FDA Rejects BioMarin’s Application for Approval of Hemophilia A Gene Therapy

The U.S. Food and Drug Administration issued a complete response letter to BioMarin Pharmaceutical, indicating it would not approve its experimental gene therapy for severe hemophilia A without further data demonstrating its durability.

 The news sent BioMarin shares fell more than percent to as low as $74.56. The FDA’s decision is a blow not only for BioMarin, but also for patients with the most severe form of hemophilia who had been looking forward to a potential once-and-done treatment.

Approximately one in 10,000 people have hemophilia A, an X-linked genetic disorder that is usually passed down from parents to children, with about one third of cases caused by a spontaneous mutation.

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. Those with the most severe form of hemophilia A make up approximately half of the hemophilia A population, and often experience painful, spontaneous bleeds into their muscles or joints.

The standard of care for these individuals 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 late May, BioMarin reported results from an open-label phase 1/2 study of the gene therapy noting that 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 years’ 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 said this is the first time the FDA has made this recommendation, and had not previously raised the issue during development or review. The FDA recommended that BioMarin complete the phase 3 study and submit two-year follow-up safety and efficacy data on all study participants. In the complete response letter, the FDA concluded that the differences between the phase 1/2 and the phase 3 studies limited its ability to rely on the phase 1/2 study to support durability of effect. The phase 3 study was fully enrolled in November 2019, and the last patient will complete two years of follow up in November 2021.

BioMarin plans to meet with the agency in the coming weeks to align on the next steps to obtain approval.

 “We remain committed to the hemophilia community and to leading the way to the first ever gene therapy in hemophilia A,” said Jean-Jacques Bienaimé, chairman and CEO of BioMarin. “We are surprised and disappointed that the FDA introduced new expectations for the first time in the Complete Response Letter.  We are confident in valoctocogene roxaparvovec gene therapy and its potential to redefine the treatment paradigm for people with hemophilia A.”

 The company’s application was based on the phase 3 study interim analysis of study participants treated with the experimental gene therapy manufactured by the to-be-commercialized process and three-year data from the phase 1/2 study.

The FDA had granted valoctocogene roxaparvovec Priority Review status and Breakthrough Therapy and Orphan Drug designations.

BioMarin said ongoing valoctocogene roxaparvovec clinical trials will continue while it exploring next steps to obtain approval.  The European Medicines Agency review of the company’s Marketing Authorization Application for valoctocogene roxaparvovec is ongoing.

 Photo: Jean-Jacques Bienaimé, chairman and CEO of BioMarin