1. At least two years after gene transfer, valoctocogene roxaparvovec demonstrated durability of factor VIII activity and bleeding reduction in hemophilia A patients.

2. Valoctocogene roxaparvovec was associated with no new serious adverse events related to treatment in the two years following initiation.

Evidence Rating Level: 1 (Excellent)

Study Rundown: A prior open-label multicenter phase three study demonstrated that men with hemophilia A who received valoctocogene roxaparvovec in one dose as a peripheral vein infusion demonstrated significantly higher factor VIII activity than the imputed baseline. Valoctocogene roxaparvovec is an adeno-associated virus vector that transfers a B-domain-deleted human factor VIII coding sequence, providing endogenous factor VIII protein production in hepatocytes of persons with hemophilia A. However, there is a gap in knowledge as to understanding the change in the annualized treated bleeding rate at two or more years after gene transfer in patients treated with valoctocogene roxaparvovec. Overall, this study found that over a two year period, valoctocogene roxaparvovec infused as a single dose of 6×10^13 vg per kilogram provided control of bleeding that was superior to factor VIII prophylaxis in adult men with severe hemophilia A, and has been granted conditional marketing authorization by the European Medicines Agency. Although, this study was limited by the lack of assessment of physical activity or risk-taking in the context of bleeding episodes and the lack of formal joint-health scoring after baseline. Nevertheless, these study’s findings are significant, as they demonstrate that valoctocogene roxaparvovec can serve as a durable and safe treatment in severe hemophilia A.

Click to read the study in NEJM

Relevant Reading: Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A

In-Depth [open-label phase 3 clinical trial]: This single-group open-label phase three GENEr8-1 trial enrolled patients with severe hemophilia A. Patients who were at least 18 years of age, had severe hemophilia A (factor VIII activity level, <1 IU per deciliter), were receiving regular prophylaxis with exogenous factor VIII, and had no history of factor VIII inhibitors or anti-AAV5 antibodies were eligible for the study. Patients who did not fit these inclusion criteria were excluded from the study. Enrolled participants received valoctocogene roxaparvovec in one dose of 6×10^13 vg per kilogram. The primary outcome measured was bleeding episodes as well as factor VIII activity. Outcomes in the primary analysis were assessed via a quantitative pharmacokinetic model and a linear mixed-effects approach to extrapolate mean and median endogenous factor VIII activity. Based on the primary analysis, the mean annualized treated bleeding rate decreased by 84.5% from baseline (p<0.001) among the participant when measured at week 104. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics. Furthermore, the half-life of the transgene-derived factor VIII production system was estimated to be 123 weeks (95% Confidence Interval, 84 to 232). Regarding the risk of joint bleeding, at a transgene-derived factor VIII level of 5 IU per deciliter measured with a chromogenic assay, participants would have 1.0 episode of joint bleeding per year. At two years post-infusion, no new serious adverse events related to treatment had occurred. In summary, this study found that valoctocogene roxaparvovec is durable, effective, and safe in the treatment of hemophilia A at least two years after gene transfer.

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