Roctavian, Potential Hemophilia A Gene Therapy, Gets Fresh FDA Support

The U.S. Food and Drug Administration (FDA) has given regenerative medicine advanced therapy (RMAT) designation to Roctavian, an investigational gene therapy by BioMarin Pharmaceutical for severe hemophilia A.

The designation is “a critical program to advance the efficient development and regulatory review of regenerative medicine products that have the potential to address unmet needs” in serious or life-threatening conditions, the Alliance for Regenerative Medicine, which played a critical role in the creation of this program, said in a press release.

RMAT designation complements the breakthrough therapy designation that Roctavian received in 2017 for the same indication, allowing for early, close, and frequent interaction with the FDA.

One additional RMAT feature is that, should accelerated approval be given, further clinical evidence required to confirm the therapy’s benefits and achieve a full approval may come from sources other than the traditional confirmatory clinical trial.

Accelerated, or conditional, approval is granted to treatments whose immediate availability fulfills an unmet medical need, provided that early evidence supports its benefits outweighing potential risks.

Roctavian has also been designated an orphan drug in both the U.S. and Europe, and a priority medicine in Europe for the treatment of severe hemophilia A; all are meant to speed its development and review.

“During Bleeding Disorders Awareness Month, we applaud the FDA for its efforts to recognize the potential of cell and gene therapies to help people with hemophilia who have medical needs not currently addressed,” said Leonard A. Valentino, MD, president and CEO of the National Hemophilia Foundation, which initiated Bleeding Disorders Awareness Month to celebrate and honor the bleeding disorders community.

Roctavian (valoctocogene roxaparvovec) uses a modified and harmless adeno-associated virus, called AAV5, to deliver a shorter but functional copy of F8 — the gene that provides instructions to produce the clotting factor VIII (FVIII) that is missing in people with hemophilia A.

The therapy is given through a single infusion directly into the bloodstream, and designed to deliver the functional gene copy to cells in the liver, the main producer of clotting factors in the body.

As such, Roctavian is expected to increase the production of FVIII and reduce, or possibly eliminate, the need for prophylactic (preventive) FVIII replacement therapy, a current standard treatment used to avoid spontaneous bleeding episodes in these patients.

“This designation confirms our belief in this treatment’s potential to address unmet medical needs for people with hemophilia A at this time,” said Hank Fuchs, MD, president of BioMarin’s worldwide research and development.

“We look forward to continuing a productive dialogue with the FDA around the RMAT designation,” and the agency’s “request to see two years of data from the Phase 3 study to evaluate the safety and efficacy of this investigational treatment option that could potentially provide a transformational treatment choice for the hemophilia community,” Fuchs said.

In August, the FDA decided to delay its decision on Roctavian’s approval until two-year data from the company’s Phase 3 GENEr8-1 clinical trial (NCT03370913) were available. A similar decision was taken by the European Medicines Agency (EMA), which asked for one more year of data.

GENEr8-1 is evaluating the safety and effectiveness of a single dose of Roctavian (6e13 vector genomes/per kilogram) in 134 adults with severe hemophilia. It is reported to be the largest global Phase 3 study to date for any gene therapy in any disease.

Top-line data of at least one year of follow-up showed that the trial met both its main and secondary goals, with the therapy effectively increasing FVIII to nearly normal levels, and lowering the annualized bleeding rate by 84% and the need for replacement therapy by 99%, the company reported in January.

Notably, 80% of participants became bleed-free from week five after treatment.

But a decline in the therapy’s durability in sustaining factor VIII production, possibly affecting production at levels necessary to control bleeding, was noted in both this Phase 3  trial and in an earlier Phase 1/2 trial (NCT02576795), which took place in the U.K. These declines factored in the EMA and FDA requests for more Phase 3 data.

A slower decline was evident in a subgroup of 17 patients given a single infusion at least two years ago in GENEr8-1 compared with the drop seen in the Phase 1/2 study, BioMarin reported in its January release of top-line trial findings.

Results also showed that Roctavian was generally well-tolerated, with no new safety concerns identified. The most commonly reported adverse event was high levels of a liver enzyme called alanine aminotransferase — suggestive of liver damage and a common event in gene therapies.

A total of 22 participants reported 43 serious adverse events, all of which resolved. No clotting-related adverse events were reported, and no patients developed antibodies against FVIII, which might impair treatment effectiveness.

BioMarin plans to re-submit a regulatory application with these one-year data to the EMA before the end of June, pending confirmation in planned pre-submission meetings.

The company also expects to meet with the FDA to share these results and review the two-year data request. The last treated patient will complete two years of follow-up in November, meaning an FDA decision may not be possible before the end of this year or in 2022.