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In men with severe hemophilia A, a single infusion of valoctocogene roxaparvovec significantly increased factor VIII activity and reduced annualized rates of factor VIII concentrate use and bleeding, a phase III study found.

Among 132 HIV-negative men who had been receiving standard factor VIII prophylaxis, the mean factor VIII activity level at weeks 49 through 52 after infusion increased by 41.9 IU/dL from baseline (95% CI 34.1-49.7, P<0.001), with a median change of 22.9 IU/dL, reported Margareth C. Ozelo, MD, PhD, of the University of Campinas in Brazil, and colleagues.

Additionally, in a subgroup of 112 patients, the mean annualized rates of factor VIII concentrate use and bleeding after week 4 decreased by 98.6% and 83.8%, respectively (P<0.001 for both), they noted in the .

In an , Courtney D. Thornburg, MD, of Rady Children's Hospital San Diego and the University of California San Diego Health Sciences, noted that valoctocogene roxaparvovec -- an adeno-associated virus 5 (AAV5)-based gene therapy vector that targets factor VIII complementary DNA expression in the liver -- has been granted a breakthrough therapy designation and a regenerative medicine advanced therapy designation from the FDA.

"If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia," she wrote.

All participants had at least one adverse event with valoctocogene roxaparvovec, the most common of which were elevations in alanine aminotransferase levels (85.8%), headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). Additionally, 16.4% experienced a serious adverse event.

"Safety is a key consideration with any new therapy and is of utmost concern in a population devastated by virally contaminated blood products in the 1980s and early 1990s," wrote Thornburg.

Nearly 80% of participants received glucocorticoids for alanine aminotransferase increases, with 71.8% reporting associated adverse events, including acne, insomnia, Cushing's syndrome, and weight gain.

"Fortunately, this is a short-term problem, but further investigation is needed to inform best practices for the prevention and treatment of elevations in alanine aminotransferase levels to optimize transgene expression and minimize the need for immunosuppressants," Thornburg noted. "Moreover, follow-up is critical to assess long-term safety."

The open-label, single-group, multicenter, phase III GENEr8-1 trial included men ages 18 and older who did not have pre-existing anti-AAV5 antibodies or a history of development of factor VIII inhibitors, and who had been receiving prophylaxis with factor VIII concentrate. HIV was added as an exclusion criterion after a protocol amendment.

The modified intention-to-treat population included 132 HIV-negative men (mean age at enrollment 31.4), 17 of whom received an infusion at least 2 years before the data cutoff. The rollover population of 112 men had participated in a , which included at least 6 months of prospective data on bleeding and factor VIII concentrate use with standard-of-care prophylaxis.

Among these 112 patients, mean and median annualized factor VIII concentrate use at baseline was 3,961.2 IU/kg per year and 3,754.4 IU/kg per year, respectively. After week 4, these dropped to 56.9 IU/kg per year and 0 IU/kg per year. The mean and median annualized factor VIII infusion rates were 135.9 and 128.6 infusions per year at baseline, which fell to 2 and 0 infusions per year after week 4.

For treated bleeding episodes in this group, the mean and median annualized rates were 4.8 and 2.8 bleeds per year at baseline, which declined to 0.8 and 0 bleeds per year after week 4. The mean change from baseline met the criteria for superiority to factor VIII prophylaxis (P<0.001), the authors noted.

"Additional follow-up of the participants ... will be required in order to determine the durability of clinical benefit with respect to reduced bleeding and the cessation of prophylaxis resulting from endogenous factor VIII production," Ozelo and colleagues wrote.

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