BioMarin Preparing to Submit Marketing Authorization Applications for Valoctocogene Roxaparvovec

BioMarin Pharmaceuticals is planning to submit marketing authorization applications to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) seeking approval of valoctocogene roxaparvovec, its investigational gene therapy for the treatment of adults with hemophilia A, before the end of the year.

Valoctocogene roxaparvovec is an experimental gene therapy based on the use of adeno-associated virus (AAV) vectors. It delivers a functional copy of clotting factor VIII that people with hemophilia A are missing. The Phase 3 GENEr8-1 trial (NCT03370913) is still recruiting participants.

The investigational treatment has received breakthrough therapy designation from the FDA, and priority medicines, or PRIME designation from the EMA. It also has orphan drug status from both regulatory agencies, which qualify BioMarin for various development incentives.

Now, valoctocogene roxaparvovec is taking the next step toward possible approval in the U.S. and the E.U.

“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,” Hank Fuchs, MD, president of global research and development at BioMarin, said in a press release.

“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,” Fuchs added.

The planned marketing authorization submissions are based on the latest findings from a Phase 1/2 trial (NCT03520712), and on data from an interim analysis of the ongoing Phase 3 GENEr8-1 trial (NCT03370913). BioMarin launched the studies to assess the effects of valoctocogene roxaparvovec in people with severe hemophilia A.

The latest findings from the Phase 1/2 trial were presented at the 27^th International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress, held recently in Melbourne, Australia. John Pasi, MB, ChB, PhD, chief investigator for the Phase 1/2 trial and principal investigator of the Phase 3 GENEr8-1 study, presented the key findings. The data show that:

• A single administration of valoctocogene roxaparvovec at a dose of 6e13 vg/kg (vector genomes per kilogram) was sufficient to control bleeding episodes, and to minimize the need for factor VIII infusions, over the course of three years in a small group of people with hemophilia A.
• The mean annualized bleeding rate (ABR) decreased from 16.3 at baseline, or the start of the trial, to 0.6 three years after therapy administration. That corresponds to a reduction of 96% in individuals’ mean ABR.
• The mean factor VIII usage decreased from 136.7 infusions per year at the start of the study to 5.5 infusions per year three years after therapy administration. That  also corresponds to a reduction of 96% in the participants’ mean annualized factor VIII usage rate.
• The levels of clotting factor VIII remained stable over the course of three years following valoctocogene roxaparvovec administration. None of the participants required prophylactic treatment.
• Valoctocogene roxaparvovec was generally well-tolerated by patients. None developed inhibitors to factor VIII, and none withdrew from the study due to adverse events.

The new submissions also will be supported by data from an interim analysis of the Phase 3 GENEr8-1 study. That study is still recruiting patients to reach its target enrollment goal of 130 participants. BioMarin says it is expecting to hit the trial’s target enrollment goal later this year.

The final data from GENEr8-1 won’t be required for the submission of the therapy’s first marketing authorization applications. But it will be the foundation to attest to the treatment’s expected clinical superiority compared with prophylactic factor VIII replacement therapy, the current standard of care.

“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 Pasi, also a professor at the Barts and the London School of Medicine and Dentistry.  “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.”

Valoctocogene roxaparvovec will be the first gene therapy for hemophilia whose marketing authorization applications will be reviewed by health authorities for potential approval in the U.S. and in the E.U.