ROCTAVIAN is a One-Time, Single-Dose Treatment Available for Adults with Severe Hemophilia A to Control Bleeds

ROCTAVIAN's Approval was Based on Durability, Efficacy and Safety Results from the Largest and Longest Phase 3 Study for a Gene Therapy for Hemophilia

Majority of Patients Continued to Respond to ROCTAVIAN Treatment over 3 Years

Conference Call and Webcast to be Held at 4:30 p.m. Eastern Time on Thursday, June 29, 2023 

SAN RAFAEL, Calif., June 29, 2023 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN), a global biotechnology company dedicated to transforming lives through genetic discovery, today announced that the United States Food and Drug Administration (FDA) approved ROCTAVIAN™ (valoctocogene roxaparvovec-rvox) gene therapy for the treatment of adults with severe hemophilia A (congenital factor VIII (FVIII) deficiency with FVIII activity <1 iu dl) without antibodies to adeno-associated virus serotype 5 (aav5) detected by an fda-approved test.< p>

The one-time, single-dose infusion is the first approved gene therapy for severe hemophilia A in the U.S. ROCTAVIAN was first approved by the European Medicines Agency in August 2022.

"Adults with severe hemophilia A face a lifelong burden, with frequent infusions and a high risk of health complications, including uncontrolled bleeding and irreversible joint damage," said Dr. Steven Pipe, professor of pediatrics and pathology at the University of Michigan and an investigator in the Phase 3 study.  "The approval of ROCTAVIAN, as the first gene therapy for severe hemophilia A, has the potential to transform the way we treat adults based on years of bleed control following a single, one-time infusion."

Hemophilia A is a lifelong, genetic condition caused by a mutation in the gene responsible for producing a protein called FVIII, which is necessary for blood clotting. When severely deficient in amount, the condition puts people with hemophilia A at risk for painful and potentially life-threatening bleeds, which can occur spontaneously. With the current standard of care, individuals undergo lifelong preventative therapy, receiving infusions or injections at burdensome routine intervals to maintain enough clotting factor in the bloodstream to prevent bleeds. ROCTAVIAN is designed to replace the function of the mutated gene, allowing people with severe hemophilia A to produce their own FVIII and thereby limit bleeding episodes.

"Today's approval of ROCTAVIAN builds on BioMarin's proven track record of advancing treatments that target the underlying cause of life-threatening genetic conditions, which has produced eight best- or first-in-class commercial therapies," said Jean-Jacques Bienaimé, chairman and chief executive officer of BioMarin. "We are proud to now offer adults with severe hemophilia A, a one-time, single-dose treatment option. We are especially grateful to the bleeding disorders community for its support of this program, and to all the patients and healthcare providers who participated in our clinical trials."

ROCTAVIAN is manufactured at the company's facility in Novato, California. The BioMarin-owned site is one of the largest gene therapy manufacturing facilities of its kind and will allow the company to meet commercial demand throughout its product lifecycle.

Largest Phase 3 Gene Therapy Study in Hemophilia to Report More Than Three Years of Data

The FDA approval is based on data from the global Phase 3 GENEr8-1 study, the largest Phase 3 trial of any gene therapy in hemophilia. Of the 134 patients who received ROCTAVIAN in the study, 112 patients had baseline annualized bleeding rate (ABR) data prospectively collected during a period of at least six months on FVIII prophylaxis prior to receiving ROCTAVIAN. The remaining 22 patients had baseline ABR collected retrospectively. All patients were followed for at least 3 years.

As reported in the FDA-approved labeling for ROCTAVIAN, the 112 patients in whom 6-month baseline ABR was collected prospectively experienced a mean ABR reduction of 52% after receiving ROCTAVIAN (2.6 bleeds/year) through end of follow-up (median of three years) compared to their baseline ABR while receiving routine FVIII prophylaxis (5.4 bleeds/year).  This result was based on an FDA analysis that imputed an ABR of 35 in 13 patients for the periods when these patients were on prophylaxis. These patients also reported a substantial reduction in the rate of spontaneous bleeds and joint bleeds following treatment with ROCTAVIAN (observed mean ABR of 0.5 bleeds/year for spontaneous bleeds and 0.6 bleeds/year for joint bleeds) compared to their baseline rate while receiving routine FVIII prophylaxis (observed mean ABR of 2.3 bleeds/year for spontaneous bleeds and 3.1 bleeds/year for joint bleeds).

The majority of study participants continued to respond to treatment through year three and beyond, without supplemental use of regular prophylaxis.

BioMarin will continue to monitor the long-term effects of treatment with an extension study that will follow all clinical trial participants for up to 15 years, as well as post-approval studies to follow those dosed in a real-world setting for 15 years or more. 

Data Presented at the International Society on Thrombosis and Haemostasis (ISTH) 2023 Congress

Additionally, results from the three-year analysis of the Phase 3 GENEr8-1 study that were presented on Sunday at ISTH showed that study participants had an 82.9% reduction in treated bleeds overall compared with baseline. The study also found ROCTAVIAN led to a 96.8% reduction in FVIII usage overall compared with baseline.

Ensuring Access: Hemophilia Treatment Centers (HTCs) and Outcomes-Based Warranty Program

BioMarin will begin educating physicians and patients about ROCTAVIAN immediately to ensure the hemophilia community is aware of this new treatment option.

As part of the development of ROCTAVIAN, BioMarin has worked with private and public payers in the U.S. in parallel to enable access, with the goal of ensuring that every eligible adult interested in ROCTAVIAN is able to receive treatment.

A key component of the company's approach to access is the outcomes-based warranty, which will be offered to all U.S. insurers. The warranty will reimburse government and commercial payers up to 100% of wholesale acquisition cost in the event that a person does not respond to ROCTAVIAN. If an individual treated with ROCTAVIAN loses response at any time in the first four years after dosing, BioMarin will reimburse payers on a prorated basis for the cost of treatment.

Most people with hemophilia receive care at HTCs. The company is working closely with the leading U.S. HTCs to ensure that the centers are prepared to administer ROCTAVIAN following today's approval. 

"Our teams have been working for many months to ensure that the people who are eligible for ROCTAVIAN have access to this first-in-class medicine," said Jeff Ajer, executive vice president and chief commercial officer of BioMarin. "We appreciate the close partnership with health insurers, hemophilia treatment centers and the hemophilia community to ensure the greatest access for people with severe hemophilia A."

It is estimated that there are approximately 6,500 adults living with severe hemophilia A in the U.S. BioMarin expects approximately 2,500 of those adults to be eligible to receive ROCTAVIAN with this initial approval.

Investor Conference Call and Webcast to be Held at 4:30 p.m. Eastern Time on Thursday, June 29, 2023

BioMarin will host a conference call and webcast to discuss the approval at 4:30 p.m. Eastern Time today, Thursday, June 29, 2023. This event can be accessed in the investor section of the BioMarin website at https://investors.biomarin.com/events-presentations.

Robust Ongoing 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 1/2 and Phase 3 GENEr8-1 studies, the company is also conducting a single-arm, open-label study to evaluate the efficacy and safety of ROCTAVIAN at a dose of 6e13 vg/kg with prophylactic corticosteroids in people with severe hemophilia A (Study 270-303). There is also an ongoing study with the 6e13 vg/kg dose of ROCTAVIAN in people with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) and a study with the 6e13 vg/kg dose of ROCTAVIAN in people with severe hemophilia A with active or prior FVIII inhibitors (Study 270-205).

Safety Summary

Safety results for 134 patients have been reported through three years, demonstrating that ROCTAVIAN was well-tolerated.

The Prescribing Information includes Warnings and Precautions for infusion-related reactions, hepatotoxicity, thromboembolic events and theoretical risk of hepatocellular carcinoma.

Patients with detectable pre-existing antibodies to AAV5, active infections, history of thrombosis, immunosuppressive disorders and liver dysfunction were excluded. All patients had a median follow-up of 162 weeks (range: 66 to 255 weeks). The most common adverse reactions (≥ 5%) to ROCTAVIAN were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. ROCTAVIAN is contraindicated for patients with active infections, either acute or uncontrolled chronic, known significant hepatic fibrosis (stage 3 or 4), or cirrhosis and a known hypersensitivity to mannitol.

The most common laboratory abnormalities were alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CPK), factor VIII activity levels, gamma-glutamyl transferase (GGT) and bilirubin > upper levels of normal (ULN). The majority of patients in the clinical trial required corticosteroids for ALT elevation (median duration of corticosteroid use was 35 weeks). See additional safety information in the Prescribing Information and Important Safety Information below.

Patient Support for Accessing ROCTAVIAN

To reach a BioMarin RareConnections® case manager, please call 1-833-ROCTAVIAN (1-833-762-8284), or email roctaviansupport@biomarin-rareconnections.com. For more information about ROCTAVIAN, please visit BioMarin.com or contact BioMarin Medical Information at medinfo@bmrn.com.

About Hemophilia A

Hemophilia A, also called FVIII deficiency or classic hemophilia, is an X-linked genetic disorder caused by missing or defective FVIII, 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.

People living with hemophilia A lack sufficient functioning FVIII 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