FDA gets out its red pen again, rejecting BioMarin's gene therapy valrox amid durability worries

BioMarin’s shares plummeted in early Wednesday trading after the FDA refused to approve its hemophilia A gene therapy valoctocogene roxaparvovec.

The U.S. regulator, which had earlier said there was no need for an AdComm for the drug, also known as valrox, has issued a complete response (CRL) letter that could cause a major delay for any future approval, and nixed what would have been the first-ever approval for a gene therapy in the bleeding disorder.

While the removal of an AdComm was seen as a positive, it’s not all been smooth sailing: Three-year data on its candidate were reported last May but sparked concerns about the durability of the therapy after factor VIII levels seemed to fall off after 12 to 18 months, raising the possibility that patients might need to be re-dosed to maintain protection against bleeds.

And it is durability the FDA has concerns over, though BioMarin contends this is the first it’s heard about it. “Having previously agreed with the Agency on the extent of data necessary to support the BLA, the FDA introduced a new recommendation for two years of data from the company's ongoing 270-301 study (phase 3) to provide substantial evidence of a durable effect using Annualized Bleeding Rate (ABR) as the primary endpoint,” the company said in a detailed statement.

“The Agency first informed the company of this recommendation in the CRL having not raised this at any time during development or review.”

The FDA now says it must finish off that phase 3 and then submit two-year follow-up safety and efficacy data on all study participants. “FDA concluded that the differences between Study 270-201 (Phase 1/2) and the phase 3 study limited its ability to rely on the phase 1/2 study to support durability of effect,” BioMarin said.

The late-stage test was fully enrolled last November, but the last patient will not have completed two years of follow-up until next November.

BioMarin’s shares fell more than 20% premarket Wednesday on the news, partially boosting its rivals at Spark/Roche, Pfizer et al, although this has proved a rocky R&D path for all involved.

BioMarin will now meet with the FDA in the “coming weeks to align on the next steps to obtain approval.” It is still being reviewed in Europe.

This is the second big rejection of the week, coming after the FDA knocked back Gilead’s blockbuster hopeful filgotinib over safety issues. This also comes after concerns that the FDA was lowering the bar for new meds.

“We remain committed to the hemophilia community and to leading the way to the first ever gene therapy in hemophilia A,” said Jean-Jacques Bienaimé, chairman and chief of BioMarin. “We are surprised and disappointed that the FDA introduced new expectations for the first time in the Complete Response Letter. We are confident in valoctocogene roxaparvovec gene therapy and its potential to redefine the treatment paradigm for people with hemophilia A.”

Analysts at Piper Sandler said: “We are shocked by this development as management, as recently as last week during our virtual West Coast bus tour, was uber bullish regarding this agent’s commercial prospects, saying 2021 consensus was “not heroic.””