roll & Chance: Consultancy.

Motixafortide, a novel CXCR4 inhibitor peptide with high affinity CXCR4 receptor occupancy and extended pharmacodynamic effects, was recently FDA approved for mobilizing HSCs in individuals with multiple myeloma. Here we are testing motixafortide for mobilizing HSCs in individuals with sickle cell disease.