Phase 3 Trial of Valoctocogene Roxaparvovec Finds Stable, Durable Annualized Bleed Control for Severe Hemophilia A


The mean annualized bleed rate was reduced by 80% from baseline and Factor VIII usage was reduced by 94% in year 3 compared to baseline.

Results from the ongoing phase 3 GENEr8-1 trial of valoctocogene roxaparvovec (Roctavian; BioMarin Pharmaceutical Inc.) found stable and durable annualized bleed control among patients with severe hemophilia A.

Valoctocogene roxaparvovec is an investigational 1-time gene therapy indicated for the treatment of adults with severe hemophilia A. The GENEr8-1 study is the largest and longest global phase 3 study to date for any gene therapy in hemophilia, with 134 patients.

The global GENEr8-1 study is evaluating the superiority of valoctocogene roxaparvovec at the 6e13 vg/kg dose compared with the current standard of care, Factor VIII prophylactic therapy. All participants had severe hemophilia A at baseline, defined as less than or equal to 1 IU/dL of Factor VIII activity.

The study included 134 participants, all of whom had a minimum of 36 months of follow-up at the time of the data cutoff. The first 22 participants were directly enrolled into the phase 3 study, 17 of whom were HIV-negative and dosed at least 4 years prior to the data cutoff date.

The remaining 112 participants completed at least 6 months in a separate non-interventional study to prospectively assess bleeding episodes, Factor VIII use, and health-related quality of life while receiving Factor VIII prophylaxis prior to rolling over to receive a single infusion of valoctocogene roxaparvovec in the GENEr8-1 study.

According to the trial results, the mean annualized bleed rate was reduced by 80% from baseline and Factor VIII usage was reduced by 94% in year 3 compared to baseline. The mean number of bleeding episodes per year went from 1 in year 3 to 0.8 in year 4, whereas the mean number of Factor VIII infusions increased from 8.4 in year 3 to 11.1 in year 4. Additionally, 92% of patients were off prophylaxis at the end of year 3 and those who returned to Factor VIII or emicizumab prophylaxis did so safely, according to the study.

In response to an FDA request and consistent with other gene therapy trials for hemophilia, the company also analyzed annualized bleeding rate for all bleeds, regardless of whether those bleeds were treated with exogenous Factor VIII replacement. This analysis found similar results to the earlier trial results.

The mean annual bleeding rate for all bleeds was 1.4 in year 3 and 1.6 in year 4. The median was 0.0 in year 3 and 1.0 in year 4.

“We continue to learn more about the durability, safety, and efficacy of valoctocogene roxaparvovec,” said investigator Steven Pipe, MD, in a press release. “I am encouraged to see the consistent clinical response and the significant number of study participants who remain off prophylaxis after 3 years. This shows the potential transformative impact of this single treatment event for people with severe hemophilia A.”

Overall, to date, a single 6e13 vg/kg dose of valoctocogene roxaparvovec has been well tolerated with no delayed-onset treatment-related adverse events (AEs). In year 3, no new treatment-related serious AEs or grade 3 AEs attributed to valoctocogene roxaparvovec or corticosteroid use emerged.

The most common AEs associated with valoctocogene roxaparvovec have occurred early and included transient infusion-associated reactions and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae. Alanine aminotransferase elevation has remained the most common AE to the drug.

Other AEs have included aspartate aminotransferase elevation (63%), nausea (34%), headache (34%), and fatigue (28%). No participants have developed inhibitors to Factor VIII, thromboembolic events, or malignancy associated with valoctocogene roxaparvovec.

These findings will be shared with the FDA as part of the agency’s ongoing review of the Biologics License Application for valoctocogene roxaparvovec. The Prescription Drug User Fee Act has been set for March 31, 2023, subject to possible agency extension. The FDA has also granted Regenerative Medicine Advanced Therapy designation to valoctocogene roxaparvovec in March 2021, Breakthrough Therapy Designation in 2017, and Orphan Drug Designation.

“The 3-year data reinforce our belief that Roctavian has the potential to fundamentally transform the treatment of severe hemophilia A for patients and eliminate the burden of prophylaxis,” said Hank Fuchs, MD, president of worldwide research and development at BioMarin, in the press release. “We look forward to sharing these data with the FDA as part of our ongoing regulatory review. We remain grateful to the bleeding disorders community for its support of our robust clinical program.”


BioMarin Announces Stable and Durable Annualized Bleed Control for Roctavian in Largest Phase 3 Gene Therapy Study in Adults with Severe Hemophilia A; 134-Participant Study Met All Primary and Secondary Efficacy Endpoints at 3-Year Analysis. News release. BioMarin; January 8, 2023. Accessed January 13, 2023.

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