Rare Daily Staff

BioMarin Pharmaceutical said that it plans to submit marketing applications to both the U.S. Food and Drug Administration and the European Medicines Agency in the fourth quarter of this year for its experimental hemophilia A gene therapy.

The decision puts BioMarin on track to be the first company to seek regulatory approval for a hemophilia gene therapy of any kind.

People living with hemophilia A lack enough factor VIII protein to help their blood clot and are at risk for painful and potentially life-threatening bleeds from even modest injuries. In cases where the condition is severe, people with hemophilia A experience painful, spontaneous bleeds into their muscles or joints. Even with the use of replacement factor VIII therapy, many people continue to experience bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

BioMarin’s experimental gene therapy valoctocogene roxaparvovec is an AAV-factor VIII gene therapy designed to restore adequate levels of factor VIII for normal clotting. The therapy is being developed as a one-time treatment for adults with severe hemophilia A and could eliminate the need for ongoing factor VIII treatments. The standard of care for most hemophilia A patients who are severely affected today is a regimen of intravenous infusions three times per week.

BioMarin said its submission to regulators will be based on updated three-year phase 1/2 data and the recently completed phase 3 interim analysis of patients treated with material from its soon-to-be-commercialized gene therapy manufacturing process. 

“People with severe hemophilia A continue to experience clinically relevant breakthrough bleeds despite the current standard of care and can be limited in their physical activities,” said John Pasi, professor at Barts and the London School of Medicine and Dentistry and the chief investigator for the valoctocogene roxaparvovec phase 1/2 study and a principal investigator for the phase 3 study. “Valoctocogene roxaparvovec represents a potentially transformative investigative therapy that could improve patients’ quality of life, including consequences of bleeding, physical functioning, role functioning, emotional impact, treatment concern, and worry.”

Pasi presented data in a late-breaking abstract session on the efficacy and safety of valoctocogene roxaparvovec in an ongoing phase 1/2 study at the 27th International Society on Thrombosis and Haemostasis 2019 Congress in Melbourne, Australia. 

The three-year update of the 6e13 vg/kg dose cohort in the phase 1/2 study demonstrated that bleed rate control and reduction in Factor VIII usage was maintained for a third year following a single administration of valoctocogene roxaparvovec. 

In the year prior to study entry, the mean Annualized Bleed Rate (ABR) was 16.3 and the median was 16.5. Over three years, the ABR fell to a mean of 0.6 and a median of zero. This represents a 96 percent reduction in participants’ mean ABR, and there was 100 percent resolution of target joints. There was also a 96 percent reduction in participants’ mean annualized Factor VIII usage rate over three years, and all participants remain off Factor VIII prophylaxis. 

Factor VIII levels sustained over a three-year period, with factor VIII expression entering a plateau phase where the rate of decline has substantially slowed, which could be indicative of durable, long-term expression. 

Overall, valoctocogene roxaparvovec continues to be well-tolerated by participants across all doses in the phase 1/2 and phase 3 studies. No participants developed inhibitors to factor VIII, and no participants withdrew from the study. All participants have remained off factor VIII prophylaxis. Transient liver biomarker abnormalities and infusion-associated reactions have been the primary treatment-related adverse events, with no incidence of delayed adverse events.

While the planned regulatory submissions in 4Q 2019 will be based on an interim analysis of the phase 3 GENEr8-1 study results, the trial will continue enrollment until reaching its planned completion target of 130 total patients. Completion of this portion of the study is not required for initial marketing authorizations of valoctocogene roxaparvovec. The final analysis from the phase 3 GENEr8-1 study will serve as the basis for evaluating the clinical superiority of valoctocogene roxaparvovec to prophylactic factor VIII replacement therapy. 

Regulators previously granted valoctocogene roxaparvovec Breakthrough Therapy designation in the United States and the Priority Medicines (PRIME) regulatory initiative in Europe, as well as Orphan Drug designation.

“We applaud the FDA’s efforts to incorporate the patient voice in the regulatory review process. Powerful and moving testimonials from clinical study participants have helped serve as a critical element in the FDA’s considerations of potentially the first commercially available gene therapy for any type of hemophilia,” said Hank Fuchs, president of global research and development at BioMarin. “As important, we commend the EMA PRIME initiative for enabling enhanced interactions and early dialogue that have optimized our development plans and have helped speed up evaluation of this novel investigational gene therapy.”

Photo: Hank Fuchs, president of global research and development at BioMarin

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