Most men with hem A bleed-free 5 years after 1 Roctavian dose
Phase 3 trial shows treatment improved quality of life
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A single dose of the gene therapy Roctavian (valoctocogene roxaparvovec-rvox) continues to prevent bleeds and the need for preventive treatment (prophylaxis) for up to five years in most treated men with severe hemophilia A, according to final Phase 3 trial results.
Activity of factor VIII (FVIII), the clotting protein missing or defective in hemophilia A, remained generally stable between years four and five in most patients. Treatment also led to clinically meaningful improvements in quality of life, with no new safety concerns reported.
“[Roctavian] provides durable [bleed control], FVIII activity, and improved health-related quality of life for [up to] 5 years with no new safety signals,” the researchers wrote.
The study, “Durability of efficacy, safety, and quality of life 5 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A: Final phase 3 GENEr8-1 trial results,” was published in Research and Practice in Thrombosis and Haemostasis. It was funded by BioMarin Pharmaceutical, the company that developed Roctavian.
Hemophilia A is caused by mutations in the gene that provides instructions for making FVIII. As a result, people with the condition produce little or no functional FVIII, leading to excessive and prolonged bleeding episodes. Standard treatment involves regular, lifelong infusions of FVIII replacement therapy to restore the levels of the missing clotting protein and prevent bleeds. However, frequent administration can be burdensome, and breakthrough bleeds may still occur.
Treatment aims to help body produce functional protein
Roctavian is designed to deliver a working copy of the gene that encodes FVIII to liver cells, enabling the body to produce its own functional FVIII. By doing so, the therapy aims to lower the risk of bleeds and reduce or potentially eliminate the need for factor replacement therapies.
The gene therapy was approved in the U.S. in 2023, largely based on three-year data from the Phase 3 GENEr8-1 trial (NCT03370913). The study tested a single infusion of Roctavian in 134 men with severe hemophilia, defined as FVIII activity of 1 international unit per deciliter (IU/dL) or lower, who had been receiving standard preventive therapy for at least one year.
Three years after dosing, most participants were bleed-free and did not require regular factor replacement therapy. At four years, most remained free of bleeds requiring treatment, and the majority continued to be off prophylaxis.
The study reported the final efficacy and safety results from the Phase 3 GENEr8-1 trial, showing that treatment with Roctavian provides durable clinical benefits and improvements in quality of life for up to five years, with a consistent safety profile. Overall, 128 of 134 participants completed the study.
Sustained reductions in bleeding were seen over time. Among 112 patients whose bleeding rates had been tracked for at least six months before Roctavian, annual bleeds requiring treatment fell by 83.3% during follow-up, while overall annual bleeds decreased by 78.1%. In year five, these patients experienced a mean of 0.6 treated bleeds per year, indicating that most had none.
The need for FVIII replacement therapy also decreased significantly among these patients. The mean number of yearly FVIII infusions was 6.9, a 94.9% reduction compared with before treatment.
Across the study population, most participants (80.8%) remained off prophylaxis by the end of the study, with 25 participants having resumed preventive treatment across all follow-ups.
Consistent with these findings, data from 132 patients with available FVIII measurements at year five showed that the mean FVIII activity level was 13.7 IU/dL. These levels were slightly lower than those reported at four years, but remained consistent with mild hemophilia. At the end of year five, 11 participants (8.3%) had FVIII levels in the normal range.
Similar to earlier time points after treatment, participants also reported improvements in health-related quality of life (HRQOL), as measured by the Haemo-QOL-A questionnaire. Over five years, the Haemo-QOL-A total score increased by 5.5 points among participants who had not resumed prophylaxis, a change considered clinically meaningful. Significant gains were seen in domains assessing the consequences of bleeding and treatment-related concerns.
These results “suggest that improving bleeding rates several years after infusion with a single treatment could improve psychological and behavioral aspects of the experience of hemophilia and its management, as demonstrated by improvements in Consequences of Bleeding and Worry domain scores,” the researchers wrote.
Roctavian was generally well tolerated. Consistent with earlier reports, the most common side effects included mild changes in liver function, nausea, fatigue, and headache. No new safety concerns were reported over long-term follow-up.
“[Roctavian] provided durable [bleed control] and HRQOL benefits for 5 years in the majority of participants following a single infusion, with a consistent and manageable safety profile,” the researchers concluded.
