Valoctocogene Roxaparvovec Nearing Potential Hemophilia A FDA Decision


The investigative gene therapy achieved significant phase 3 endpoints, after receiving feedback from the FDA on its efficacy outcomes in 2020.

Valoctocogene Roxaparvovec Nearing Potential Hemophilia A FDA Decision

After various setbacks and delays, gene therapy valoctocogene roxaparvovec (Roctavian) may achieve significant regulatory landmarks in the treatment of hemophilia A in 2022.

The BioMarin investigational adeno-associated virus 5 (AAV5) gene therapy achieved phase 3 efficacy marks in significantly reduced bleeding, factor VIII production and concentrate use relative to standard factor VIII prophylaxis over 51 mean weeks of follow-up last month. Now, the company is again seeking US Food and Drug Administration (FDA) approval for the treatment of hemophilia A—a bleeding disorder prevalent in about 1 in every 4000-5000 male births.

The FDA previously issued a Complete Response Letter (CRL) to BioMarin for its submission of the gene therapy as a regulated treatment for severe hemophilia A, in August 2020. The basis of the CRL was due to a lack of substantial evidence showing durable effect via the annualized bleeding rate as a primary endpoint in treated patients from the trial.

Despite previously receiving Priority Review, Breakthrough Therapy and Orphan Drug designations, the company was recommended by the FDA in the CRL that investigators complete the phase 3 trial, which was anticipated for November 2021 at the time.

In the completed trial, published and presented this March, investigators observed the following improved outcomes among adult men with hemophilia A treated with valoctocogene roxaparvovec:

  • 41.9 IU/dL increased mean factor VIII activity level at week 49 (95% CI, 34.1 – 49.7; P <.001)
  • 98.6% decreased mean annualized factor VIII concentrate use rate after week 4 (P <.001)
  • 83.8% decreased mean annualized treated bleeding rates after week 4 (P <.001)

Investigators additionally observed 22 (16.4%) serious adverse events among trial participants, though no development of factor VIII inhibitors nor thrombosis in any participants. As the team noted, hemophilia A-targeting gene therapy may provide a steady, endogenous factor VIII activity maintenance without the need of regular prophylaxis—with some regimens requiring 3 weekly infusions.

“The expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible,” investigators wrote. “Overall, the risk–benefit profile appears favorable; we look forward to learning more about the long-term durability and safety of the treatment as we continue to follow the participants in this study.”

While awaiting a potential final decision from the FDA later this year, BioMarin leadership has expressed confidence in what they described as a “more complete understanding of the full data set of this potentially transformative medicine.”

"Valoctocogene roxaparvovec has been studied longer than any other gene therapy for hemophilia A, and year after year, we continue to increase our knowledge of how this investigational therapy may potentially benefit the lives of people with hemophilia A,” Hank Fuchs, MD, President of Worldwide Research and Development at BioMarin, said in a statement. “We are grateful to the study participants and investigators for their essential role in this development program, which includes GENEr8-1, the largest gene therapy study in hemophilia A."

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