FDA’s Rejection of Hemophilia Gene Therapy Raises Questions for Gene Therapy’s Future

Following a priority review, the FDA chose not to approve valoctocogene roxaparvovec, a one-time gene therapy for hemophilia A, seeking more evidence to support the treatment’s durability. The agency recommended BioMarin Pharmaceutical, the manufacturer, complete the ongoing phase III trial of the therapy and submit 2 years of follow-up safety and efficacy data on all study participants.

Valoctocogene roxaparvovec will maintain its breakthrough therapy and orphan drug designations.

The agency’s decision was based on differences between the phase I/II and phase III trials of the treatment, which used annualized bleeding rate (ABR) as their primary endpoints. The FDA claims that differences between the studies limited the ability to rely on the phase I/II results to support the therapy’s durability.

Industry experts have voiced concern that the rejection could indicate a shift toward more stringent standards for approval of this class of therapies. Other one-time gene therapies for rare diseases were previously approved based on small studies, such as the 2019 approval for Novartis’ onasemnogene abeparvovec-xioi for spinal muscular atrophy (based on 2 years of data) and the 2017 approval of Spark Therapeutics’ voretigene neparvovec-rzyl for inherited vision loss (based on a year-long trial of 31 patients).

“This is a potential chink in the armor for the field of gene therapy,” said Anthony Davies, PhD, CEO of Dark Horse Consulting Group, a gene and cell therapy consulting firm. “The door has opened for a stronger requirement for long-term clinical data to support approvals.”

Others in the industry insist the decision is specific to BioMarin and the therapy itself, rather than a sign of a shift within the agency.

“I don’t interpret this as something that should alarm the entire field,” said Kathy High, MD, cofounder and former President of Spark Therapeutics.

Sources: BioMarin press release, August 19, 2020; STAT, August 19, 2020; STAT, August 20, 2020.