FDA Grants Valoctocogene Roxaparvovec RMAT Designation for Hemophilia A

Hank Fuchs, MD

The FDA has granted a regenerative medicine advanced therapy (RMAT) designation to valoctocogene roxaparvovec (BMN 270) as a potential treatment for patients with hemophilia A, according to a statement from BioMarin, the company developing the gene therapy.

In August 2020, BioMarin received a complete response letter from the FDA for valoctocogene roxaparvovec as a treatment for severe hemophilia A. The agency requested long-term data from the single-arm phase 3 GENEr8-1 study to further establish the efficacy of the therapy on annualized bleeding rates (ABR) at 2 years post treatment. In early January, BioMarin released data from a mean 71.6-week follow-up indicating an ABR reduction from baseline of 84% with valoctocogene roxaparvovec.

"We are encouraged that the FDA granted RMAT Designation to valoctocogene roxaparvovec. This designation confirms our belief in this treatment's potential to address unmet medical needs for people with hemophilia A at this time," Hank Fuchs, MD, president of Worldwide Research and Development at BioMarin, said in a statement. "We look forward to continuing a productive dialogue with the FDA around the RMAT designation, which provides options for the agency to leverage data post approval, while also recognizing the agency's initial request to see 2 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."

The RMAT designation is intended for cell and certain gene therapies that treat, reverse, or cure serious or life-threatening diseases. The designation is meant to expedite the development of therapies with promising preliminary evidence. In addition to this designation, the agency also previously granted the agent orphan drug and breakthrough therapy designations.

The ongoing phase 3 GENEr8-1 study included 134 adult participants with hemophilia A and residual FVIII levels ≤1 IU/dL. Valoctocogene roxaparvovec, an AAV5 gene therapy, was administer in a single 613 vg/kg dose infusion. The primary outcome was median change in FVIII activity and the secondary end points were annualized utilization of exogenous FVIII replacement therapy and ABR.

In the data released in January, patients experienced 4.8 annualized bleeds at baseline compared with 0.8 post-infusion with valoctocogene roxaparvovec, representing a statistically significant improvement (P <.0001). In a pre-specified observational rollover group (n = 112), 80% were bleed-free by week 5. In this group, mean annualized factor VIII was reduced by 99%, from an annualized rate of 135.9 to 2.0 infusions per year (P <.0001).

At 1-year post-infusion with valoctocogene roxaparvovec in the rollover group, the median factor VIII expression level was 24.2 UI/dL and the mean was 43.6 UI/dL. In a subset of HIV-negative patients dosed 2 or more years prior to the data cutoff, the median factor VIII expression level was 23.9 IU/dL at week 52 and 14.7 IU/dL by week 104. The mean was 42.2 IU/dL at week 52 and dropped to 24.4 IU/dL at week 104; however, there was 1 patient who was lost to follow up at 2 years who was calculated as 0 at the week 104 analysis. This group of patients maintained a mean ABR of 0.9.

"Although factor replacement therapy has been shown to be a safe and effective treatment modality in hemophilia, it suffers both from incomplete prevention of joint disease and having a high treatment burden with recurring needs for intravenous infusions, which can limit important daily activities out of fear of bleeds," Guy Young, MD, director, Hemostasis and Thrombosis Program at Children's Hospital Los Angeles and Professor of Pediatrics (Clinical Scholar), Keck School of Medicine of University of Southern California, said when the data were released. "Novel therapeutic approaches such as gene therapy offer the prospect for both complete prevention of bleeds and subsequent joint damage and eliminating the burden associated with current treatments resulting in an improved quality of life."

One of the benefits of the RMAT designation is the ability to gain an accelerated approval with additional clinical evidence submitted subsequently as support, BioMarin noted in their release. In January, BioMarin noted that it would continue meeting with the FDA on the 2-year data request and would hold conversations with the European Medicines Agency on the submission of the 1-year data. If these talks went well, the company plans to submit a marketing authorization application in the second quarter of 2021.

"Over the past seven years, we have conducted rigorous scientific research and clinical programs to address the unmet medical needs of people with severe hemophilia A," Fuchs said at the time of the data release. "We are very encouraged by these data and look forward to working with regulatory authorities, treating physicians, and people with hemophilia A to further understand the potential of this gene therapy."

A number of phase 1/2 studies also continue to assess the safety and efficacy of valoctocogene roxaparvovec. In one, the therapy is under exploration in 10 participants with pre-existing AAV5 antibodies and in another it is being examined in patients with hemophilia A on active or prior FVIII inhibitors.