Etuvetidigene autotemcel for the treatment of Wiskott-Aldrich Syndrome

ABSTRACT BACKGROUND: Wiskott-Aldrich Syndrome (WAS) is a rare, X-linked, life-threatening inborn error of immunity and platelet disorder caused by WAS protein (WASP)-encoding gene mutations. Etuvetidigene autotemcel (etu-cel) is an autologous gene therapy (GT) consisting of hematopoietic stem progenitor cell (HSPCs) transduced ex vivo with a lentiviral vector encoding human WAS cDNA. METHODS Etu-cel was intravenously infused after rituximab and reduced-intensity conditioning. Data from WAS patients treated in two prospective open-label clinical trials (phase I/II n=8; phase III n=10) and one expanded access program (EAP) (n=9) were integrated to evaluate efficacy and safety of etu-cel. Primary efficacy endpoints were overall survival, rate of severe infections from 6 to 18 months after GT and rate of moderate/severe bleeding episodes in the first 12 months post-treatment compared with 1 year prior to GT. Secondary efficacy endpoints included engraftment of gene-corrected cells, WASP expression, T-cell function, platelet count, autoimmunity and eczema over time. Safety endpoints included adverse events (AEs), immune response to transgene, development of replication-competent lentivirus (RCL) and abnormal clonal proliferation (ACP). RESULTS Median follow-up was 5.7 years (range: 0.4-13.3). Median age at treatment was 2.6 years (range: 1.0-35.1). Overall survival was 96%; one EAP subject died early post-GT due to deterioration of a pre-existing neurological condition. The rate of severe infections per person-year of observation (PYO) decreased from 2.00 (95% CI: 1.50-2.61) pre-GT to 0.15 (95% CI: 0.04-0.39) in the 6-18 months period post-GT. The rate of moderate and severe bleeding events per PYO decreased from 2.00 (95% CI: 1.50-2.61) to 0.80 (95% CI: 0.49-1.22) in the 12 months after GT. After GT, multilineage engraftment of gene-corrected cells was sustained over time. WASP expression in platelets and lymphocytes increased. Platelet count, T-cell functionality, eczema and autoimmunity improved. The most common adverse event ≥ grade 3 was device related infection. Etu-cel was well-tolerated with no treatment-related adverse events and no evidence of insertional oncogenesis. CONCLUSIONS With up to 13 years follow-up, etu-cel demonstrates a favorable benefit-risk profile, leading to sustained long-term clinical benefit. (Funded by GlaxoSmithKline [GSK], Orchard Therapeutics, Fondazione Telethon; ClinicalTrials.gov numbers: NCT01515462 , NCT03837483 )