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

Background: Fanconi anemia (FA) is an inherited deoxyribonucleic acid (DNA) repair disorder that results in progressive bone marrow failure (BMF) in childhood and predisposition to hematologic malignancies and solid tumors. Approximately 60 to 70% of cases result from mutations in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative for FA-related BMF. Although survival exceeds 80% in experienced transplant centers, adverse effects including 100-day mortality and increased cancer risk limit overall success. The current gene therapy studies utilize autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) and rely upon the proliferative advantage of gene-corrected FA HSPCs, enabling engraftment without antecedent conditioning, as demonstrated in pre-clinical studies and the FANCOLEN-I clinical trial conducted in Madrid, Spain. We report results from global RP-L102 studies using "Process B” manufacturing optimizations including transduction enhancers, commercial grade vector, and modified cell processing.

Methods: Patients with FANCA mutations, age ≥1 year with no HLA-matched sibling donor and at least 30 CD34+ cells/µL in bone marrow (BM) are eligible. Peripheral blood (PB) mononuclear cells are collected via leukapheresis on 2 consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. Following leukapheresis, CD34+ cells are enriched, transduced with a lentiviral vector carrying the FANCA gene, and infused without cryopreservation or conditioning. Patients are followed for 3 years post-infusion for safety assessments (including replication competent lentivirus [RCL] and insertion site analysis [ISA]) and for evidence of efficacy (increasing PB and BM vector copy number [VCN] and mitomycin-C [MMC] resistance in BM colony forming cells [CFCs]), along with stabilization/correction of cytopenias.

Results: As of April 2022, 12 patients age 2 to 6 years have received RP-L102. Sustained engraftment has been demonstrated in 6 of 9 evaluable patients with ≥12 months of follow up as indicated by peripheral blood mononuclear cell (PBMC) VCN. Five of these 6 patients have increasing BM CFC MMC resistance ranging from 51-94% at 18-24 months with concurrent hematologic stabilization. Concurrent with phenotypic correction, genetic correction has been seen as indicated by increasing PBMC VCN (range 0.35-0.58) and bone marrow mononuclear cell (BMMC) VCN (0.17-1.03). One patient without evidence of genetic correction had progressive BMF and underwent successful alloHSCT. A transient serious Grade 2 RP-L102 infusion-related reaction was observed in one patient and resolved without sequelae. There has been no evidence of RP-L102 related RCL, clonal dominance or oncogenic integrations.

Conclusions: Comprehensive efficacy was identified in 5 of 9 patients with ≥1 year of follow up as demonstrated by increasing BM CFC MMC resistance, concomitant genetic markings and hematologic stabilization. Progressive engraftment of gene-corrected cells was identified in the absence of antecedent conditioning and attendant risks. Updated safety and efficacy data for patients with ≥12 months of follow up will be presented.

Czechowicz:Teiko Bio: Consultancy, Current holder of stock options in a privately-held company; STRM.BIO: Research Funding; Rocket Pharmaceuticals, Inc.: Research Funding; GV: Consultancy, Current equity holder in publicly-traded company; Editas Medicine: Current equity holder in publicly-traded company; Magenta Therapeutics: Current equity holder in publicly-traded company, Other: Intellectual Property Rights; Beam Therapeutics: Consultancy, Current equity holder in publicly-traded company; Decibel Therapeutics: Current equity holder in publicly-traded company; Stemodontics: Consultancy, Current holder of stock options in a privately-held company; Global Blood Therapeutics: Current equity holder in publicly-traded company; Spotlight Therapeutics: Consultancy, Current equity holder in publicly-traded company; Jasper Therapeutics: Other: Intellectual Property Rights; Gilead Sciences: Other: Intellectual Property Rights. Sevilla:Novartis: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria; SOBI: 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 Díaz, 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; SOBI: Consultancy, Honoraria; Orchard Therapeutics: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria. Zubicaray:Novartis: Consultancy. Río:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Patents & Royalties: PR has licensed medicinal products and receives research funding and equity., Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Patents & Royalties: Dr. Navarro has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Research Funding. Choi:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Wagner:ASC Therapeutics: Consultancy; Bluebird Bio: Consultancy; Vertex Pharmaceuticals: Consultancy; Magenta Therapeutics: Consultancy; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Rao:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Thrasher:Orchard Therapeutics: Consultancy; Rocket Pharmaceuticals: Consultancy; 4bio capital: Consultancy; Generation Bio: Consultancy, Current equity holder in publicly-traded company. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Patents & Royalties: J.Bueren is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, may be entitled to receive financial benefits from the licensing of such patents and receives funding for research., Research Funding.