Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A

Introduction Valoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. Aim To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). Methods Men >= 18 years of age with severe haemophilia A (FVIII <= 1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 x 10(13) vg/kg dose, n = 7) and 4 years (4 x 10(13) vg/kg dose, n = 6). Results Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 x 10(13) and 4 x 10(13) vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was -0.14 (95% confidence interval [CI]: -.32 to .03) IU/dl/wk in the 6 x 10(13) vg/kg cohort in year 5 and -.06 (95% CI: -.14 to .01) IU/dl/wk in the 4 x 10(13) vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 x 10(13) vg/kg cohort; all six Haemo-QOL-A domain scores increased. For the 4 x 10(13) vg/kg cohort, high baseline Haemo-QOL-A scores persisted. Conclusion These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A.