FDA Grants BioMarin RMAT Designation for Experimental Hemophilia A Gene Therapy

Rare Daily Staff

The U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy designation to BioMarin Pharmaceuticals’ experimental gene therapy for the treatment of adults with severe hemophilia A.

Hemophilia A, also called Factor VIII deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective Factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a new mutation that was not inherited. Approximately 1 in 10,000 people have Hemophilia A.

People living with hemophilia A lack sufficient functioning Factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A, approximately half of sufferer, often experience painful, spontaneous bleeds into their muscles or joints.

The standard of care for individuals with severe hemophilia A is a prophylactic regimen of replacement Factor VIII infusions administered intravenously up to two to three times per week or 100 to 150 infusions per year. Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

BioMarin’s therapy, valoctocogene roxaparvovec, is an AAV-factor VIII gene therapy designed to restore adequate levels of factor VIII for normal clotting. It is being developed as a one-time treatment for adults with severe hemophilia A and could eliminate the need for ongoing factor VIII treatments.

In August, the FDA issued a Complete Response Letter to BioMarin’s Biologics License Application for valoctocogene roxaparvovec. BioMarin had reported results from an open-label phase 1/2 study of the gene therapy in which all study participants remain off prophylactic therapy after a single dose. But the data also showed that factor VIII activity levels declined with the most recent year’s observations, even as BioMarin said they remained in a range to prevent spontaneous bleeding events.

This is what worried the FDA. In rejecting BioMarin’s Biologics License Application, the agency introduced a new recommendation for two years of data from the BioMarin’s ongoing phase 3 study to provide substantial evidence of a durable effect using Annualized Bleeding Rate as the primary endpoint.

BioMarin plans to meet with FDA to review the two-year data request and share the phase 3 GENEr8-1 results that were announced in January. In the EU, BioMarin is targeting submission of the Marketing Authorization Application (MAA) with these results to the EMA in the second quarter of 2021 pending confirmation in planned pre-submission meetings.

Regenerative Medicine Advanced Therapy (RMAT) is an expedited program intended to facilitate development and review of regenerative medicine therapies that are intended to address an unmet medical need in patients with serious conditions. The RMAT designation is complementary to the Breakthrough Therapy designation, which BioMarin received in 2017, allowing early, close, and frequent interactions with the FDA. One additional feature of the RMAT program is that sponsors of products that have been granted RMAT designation and which receive accelerated approval may be able to fulfill the post-approval requirements from clinical evidence obtained from sources other than the traditional confirmatory clinical trials.

“This designation confirms our belief in this treatment’s potential to address unmet medical needs for people with hemophilia A at this time,” said Hank Fuchs, president of Worldwide Research and Development at BioMarin.

In addition to the RMAT and Breakthrough Therapy designations, BioMarin’s hemophilia A gene therapy has also has received orphan drug designation from the FDA and EMA for the treatment of severe hemophilia A.

Photo: Hank Fuchs, president of Worldwide Research and Development at BioMarin