Two years after gene transfer using valoctocogene roxaparvovec, recipients had sufficient factor VIII activity and bleeding reduction, a study shows. “Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A,” the researchers conclude.
The open-label, single-group, multicenter, phase 3 trial included 134 men with severe hemophilia A who were receiving factor VIII prophylaxis. A single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight produced these effects on a primary end point of the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion: “At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P <0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred.”
Editorial: “This report on 2-year safety and efficacy data and the model of the anticipated expression durability after valoctocogene roxaparvovec infusion provides insight into observations that have emerged from clinical trial investigation,” writes an editorialist. “These data will directly inform therapeutic decision making in Europe, where valoctocogene roxaparvovec is conditionally approved, and potentially in the United States, where a biologics licensing application is under repeat review. The goal of hemophilia gene therapy — to provide safe, durable, and predictable therapeutic benefit to all patients who receive a vector — has not wavered; future efforts progressing to this ultimate objective will be informed by investigating and addressing questions that have emerged from this seminal accomplishment.”