If Approved, Would Be 1st Gene Therapy in U.S. for Treatment of Severe Hemophilia A

PDUFA Target Action Date is March 31, 2023

SAN RAFAEL, Calif., Oct. 12, 2022 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced today that the U.S. Food and Drug Administration (FDA) accepted the Company's resubmission of the Biologics License Application (BLA) for its investigational AAV gene therapy, valoctocogene roxaparvovec, for adults with severe hemophilia A. The Prescription Drug User Fee Act (PDUFA) target action date is March 31, 2023. At this time, the FDA has not communicated any plans to hold an advisory committee meeting.  If approved, valoctocogene roxaparvovec would be the first gene therapy in the U.S. for the treatment of severe hemophilia A.

"This BLA resubmission is an important step that brings us closer to delivering a gene therapy treatment choice to address the unmet needs of people with severe hemophilia A in the United States.  We'd like to extend our sincere gratitude to the bleeding disorders community, study participants, and investigators who have been an integral part of this journey with BioMarin. We look forward to working closely with the Agency on our application for this potentially transformative therapy," said Hank Fuchs, M.D., President of Worldwide Research and Development at BioMarin. "In this application, we have provided a substantial body of evidence that supports the safe and effective use of valoctocogene roxaparvovec for the treatment of adults with severe hemophilia A. In addition, we have proposed 15 years of follow-up for all clinical study participants, as well as a post-approval registry study to follow patients dosed in a real-world setting, to further characterize long-term effects on safety and efficacy that will contribute to increasing the body of knowledge of AAV gene therapy in severe hemophilia A. While we recognize the potential for the Agency to extend the PDUFA action date to review additional long-term follow up data, we are pleased the FDA has initiated its review of the BLA without requesting additional data."

The BLA resubmission incorporates the Company's responses to all deficiencies identified in the FDA Complete Response (CR) Letter of August 18, 2020. The BLA includes a substantial amount of data from the valoctocogene roxaparvovec clinical development program, the most extensively studied gene therapy for severe hemophilia A, including two-year outcomes from all study participants in the global GENEr8-1 Phase 3 study. The GENEr8-1 Phase 3 study demonstrated stable and durable bleed control, including a reduction in the mean annualized bleeding rate (ABR) and the mean annualized Factor VIII infusion rate. In addition, the data package includes supportive evidence from five years of follow-up from the 6e13 vg/kg dose cohort in the ongoing Phase 1/2 dose escalation study. The BLA also includes a proposed long-term extension study following all clinical trial participants for up to 15 years, as well as a post-approval registry study to follow patients dosed in a real-world setting. 

The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to valoctocogene roxaparvovec in March 2021. RMAT is an expedited program intended to facilitate development and review of regenerative medicine therapies, such as valoctocogene roxaparvovec, that are expected to address an unmet medical need in patients with serious conditions. The RMAT designation is complementary to Breakthrough Therapy Designation, which the Company received for valoctocogene roxaparvovec in 2017.

In addition to the RMAT Designation and Breakthrough Therapy Designation, BioMarin's valoctocogene roxaparvovec also received orphan drug designation from the EMA and FDA for the treatment of severe hemophilia A. Orphan drug designation is reserved for medicines treating rare, life-threatening or chronically debilitating diseases. The European Commission (EC) granted conditional marketing authorization to valoctocogene roxaparvovec gene therapy under the brand name ROCTAVIAN™ on August 24, 2022.

Robust Clinical Program

BioMarin has multiple clinical studies underway in its comprehensive gene therapy program for the treatment of severe hemophilia A. In addition to the global Phase 3 study GENEr8-1 and the ongoing Phase 1/2 dose escalation study, the Company is also conducting a Phase 3, single arm, open-label study to evaluate the efficacy and safety of valoctocogene roxaparvovec at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with severe hemophilia A (Study 270-303). Also ongoing are a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) and a Phase 1/2 Study with the 6e13 vg/kg dose of valoctocogene roxaparvovec in people with severe hemophilia A with active or prior Factor VIII inhibitors (Study 270-205).

Safety Summary

Overall, to date, a single 6e13 vg/kg dose of valoctocogene roxaparvovec has been well tolerated with no delayed-onset treatment related adverse events. The most common adverse events (AE) associated with valoctocogene roxaparvovec have occurred early and included transient infusion associated reactions and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae. Alanine aminotransferase (ALT) elevation, a laboratory test of liver function, has remained the most common adverse drug reaction. Other adverse reactions have included aspartate aminotransferase (AST) elevation (101 participants, 63%), nausea (55 participants, 34%), headache (54 participants, 34%), and fatigue (44 participants, 28%). No participants have developed inhibitors to Factor VIII, thromboembolic events or malignancy associated with valoctocogene roxaparvovec.

About 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 (Factor VIII levels