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)

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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.

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