BioMarin Pharmaceutical announced the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to the Company's Biologics License Application (BLA) for valoctocogene roxaparvovec gene therapy for severe hemophilia A. The FDA issues a CRL to indicate that the review cycle for an application is complete and that the application is not ready for approval in its present form.

Having previously agreed with the Agency on the extent of data necessary to support the BLA, the FDA introduced a new recommendation for two years of data from the Company's ongoing 270-301 study (Phase 3) to provide substantial evidence of a durable effect using Annualized Bleeding Rate (ABR) as the primary endpoint. The Agency first informed the Company of this recommendation in the CRL having not raised this at any time during development or review. The Agency recommended that the Company complete the Phase 3 Study and submit two-year follow-up safety and efficacy data on all study participants. FDA concluded that the differences between Study 270-201 (Phase 1/2) and the Phase 3 study 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.

The Company 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 Chief Executive Officer 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 application was based on the Phase 3 study interim analysis of study participants treated with investigational product 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. Valoctocogene roxaparvovec maintains Breakthrough Therapy and Orphan Drug designations.

The ongoing valoctocogene roxaparvovec clinical trials will continue while BioMarin is exploring next steps to obtain approval. The European Medicines Agency (EMA) review of the Company's Marketing Authorization Application (MAA) for valoctocogene roxaparvovec is ongoing.

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 (FVIII levels <1%) often experience painful, spontaneous bleeds into their muscles or joints. Individuals with the most severe form of hemophilia A make up approximately 50 percent of the hemophilia A population. People with hemophilia A with moderate (FVIII 1-5%) or mild (FVIII 5-40%) disease show a much-reduced propensity to bleed. 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.

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.