A Phase 1/2 Study of Lentiviral-Mediated Ex-Vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I): Results from Phase 1

Introduction: LAD-I is a rare inherited disorder of leukocyte (primarily neutrophil) adhesion to endothelial cell surfaces, migration, and chemotaxis resulting from ITGB2 gene mutations encoding for the β2-integrin component, CD18. Severe LAD-I (i.e., CD18 expression on <2% of PMNs) is characterized by recurrent severe infections, impaired wound healing, and childhood mortality. Although allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative, its utilization and efficacy are limited by HLA-matched donor availability and risk of graft-versus-host disease (GVHD). RP-L201-0318 (clinical trials.gov # NCT03812263) is a phase 1/2 open-label clinical trial evaluating the safety and efficacy of autologous CD34+ cells transduced with a lentiviral vector (LV) carrying the ITGB2 gene encoding for CD18 (Chim-CD18-WPRE) in severe LAD-I.

Methods: Pediatric patients ≥ 3 months old with severe LAD-I (demonstrated by CD18 expression on <2% PMNs and at least 1 prior significant bacterial or fungal infection) are eligible. Peripheral blood (PB) HSCs are collected via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and Plerixafor. CD34+ cells are selected, transduced with Chim-CD18-WPRE LV, and cryopreserved. Myeloablative conditioning with busulfan (with therapeutic drug monitoring (TDM) to adjust dosing to enable target area under the curve (AUC)) is administered, followed by infusion of the investigational drug product (RP-L201). Patients are followed for safety assessments (i.e., replication competent lentivirus (RCL) and insertion site analysis (ISA)), and efficacy -- survival to age 2 and at least 1-year post-infusion without alloHSCT, increase in neutrophil CD18 expression to at least 10%, PB vector copy number (VCN), decrease in infections and/or hospitalizations, and resolution of skin or periodontal abnormalities.

Results: Two patients (ages 9 and 3) were treated in Phase 1. Both have a history of recurrent severe infections, documented ITGB2 mutations, and baseline CD18, CD11a, and CD11b expression < 1%. Mobilization and apheresis procedures were performed successfully and busulfan was administered at the target AUC. Investigational product comprised of 4.2x10⁶ CD34+ cells/kg with VCN of 3.8 copies/cell (liquid culture) for Patient 1 and 2.8x10⁶ CD34+ cells/kg with VCN of 2.5 for Patient 2 and were infused without complications. No serious treatment-emergent adverse events were reported. Neutrophil engraftment was observed in < 3 weeks in both patients. For Patient 1, PB PMN CD18 expression 6 months post-treatment was 47% (sustained from 45% at 3-months, vs. < 1% at baseline), with PB VCN of 1.3. Skin lesions present at baseline were resolving with no new lesions. Replication competent lentiviral (RCL) testing at 3 months and 6 months post-infusion were negative. Safety and efficacy data 12-months post-treatment for Patient 1 and 6-months post-treatment for Patient 2 will be available at the time of presentation.

Conclusion: Initial results from Phase 1 demonstrate preliminary safety and efficacy of RP-L201 for reversal of severe LAD-I. Enrollment of patients in the Phase 2 study is underway.