Interim Results from an Ongoing Phase 1/2 Study of Lentiviral-mediated Ex-vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I)

Background: Leukocyte adhesion deficiency-I (LAD-I) results from mutations in ITGB2 encoding the β2-integrin CD18. Severe LAD-I (<2% CD18+ polymorphonucleocytes [PMNs]) causes severe and often refractory infections, impaired wound healing, and frequent childhood mortality. Allogeneic hematopoietic stem cell transplant is potentially curative but limited by donor availability, graft-versus-host disease, and graft failure. RP-L201-0318 (NCT03812263) employs autologous CD34+ cells transduced with a lentiviral vector carrying ITGB2.

Methods: Patients ≥3 months old with severe LAD-I were enrolled. Hematopoietic stem and progenitor cells (HSPCs) were collected via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor and transduced ex-vivo with Chim-CD18-WPRE-LV. Myeloablative therapeutic drug monitoring (TDM) busulfan conditioning preceded RP-L201 infusion. Patients are followed for safety and efficacy including survival to age 2 and ≥1-year post-infusion, peripheral blood [PB] PMN CD18 expression, PB vector copy number [VCN], neutrophilia improvement, decrease in infections/hospitalizations, and resolution of skin/periodontal abnormalities.

Results: Nine patients (ages 5 months to 9 years) received RP-L201, all with follow-up of 3 to 24 months. RP-L201 cell doses ranged from 2.8x106 to 10x106 CD34+ cells/kg with a drug product VCN of 1.8 to 3.8. All 9 patients demonstrated PMN CD18 restoration with median expression of 56.3% and sustained, stable genetic markings with median peripheral blood mononuclear cell VCN of 1.53. At 1 year, the overall survival (OS) rate is 100% per Kaplan-Meier estimate. Neutrophilia resolved uniformly. Hospitalizations and severe infections were significantly reduced following therapy. The safety profile has been highly favorable with no RP-L201-related serious adverse events (SAEs); insertion site analyses indicate polyclonal integration patterns.

Conclusion: RP-L201 confers durable reversal of the severe LAD-I phenotype with improved clinical course in 9 of 9 pediatric patients.

Booth:SOBI: Consultancy, Honoraria; Orchard Therapeutics: Consultancy, Honoraria; Takeda: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy; Takeda: Honoraria; GSK: Honoraria. Sevilla: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 Díaz, and may be entitled to receive financial benefits from the licensing of such patents; licensed medical products from Rocket Pharma.; SOBI: Consultancy, Honoraria. Rao:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chitty Lopez:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Almarza:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zubicaray:Novartis: Consultancy. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. de Oliveira:Bluebird Bio: Research Funding; Orchard Therapeutics: 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. Mesa-Núñez: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. 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. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Kohn:Cimeio Therapeutics: Consultancy; Innoskel: Consultancy; MyoGene Bio: Consultancy, Other: Membership on Scientific Advisory Board; Pluto Immunotherapeutics: Consultancy, Other: Membership on Scientific Advisory Board; Allogene Therapeutics: Consultancy, Other: Member of Scientific Advisory Board; ImmunoVec: Consultancy; TransformaTx: Consultancy.