BioMarin to Resubmit Gene Therapy Roctavian for EU Approval in June

The European Medicines Agency (EMA) has accepted BioMarin Pharmaceutical’s request for accelerated assessment of Roctavian, the company’s investigational gene therapy for severe hemophilia A, for a second time.

Last year, BioMarin’s regulatory applications for Roctavian (valoctocogene roxaparvovec) got rejected both in Europe and in the U.S., with regulatory agencies requesting longer follow-up data from the Phase 3 GENEr8-1 trial (NCT03370913), which is investigating the efficacy of the one-time therapy in 134 patients.

Accelerated assessment is given to therapies considered of major interest for public health, particularly in terms of therapeutic innovation, by the Committee for Medicinal Products for Human Use (CHMP) and the Committee for Advanced Therapies (CAT), two arms of the EMA.

The status shortens Roctavian’s regulatory review by these committees to 150 days (about five months), instead of the standard 210-day period (about seven months).

BioMarin plans to resubmit an application in June for Roctavian, containing the requested one-year results. A CHMP opinion is expected in the first half of 2022. The committee’s opinions are generally accepted by the European Commission, which makes the final decision on whether a medication should be approved for a given indication.

“BioMarin is pleased that the EMA has granted accelerated assessment for the review of [Roctavian], which acknowledges its therapeutic innovative potential, and the unmet medical need that exists,” Hank Fuchs, MD, president of worldwide research and development at BioMarin, said in a press release.

“We continue to work closely with the EMA to make [Roctavian], the potential first gene therapy to treat hemophilia A, available as soon as possible,” Fuchs added.

If GENEr8-1 produces positive results, BioMarin also plans to resubmit a similar application between April and June 2022 to the U.S. Food and Drug Administration (FDA), with two-year data as requested by the agency. The FDA would then make a decision after a six-month review.

Roctavian is designed to increase the production of factor VIII (FVIII), the blood clotting protein that is missing in people with hemophilia A, and thereby reduce, or possibly eliminate, the need for preventive FVIII replacement therapy, a standard treatment used to avoid spontaneous bleeds in patients.

Given through a single into-the-vein injection, the therapy uses a modified and harmless version of an adeno-associated virus to deliver a shorter but working copy of F8 — the gene that provides instructions to make FVIII — to cells in the liver, the main producer of clotting factors in the body.

BioMarin’s first applications for Roctavian were supported by six-month interim data on 16 patients participating in GENEr8-1 and three-year data from a Phase 1/2 trial (NCT02576795), called Study 270–201, which is testing the therapy in 15 patients.

GENEr8-1’s top-line one-year data, announced in January, showed that the therapy met both the trial’s main and secondary goals, significantly increasing FVIII levels, and reducing bleeding rates and the need for replacement therapy.

But a decline in Roctavian’s durability in sustaining FVIII production at levels necessary to control bleeds was noted in both GENEr8-1 and Study 270–201, which likely factored in the EMA and FDA requests for more Phase 3 data.

The gene therapy has been designated an orphan drug and priority medicine in Europe, and orphan drug, breakthrough therapy, and regenerative medicine advanced therapy in the U.S. for the treatment of severe hemophilia A. All of these designations are meant to speed its development and review.

BioMarin is recruiting up to 20 adults with severe hemophilia A to participate in its Phase 3b GENEr8-3 trial (NCT04323098), which is designed to test Roctavian in combination with immunosuppressive corticosteroids that may help prevent immune reactions against the carrier virus.

The therapy is being evaluated in two other Phase 1/2 trials, including in patients with either pre-existing antibodies against AAV5 (NCT03520712) and in those with active or prior inhibitors (neutralizing antibodies) against the delivered FVIII (NCT04684940).