Lentiviral-Mediated Gene Therapy for Patients with Fanconi Anemia [Group a]: Updated Results from Global RP-L102 Clinical Trials

Background: Fanconi Anemia (FA) is a rare inherited deoxyribonucleic acid (DNA) repair disorder that results in progressive and severe bone marrow failure (BMF) within the first decade of life in 80% of patients. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative of BMF, with survival exceeding 80% in experienced centers. AlloHSCT is limited by donor availability and patients may experience short- and long-term toxicities, including 100-day transplant associated mortality, graft-vs-host disease (GvHD), and 3- to 4-fold increased cancer risk. Mozafancogene autotemcel (fanca-cel; RP-L102) is a gene therapy product comprised of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with a lentiviral vector (LV) encoding a functional copy of the FANCA gene. In contrast to alloHSCT, fanca-cel is administered without antecedent conditioning, relying on the proliferative advantage of the gene-corrected cells to enable engraftment. Here, we present data from patients with FA complementation group A (FA-A) treated with fanca-cel in global Phase 1/2 studies with ≥1 year of follow-up.

Methods: Patients with FANCA mutations, age ≥1 year, no HLA-matched sibling donor and ≥30 CD34+ cells/µL in bone marrow (BM) were eligible. Peripheral blood (PB) mononuclear cells were collected via leukapheresis after mobilization with granulocyte colony-stimulating factor (G-CSF) and plerixafor. Following CD34+ enrichment, HSPCs were transduced with an LV carrying the FANCA gene and infused without cryopreservation or conditioning. Patients are being followed for safety and efficacy (increasing vector copy number [VCN], mitomycin-C [MMC] resistance in BM colony forming cells [CFCs]), and stabilization of cytopenias for 3 years in both the parent study and subsequently in a long-term follow-up (LTFU) study.

Results: As of September 2023, 14 patients aged 1 to 6 years at enrollment have undergone successful apheresis and treatment with fanca-cel without significant complications. Mean (SD) age at infusion was 4.05 (1.65) years (range: 1.8-7.0 years); 57.1% were female and majority of the patients were White (not Hispanic or Latino). Twelve patients have ≥12 months of follow-up; mean (SD) follow-up was 2.95 (0.97) years (range: 1.5-4.5 years). Progressive and sustained genetic correction was observed in 8 of the 12 patients with ≥12 months of follow-up, indicative of the corrected cells' proliferative advantage. Improvement in BM MMC-resistance, demonstrative of phenotypic correction, was identified in 7 patients at 12 months post-gene therapy; one additional patient developed BM MMC-resistance and preliminary evidence of hematologic stabilization after 36 months, during the LTFU observation. Genetic and phenotypic correction have been associated with sustained hematologic stability. Additional data will be presented at the time of the meeting.

The most common treatment-emergent adverse events (TEAEs) were pyrexia, anemia, thrombocytopenia, upper respiratory tract infection, and neutropenia. The majority of TEAEs were mild/moderate in severity, non-serious, and unrelated to fanca-cel. One patient experienced a Grade 2 transient infusion-related reaction that resolved without additional clinical sequelae. Overall clonality and diversity indices (Gini, Shannon, and UC50) indicated predominantly polyclonal integration patterns. There were no signs of bone marrow dysplasia, clonal dominance or insertional oncogenesis related to fanca-cel. No patients developed myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Two patients were withdrawn from the study and underwent successful alloHSCT for BMF (n=1) and an unrelated thoracic non-Hodgkin lymphoma (n=1).

Conclusions: Fanca-cel is a potentially curative therapy to prevent FA-related BMF, does not require a suitable allogeneic donor, and does not confer alloHSCT-related toxicities. Progressive engraftment of gene-corrected cells was identified in 8 patients with ≥1 year of follow-up in the absence of conditioning and attendant risks. Genetic correction and concomitant phenotypic correction are associated with sustained hematologic stabilization. Fanca-cel has been well-tolerated with no significant safety signals. The risk-benefit profile of fanca-cel appears favorable.

Czechowicz:Magenta Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Decibel Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: Patent, no royalties; Beam Therapeutics: Current equity holder in publicly-traded company; Jasper Therapeutics: Patents & Royalties, Research Funding; Global Blood Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Rocket Pharma: Research Funding; Prime Medicine: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Teiko Bio: Current holder of stock options in a privately-held company; Spotlight Therapeutics: Consultancy, Current holder of stock options in a privately-held company; STRM.Bio: Research Funding; Inograft Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Editas Medicine: Current equity holder in publicly-traded company, Patents & Royalties: Patent, no royalties. Sevilla:SOBI: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy, Patents & Royalties: J.Sevilla is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez DÃaz, and may be entitled to receive financial benefits from the licensing of such patents; licensed medical products from Rocket Pharma. Booth:Rocket Pharmaceuticals Inc.: Consultancy; Chiesi Farmaceutici S.p.A.: Honoraria; Ensoma: Consultancy. Zubicaray:Novartis: Consultancy. Rio:Rocket Pharmaceuticals Inc.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Patents & Royalties: Dr. Navarro has licensed medicinal products, Research Funding. Ancliff:GSK: Current holder of stock options in a privately-held company. Rothe:Rocket Pharmaceuticals, Inc.: Research Funding. Bastone:Rocket Pharmaceuticals, Inc.: Research Funding. John-Neek:Rocket Pharmaceuticals, Inc.: Research Funding. Wang:Syneos Health: Current Employment. Choi:Rocket Pharmaceuticals, Inc.: Current Employment. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment. Wagner:Rocket Pharma: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals: Consultancy; Magenta Therapeutics: Current equity holder in private company; ASC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Garuda Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rao:Rocket Pharmaceuticals, Inc.: Current Employment. Thrasher:Orchard Therapeutics: Consultancy. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Research Funding.