FDA Review of Roctavian, Gene Therapy for Hem A, Moving Ahead

Agency no longer seeking advisory meeting in approval decision, BioMarin says

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by Steve Bryson, PhD |

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A review is continuing into a resubmitted application for approval of Roctavian (valoctocogene roxaparvovec), a gene therapy for adults with severe hemophilia A, with a planned advisory committee meeting having been canceled.

The U.S. Food and Drug Administration (FDA) had requested, but now no longer intends, to meet with BioMarin Pharmaceutical, the therapy’s developer, to further discuss its biologics license application (BLA), the company announced in a press release. Advisory committee members, representing researchers, patients, industry, and consumers, provide the agency with independent advice when evaluating new products.

“The review of a BLA is a dynamic process, and we appreciate FDA’s ongoing engagement as we work toward delivering a potentially transformative treatment choice to those patients with severe hemophilia A,” said Hank Fuchs, MD, president of Worldwide Research and Development at BioMarin. “We look forward to further dialogue with the Agency as it reviews our application.”

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Hemophilia A Patients in Roctavian Trial Largely Bleed-free at Two Years

Roctavian works via one-time delivery of healthy F8 gene to liver cells

The company also remains on track for a scheduled inspection of its manufacturing facility in California for the gene therapy.

An FDA decision on Roctavian is expected in late March, but might be delayed a few months if additional data require a longer review. If approved, Roctavian would be the first gene therapy in the U.S. for hemophilia A.

BioMarin’s initial application for Roctavian, filed in 2020, was met with an FDA request for longer follow-up data on the therapy’s effectiveness and safety.

The resubmitted BLA includes a reply to the FDA’s complete response letter, feedback, and follow-up data from the Phase 3 GENEr8-1 trial (NCT03370913) that supported its first request, as well as five years of assessments from a smaller, ongoing Phase 1/2 study (NCT02576795). The FDA had asked for GENEr8-1 findings out three years after treatment, and these data were expected to be discussed at the advisory meeting.

In hemophilia A, mutations in the F8 gene, which contains instructions for making the factor VIII (FVIII) clotting protein, lead to insufficient or dysfunctional FVIII and blood clotting problems.

Administered via a one-time infusion into the bloodstream, Roctavian allows the body to produce functional FVIII using a harmless viral vector (adeno-associated virus serotype 5, or AAV5) to deliver a healthy version of F8 to liver cells.

GENEr8-1 trial findings at two years post-treatment demonstrated the gene therapy stopped excess bleeds in more than 80% of the 134 men with severe hemophilia A enrolled. Almost all study patients also discontinued using standard FVIII replacement therapies.

BioMarin is also conducting an open-label Phase 3b trial called GENEr8-3 (NCT04323098) in 22 men with severe hemophilia A to evaluate Roctavian’s effects when given alongside anti-inflammatory corticosteroids. Initial findings in this fully enrolled trial, which is examining the therapy’s ability to reduce bleeds and the use of replacement therapies, are expected early next year.

An ongoing Phase 1/2 trial (NCT03520712) in up to 10 men with severe hemophilia A and antibodies against Roctavian’s viral vector may still be enrolling at sites in the U.K. and South Africa. A separate Phase 1/2 study (NCT04684940) in up to 20 men with severe disease and current or prior inhibitors against FVIII is now recruiting patients at sites in the U.S. (California), Italy, Taiwan, and the U.K.

Roctavian was recently given conditional European Union approval to treat adults with severe hemophilia A and no detectable antibodies to the therapy’s AAV5 vector or FVIII inhibitors.