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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)
Abstract
Background and Aims
LAD-I results from mutations in ITGB2 encoding the β2-integrin CD18. Severe LAD-I (<2% CD18+ polymorphonucleocytes [PMNs]) causes severe infections, impaired wound healing, and childhood mortality. Allogeneic hematopoietic stem cell transplant is curative; efficacy is 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. HSCs were collected via apheresis after mobilization with granulocyte-colony-stimulating-factor and plerixafor and transduced ex-vivo. Myeloablative busulfan conditioning preceded RP-L201. 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, decreased infections/hospitalizations, resolution of skin/periodontal abnormalities.
Results
Nine patients (ages 5mos-9yrs) received RP-L201, with 3–24-month available follow-up. RP-L201 cell doses ranged from 2.8x106 to 10x106 CD34+ cells/kg with a drug product VCN from 1.8-3.8. All 9 demonstrated sustained PMN CD18 restoration and VCN >0.1integration. At 1 year, the OS rate is 100% per Kaplan-Meier estimate. The patient with 24 months follow-up showed ~40% PMN CD18 expression with 1.53 PB VCN. Baseline skin lesions resolved with no new infection-related hospitalizations. Subsequent 8 patients were followed for 3-18 months, demonstrating PMN CD18 expression of 25.6-86.6%. Neutrophilia resolved uniformly. Hospitalizations and severe infections were significantly reduced following therapy. The safety profile has been highly favorable with no RP-L201-related SAEs.
Conclusions
RP-L201 confers durable reversal of the severe LAD-I phenotype with improved clinical course in 9 of 9 patients.