BioMarin Pharmaceutical said an ongoing phase 3 study of valoctocogene roxaparvovec, its investigational gene therapy treatment for adults with severe hemophilia A, achieved pre-specified clinical criteria for regulatory review in the United States and Europe, and will submit an application for approval in the third quarter of 2019.

The company also provided an update to its previously reported results of an open-label phase 1/2 study of the gene therapy, which showed that the treatment reduced annual bleed rates but also raised questions about the durability of the hoped for once-and-done gene therapy that could cost more than $2 million for a treatment.

Hemophilia A is an x-linked genetic disorder caused by missing or defective FVIII, a clotting protein. Lack of FVIII can lead to painful and potentially life-threatening bleeds from even modest injuries, and often spontaneous bleeds into muscles or joints. Although it is passed down from parents to children, about one third of cases are caused by a spontaneous mutation that was not inherited. Incidence of the rare disorder is approximately one in 10,000.

The standard of care for the 43 percent of individuals with hemophilia A who are severely affected is a prophylactic regimen of FVIII infusions administered intravenously two to three times per week.  Despite these regimens, many people continue to experience bleeds, resulting in progressive and debilitating joint damage which can have a major impact on their quality of life.

The data in the three-year update to the phase 1/2 study with valoctocogene roxaparvovec (valrox) 6e13 vg/kg dose showed substantial and sustained reductions in bleeding that required factor VIII (FVIII) infusions.

In the year prior to study entry, the mean annualized bleed rate (ABR) was 16.5 and the median was 16.3. After three years, the ABR was a mean of 0.7 and a median of zero. This represents a 96 percent reduction in mean ABR over three years, with continued absence of target joint bleeds during the three years observed.

In the first year (71 percent), second year (86 percent), and third year (86 percent) of the study, participants had zero bleeds requiring FVIII infusions compared to 14 percent who had zero bleeds requiring FVIII infusions in the year prior to study entry. There was a 96 percent reduction in mean FVIII usage over three years. In the first year (98 percent), second year (94 percent), and third year (96 percent) reduction in mean FVIII usage.

In addition, FVIII levels appeared to be approaching a plateau in year three. Although this study showed that the gene therapy was effective, it raised questions about its durability over the long term as FVIII levels have dropped year-over-year. BioMarin is facing competition to bring a hemophilia A gene therapy to market with Spark Therapeutics and Sangamo Therapeutics.

BioMarin also released interim results from an ongoing phase 3 trial of valrox earlier than expected. At six months, seven patients in the 20-patient cohort of the phase 3 GENEr8-1 study achieved FVIII levels of 40 international units per deciliter (IU/dL) or more. The annualized bleed rate was zero and the estimated mean ABR was 1.5, representing a reduction of 85 percent from baseline levels where all patients were on standard of care prophylaxis. The biotech said that met pre-specified clinical criteria for regulatory review.

In addition, there was an 84 percent reduction in median annualized FVIII usage and a 94 percent reduction in mean FVIII usage annualized between week 5 and 26.

“Reaching this pre-specified clinical endpoint is an important milestone that brings us one step closer to a potential regulatory submission in both the U.S. and Europe for valoctocogene roxaparvovec to treat adults with severe hemophilia A,” said Hank Fuchs, president of worldwide research and development at BioMarin. “Our discussions with the FDA and EMA underscore the high level of unmet need in the hemophilia community, and we look forward to continuing our productive dialogue on the submissions.”

BioMarin’s valoctocogene roxaparvovec has Breakthrough Therapy designation and Orphan Drug designation in the United States and Priority Medicines designation in the European Union. The biotech has six ongoing studies of its gene therapy program for hemophilia A.

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

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