BioMarin Says FDA Request May Delay Decision on Hemophilia A Gene Therapy Approval

Rare Daily Staff

BioMarin Pharmaceutical gave a progress update on its Biologics License Application for its AAV gene therapy for adults with severe hemophilia A that is currently under review by the U.S. Food and Drug Administration. 

As part of their review of the BLA, the FDA has scheduled its Pre-Licensure Inspection (PLI) of BioMarin’s gene therapy manufacturing facility, located in Novato, CA. As anticipated, the FDA also has requested that the company submit results from the upcoming three-year data analysis from the ongoing phase 3 GENEr8-1 Study.

While the FDA did not communicate a change to the current PDUFA target action date of March 31, 2023, the Agency stated that submission of these results may qualify as a Major Amendment, which would extend the action date by 3 months.  FDA will evaluate the additional data prior to making this determination.

“We appreciate the level of engagement from FDA this early in their BLA review cycle and are pleased to share that the inspection of our gene therapy manufacturing facility has now been scheduled,” said Hank Fuchs, president of Worldwide Research and Development at BioMarin. “Additionally, with their request related to the upcoming three-year data analysis from our phase 3 GENEr8-1 study, FDA stated that these data are expected to provide longer-term efficacy and safety information and would thus be useful to people with hemophilia A and healthcare providers in making better and more informed decisions when considering valoctocogene roxaparvovec as a treatment choice should it be approved,”

Fuchs said the company has observed positive bleed control results in the first cohort of patients who reached three years of observation in the phase 3 study, which BioMarin reported in January. The company anticipates reporting the three-year results from all participants (N=134) in early 2023.

On Oct. 12, 2022, the FDA accepted the company’s resubmission of the BLA for valoctocogene roxaparvovec.  Previously, the FDA communicated plans to hold an advisory committee meeting on a date that has yet to be confirmed per their usual practice of notification in the Federal Register.

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 granted conditional marketing authorization to valoctocogene roxaparvovec gene therapy under the brand name Roctavian on August 24, 2022.

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 one third 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 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 percent) 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 percent) or mild (Factor VIII 5-40 percent) 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.

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. 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 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.

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 elevation, a laboratory test of liver function, has remained the most common adverse drug reaction. Other adverse reactions have included aspartate aminotransferase elevation (101 participants, 63 percent), nausea (55 participants, 34 percent), headache (54 participants, 34 percent), and fatigue (44 participants, 28 percent). No participants have developed inhibitors to Factor VIII, thromboembolic events or malignancy associated with valoctocogene roxaparvovec.

Photo: Hank Fuchs, president of Worldwide Research and Development at BioMarin