FDA Accepts BioMarin's Biologics License Application (BLA) for Valoctocogene Roxaparvovec AAV Gene Therapy for Adults with Severe Hemophilia A

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 <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 (Factor VIII 1-5%) or mild (Factor VIII 5-40%) disease show a much-reduced propensity to bleed. Individuals with severe hemophilia A are treated with a prophylactic regimen of intravenous Factor VIII infusions administered 2-3 times per week (100-150 infusions per year) or a bispecific monoclonal antibody that mimics the activity of Factor VIII administered 1-4 times per month (12-48 injections or shots 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.

About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for people with serious and life-threatening genetic diseases and medical conditions. The Company selects product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products. The Company's portfolio consists of eight commercial products and multiple clinical and preclinical product candidates for the treatment of various diseases. For additional information, please visit www.biomarin.com.

Forward-Looking Statements

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc. (BioMarin), including without limitation, statements about: timing of a target PDUFA date, expectations regarding the need for an advisory committee meeting, the possibility of regulatory approval, BioMarin's expectations regarding the duration of the review procedure, valoctocogene roxaparvovec being the first commercially-available gene therapy in the U.S. for the treatment of severe hemophilia A, if approved, BioMarin's commitment to sharing longer-term data generated through its ongoing clinical trials and any post-approval studies. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: the results and timing of current and planned preclinical studies and clinical trials of valoctocogene roxaparvovec; additional data from the continuation of the clinical trials of valoctocogene roxaparvovec, any potential adverse events observed in the continuing monitoring of the participants in the clinical trials; the content and timing of decisions by the FDA and other regulatory authorities, the content and timing of decisions by local and central ethics committees regarding the clinical trials; our ability to successfully manufacture valoctocogene roxaparvovec for the clinical trials and commercially; and those and those factors detailed in BioMarin's filings with the Securities and Exchange Commission (SEC), including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's Quarterly Report on Form 10-Q for the quarter ended June 30, 2022 as such factors may be updated by any subsequent reports. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise.

BioMarin® is a registered trademark of BioMarin Pharmaceutical Inc and ROCTAVIAN™ is a trademark of BioMarin Pharmaceutical Inc.

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SOURCE BioMarin Pharmaceutical Inc.