FDA Rejects BioMarin Pharmaceuticals’ Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A
On August 19th BioMarin Pharmaceuticals announced that the USFDA issued a Complete Response Letter (CRL) to the Biologics License Application (BLA) of its breakthrough gene therapy.
By T. Chakraborty, Ph.D.
Hemophilia is an inherited bleeding disorder caused by a mutation in one of the genes that are responsible for providing the clotting factor required to form a blood clot. The two most common types of hemophilia, hemophilia A, and B are caused by the lack of clotting Factor VIII and IX, respectively. Over the years, individuals with severe hemophilia A are treated with precautionary doses of replacement Factor VIII infusions which are given intravenously to the patients up to two to three times per week or cumulatively adding up to 100 to 150 infusions per year which not only add to the economic burden of the patient but also wreaks havoc to their quality of life . Thus, better treatment options for patients with hemophilia are warranted.
BioMarin Pharmaceuticals had previously met and discussed with the FDA on the extent of data necessary to support the BLA for approval. However, the FDA introduced a new recommendation stating that it requires data for two years from the company’s ongoing Phase 3 study (270-301) to substantially prove the effect of the therapy by using Annualized Bleeding Rate (ABR) as the primary endpoint. This was communicated to the company by the FDA as a recommendation in the issued CRL and was not raised during the time of development or review of the proposed plan with the company.
The FDA further asked BioMarin to complete the Phase 3 study and submit a two-year follow-up safety and efficacy data on all study participants as the differences between phases 1/2 and 3 restricted its ability to comprehend the effect of the therapy. Based on the data provided, the FDA added that as the phase 3 study was fully enrolled in November 2019, the last patient will finish mandatory two years of follow up as of November 2021 .
Jean-Jacques Bienaimé, Chairman and Chief Executive Officer of BioMarin Pharmaceuticals, added, “We remain committed to the hemophilia community and to leading the way to the first-ever gene therapy in hemophilia A. 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 filed by the company was based on the Phase 3 study results and three-year data from the Phase 1/2 Study. Previously, the FDA had granted valoctocogene roxaparvovec designations such as Priority Review status, Breakthrough Therapy, and Orphan Drug designations. The company plans to meet with the FDA in the upcoming weeks to discuss the next steps required to score approval.
Meanwhile, BioMarin wishes to advance the ongoing clinical trials for valoctocogene roxaparvovec while it explores potential options for gaining approval. The company’s Marketing Authorization Application (MAA) is still under review with The European Medicines Agency (EMA) .
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