Gene Therapy Roctavian Prevents Bleeds Over 5 Years, Data Show

The investigational gene therapy Roctavian continues to effectively and safely prevent bleeding episodes and the need for clotting factor VIII replacement therapy in adults with severe hemophilia A, five-year data from a Phase 1/2 study show.

BioMarin Pharmaceutical, the therapy’s developer, plans to share the data in an oral presentation at the upcoming International Society on Thrombosis and Haemostasis Virtual Congress, held July 17–21, in Philadelphia.

“As a treating physician and the physician who dosed these study participants some five or more years ago, I am heartened that most of these patients have been free from bleeds and the burden of regular infusions for such a long period of time in the ongoing research into [Roctavian],” Michael Laffan, MD, professor at Imperial College London in the U.K., and chief investigator of the trial, said in a press release.

The therapy, which is administered by a single infusion directly into the bloodstream, provides a healthy copy of the F8 gene, which encodes the blood clotting protein — factor VIII (FVIII) — that is missing in people with hemophilia A.

Delivered by a harmless adeno-associated virus (AAV), Roctavian (valoctocogene roxaparvovec) is designed to restore the production of FVIII, thereby lowering the risk of spontaneous bleeds while reducing or eliminating the need for preventive (prophylactic) FVIII replacement therapy, a standard treatment for hemophilia A.

The Phase 1/2 trial (NCT02576795) is evaluating the five-year efficacy and safety of Roctavian in 15 adult men with severe hemophilia A.

Two men who received the lower doses of Roctavian — 6e12 and 2e13 vector genomes per kilogram (vg/kg) — continued to show low levels of FVIII after three years. However, effective bleeding control was observed in the remaining 13 patients, who saw their FVIII levels increase, allowing them to remain off prophylactic treatment.

The newly released data included a five-year update for seven men who received the higher dose of the therapy (6e13 vg/kg) and a four-year update for six who received Roctavian at a dose of 4e13 vg/kg.

Compared to pre-treatment, the mean cumulative annualized bleed rate (ABR) in year five for the 6e13 vg/kg group was 0.7 — corresponding to a 95% ABR reduction. There was also a 96% reduction in FVIII use over the course of five years in this group.

In year four for the 4e13 vg/kg group, the mean ABR was 1.7 — representing a 92% ABR reduction — compared to pre-infusion. Factor VIII use was also reduced by 95% through four years.

Currently, all participants in both dose groups remain off prophylactic FVIII treatment. While FVIII activity levels declined over the study period, they remain within an effective therapeutic range.

“The latest data update in this ongoing study represents the longest duration of clinical experience for any gene therapy in hemophilia A and demonstrates hemostatic [blood clotting] control with [Roctavian] out to five years in the majority of patients in this study,” said Laffan.

“With this prolonged period of observation, we gain further insight about the long-term relationship between Factor VIII expression following a single infusion of gene therapy, and the low levels of bleeds in the absence of prophylactic therapy,” he added.

Roctavian’s safety profile remained consistent with previous data, with no delayed treatment-related adverse events reported. All patients remained off corticosteroids since the first year, and none have experienced adverse blood-clotting events. No patients developed FVIII inhibitors or withdrew from the study.

The most common adverse treatment-related events occurred soon after the therapy’s infusion and included short-lived infusion-associated reactions. Brief, asymptomatic, mild to moderate elevations in the levels of certain proteins and enzymes were also reported, with no continued effects.

“We are encouraged by the consistent and dramatic bleed control observed for up to five years in this study, representing a milestone in the development of gene therapy in this patient population,” said Hank Fuchs, MD, president of worldwide research and development at BioMarin.

“It is promising that Factor VIII levels continue to remain in a range to provide hemostatic efficacy for the vast majority of patients for a meaningful period of time. Given the continued decline in Factor VIII expression, future investigation of variability and re-dosing remain critical objectives,” he added.

In addition to this Phase 1/2 trial, BioMarin is also testing Roctavian in the ongoing Phase 3 GENEr8-1 trial (NCT03370913) and is actively enrolling participants in the Phase 3b GENEr8-3 study (NCT04323098), which will evaluate the effects of the therapy when given along prophylactic corticosteroids.

“We believe these data combined with the compelling Phase 3 data we shared earlier this year, demonstrating superiority to Factor VIII prophylaxis in reducing annualized bleeding rate, provide cogent evidence to support a determination of clinical benefit,” said Fuchs.

The company plans to submit an application requesting the approval of Roctavian using one-year data from the GENEr8-1 study to the European Medicines Agency in June.

In the U.S., BioMarin plans to submit two-year follow-up efficacy and safety data on all GENEr8-1 study participants, fulfilling a request by the Food and Drug Administration (FDA) for the data to be used in a benefit-risk analysis. Assuming favorable study data, the company then plans to submit a similar request to obtain permission to distribute the therapy within the U.S. This future potential submission will be followed by a six-month FDA review process.

“It continues to be an honor and a privilege to be developing the potential first gene therapy in hemophilia A,” Fuchs said.