EC Approves BioMarin’s Roctavian, First Gene Therapy for Severe Hemophilia A

The European Commission has granted BioMarin Pharmaceutical conditional marketing authorization for gene therapy Roctavian for adults with severe hemophilia A without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5.

Photo: Jean-Jacques Bienaimé, chairman and CEO of BioMarin

A Conditional Marketing Authorization recognizes that the medicine fulfils an unmet medical need based on a positive benefit-risk assessment, and that the benefit to public health of the immediate availability on the market outweighs the uncertainties inherent to the fact that additional data are still required. BioMarin will provide further data from ongoing studies within defined timelines to confirm that the benefits continue to outweigh the risks, building on what already constitutes the largest clinical data package for gene therapy in hemophilia A.

The EC also endorsed the European Medicines Agency recommendation for Roctavian to maintain orphan drug designation, thereby granting it a 10-year period of market exclusivity. The EMA recommendation noted that, even in light of existing treatments, Roctavian may potentially offer a significant benefit to those affected with severe Hemophilia A. 

The one-time infusion is the first approved gene therapy for hemophilia A and works by delivering a functional gene that is designed to enable the body to produce Factor VIII on its own without the need for continued hemophilia prophylaxis, thus relieving patients of their treatment burden relative to currently available therapies. People with hemophilia A have a mutation in the gene responsible for producing factor VIII, a protein necessary for blood clotting.

It is estimated that more than 20,000 adults are affected by severe hemophilia A across more than 70 countries in Europe, the Middle East, and Africa. Of the 8,000 adults with severe hemophilia A in the 24 countries within BioMarin’s footprint covered by today’s EMA approval, there are an estimated 3,200 patients for whom Roctavian will be indicated.

BioMarin said it anticipates additional access to Roctavian for patients outside of the EU through named patient sales based on the EMA’s approval in countries in the Middle East, Africa, and Latin America and expects additional market registrations to be facilitated by the EMA license.

“Roctavian approval in Europe is a historic milestone in medicine and is built upon almost four decades of scientific discovery, innovation, and perseverance,” said Jean-Jacques Bienaimé, chairman and CEO of BioMarin. “We thank the European Commission for recognizing Roctavian’s value as the first gene therapy for hemophilia A, a feat that we believe will transform how healthcare professionals and the patient community think about caring for bleeding disorders

The EC based its decision on a body of data from the Roctavian clinical development program, the most extensively studied gene therapy for hemophilia A, including two-year outcomes from the global GENEr8-1 phase 3 study. The GENEr8-1 phase 3 study demonstrated stable and durable bleed control, including a reduction in the mean annualized bleeding rate (ABR) and the mean annualized factor VIII infusion rate.

In addition, the data included five and four years of follow-up from two dose cohorts in the ongoing phase 1/2 dose escalation study. BioMarin has committed to continue working with the broader community and the EMA to monitor the long-term effects of treatment.

Roctavian has been well tolerated with no delayed-onset treatment related adverse events. The most common adverse events (AE) associated with Roctavian occurred early and included transient infusion associated reactions and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae. Alanine aminotransferase (ALT) elevation (80 percent), a laboratory test of liver function, remained the most common adverse drug reaction. Other adverse reactions included aspartate aminotransferase (AST) elevation (67 percent), nausea (37 percent), headache (35 percent), and fatigue (30 percent). No participants developed inhibitors to Factor VIII, thromboembolic events, or malignancy associated with Roctavian.

The conditional approval can be converted to a standard marketing authorization based on the provision of additional data from currently ongoing Roctavian clinical studies, including longer-term follow up of patients enrolled in the pivotal trial GENEr8-1, as well as a study investigating efficacy and safety of Roctavian with prophylactic use of corticosteroids, for which enrollment is now complete.

Though BioMarin had hoped to win U.S. approval for Roctavian, the U.S. Food and Drug Administration notified the company in August 2020 that it would not approve the gene therapy without additional data to demonstrate the durability of the gene therapy. The concern was that event though all of the participants in an open-label phase 1/2 study of the gene therapy remained off prophylactic therapy after a single dose, the data also showed that factor VIII activity levels declined with the most recent year’s data, even though the participants maintained high enough levels of factor VIII to prevent spontaneous bleeding events.

The agency said it wanted to see two years of data from the phase 3 study to provide substantial evidence of a durable effect using annualized bleeding rate, the endpoint of the study. BioMarin said it is still working to bring Roctavian to eligible patients with severe hemophilia A in the United States and said it is targeting a Biologics License Application resubmission for Roctavian by the end of September 2022. Typically, BLA resubmissions are followed by a six-month review procedure. However, the company anticipates three additional months of review may be necessary based on the number of data read-outs that will emerge during the procedure.

Author: Rare Daily Staff