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A single infusion of the gene therapy valoctocogene roxaparvovec led to significantly reduced bleeding rates that persisted in men with severe hemophilia A, 2-year results from the phase III trial showed.

Among 112 men who had been receiving standard factor VIII prophylaxis with prospectively collected data at baseline, the mean change in the annualized treated bleeding rate decreased by 84.5% from baseline to week 104 (-4.1 bleeding events per year, 95% CI -5.3 to -2.9, P<0.001), reported Johnny Mahlangu, MBBCh, MMed, of University of the Witwatersrand in Johannesburg, and colleagues.

Pharmacokinetic modeling indicated that factor VIII activity levels would remain in the mild hemophilia range for at least 5 years after gene transfer. "Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden," Mahlangu and co-authors wrote in the .

Valoctocogene roxaparvovec is an adeno-associated virus (AAV) 5-based gene therapy vector that targets factor VIII complementary DNA expression in the liver. In the open-label, single-group, multicenter GENEr8-1 trial, participants received a single infusion of 6 × 10¹³ vector genomes of the gene therapy per kilogram of body weight.

Study findings at 52 weeks were published previously. Of 134 men who enrolled in the study, 132 remained at the 2-year follow-up. All participants were included in the intention-to-treat (ITT) population, 132 HIV-negative participants were included in the modified ITT population, and 112 participants previously enrolled in a non-interventional study were included in the rollover population. As of the latest data cutoff, the median follow-up was 110.9 weeks among all participants.

The mean annualized occurrence of all bleeding events during the post-prophylaxis period decreased by 77% from baseline (-4.1 per year, 95% CI -5.4 to -2.8, P<0.001) among rollover participants. In addition, the annualized rate of factor VIII use dropped by 98.2% (mean of -3,891.3 IU per/kg per year, 95% CI -4,221.0 to -3,561.5, P<0.001) in the rollover population.

Factor VIII activity measured with a chromogenic assay increased from baseline to week 104 by a mean of 22.0 IU/dL (95% CI 16.4-27.7, P<0.001) in the modified ITT population, but a decrease in factor VIII expression was observed between year 1 and year 2.

This decrease mirrored that seen in seven patients in a who received the same vector and dose. To calculate the anticipated duration of the therapeutic effect of valoctocogene roxaparvovec, the authors developed a model to estimate future factor VIII activity and determined the mean and median extrapolated factor VIII activity levels at 5 years would be 11.8 and 5.7 IU/dL, respectively, thus remaining in the mild hemophilia range.

The most common adverse event at 2 years remained elevated alanine aminotransferase levels, which occurred in 88.8% of participants and were treated with immunosuppressants.

A total of 123 participants (91.8%) had an adverse event related to valoctocogene roxaparvovec. As of the latest data-cutoff date, 24 participants (17.9%) had a serious adverse event and five (3.7%) had a serious adverse event related to valoctocogene roxaparvovec. All serious adverse events related to the gene therapy occurred within the first 52 weeks after the infusion.

In an , Lindsey George, MD, of the Perelman School of Medicine, University of Pennsylvania in Philadelphia, said the cause of the decrease in factor VIII expression is "an unanswered question." The capacity of AAV-based gene therapy to provide sustained transgene expression should be "both the goal and obligation within the current state of AAV clinical development," she wrote.

"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," George noted.

The data also will inform therapeutic decision-making in Europe where the therapy is , and potentially in the U.S., where a , she added.

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