Lentiviral hematopoietic stem and progenitor cell gene therapy with 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 (plt) disorder caused by WAS protein (WASP)-encoding gene mutations. WAS is characterized by thrombocytopenia, bleeding events, recurrent and severe infections, eczema, and increased risk of immune dysregulation and malignancy. Allogeneic hematopoietic stem cell transplantation (HSCT) can be curative but is still hampered by limited donor availability and potential complications [Burroughs et al. 2020; Albert et al. 2022]. Etuvetidigene autotemcel (Etu-cel) is an experimental autologous gene therapy (GT) with BLA in the US and MAA in Europe currently under evaluation. It consists of hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a lentiviral vector encoding human WAS cDNA under endogenous promoter control. We previously reported interim safety and efficacy data in 17 WAS subjects treated in a phase I/II clinical trial and in an expanded access program (EAP) [Ferrua et al. 2019]. We now report the results of an integrated efficacy and safety analysis in 27 WAS patients treated with Etu-cel with extended long-term follow-up. METHODS Patients received fresh (phase I/II trial, NCT01515462, n=8; EAP, n=9) or cryopreserved (phase III trial, NCT03837483, n=10) formulation of Etu-cel. Autologous CD34+ HSPCs source for drug product (DP) manufacturing consisted in bone marrow (n=5), mobilized peripheral blood (n=21) or both (n=1). Etu-cel was intravenously infused after rituximab and reduced-intensity conditioning (RIC). Primary efficacy endpoints were overall survival (OS), rate of severe infections from 6 to 18 months (mos) post-GT and rate of moderate/severe bleeding events in the first 12 mos post-GT. Secondary efficacy endpoints included engraftment of gene-corrected cells, WASP expression, T-cell function, plt 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 age at treatment was 2.6 years (range: 1.0-35.1). OS was 96% (95%CI: 82-99%); one EAP subject died 4.5 mos post-GT due to deterioration of a pre-existing neurological condition. Median follow-up in surviving patients was 5.72 years (range: 2.31-13.26). The rate of severe infections per person-year of observation (PYO) decreased from 2.00 (95%CI: 1.50-2.61) in the 12 mos before GT to 0.15 (95%CI: 0.04-0.39) in the 6-18 mos post-GT and 0.05 (95%CI: 0.01-0.16) in the >5-year post-treatment period. The rate of moderate and severe bleeding events per PYO decreased from 2.00 (95%CI: 1.50-2.61) in the 12 mos before GT to 0.80 (95%CI: 0.49-1.22) in the 12 mos after GT and 0.02 (95%CI: 0.00-0.10) in the >5-year post-treatment period. Durable multilineage engraftment of gene-corrected cells led to restoration of WASP expression in lymphocytes and plt, which resulted in ameliorated immune-cell function and plt count. Sustained immunoglobulin replacement could be stopped in all patients at a median of 320.5 days after GT (range: 91–1843) and cessation of sustained antimicrobial treatment was achieved in 25 (92.6%) patients. Plt transfusions were stopped at a median of 46.5 days after treatment (range: 9-261), with no need of thrombopoietin agonist long-term. Median plt count at year 5 post-GT was 68.3 (48.0-228.0)×109/L (n=22).Eczema resolved in all and immune dysregulation improved in most patients post-GT, with no need of prolonged immune suppression. After GT, hospitalization rate declined, and quality of life improved in all. Etu-cel was well tolerated with no treatment-related AEs, no engraftment failures, no evidence of ACP, RCL or immunogenicity. Overall, AEs following treatment with Etu-cel are consistent with those expected in WAS patients undergoing hematological reconstitution after RIC. The most common AE ≥grade 3 was device-related infection. None of the treated patients required any secondary procedures (e.g. splenectomy, HSCT) after GT. Outcome was similar across different ages, disease characteristics, WAS mutations, and DP formulations. CONCLUSIONS Results from this integrated analysis on a larger population and longer follow-up show the efficacy and safety of a single infusion of Etu-cel for the treatment of WAS. With up to 13 years follow-up, Etu-cel demonstrates a favorable benefit-risk profile, with sustained long-term significant clinical benefit.