Previously the US regulator had said that there was no need for an AdComm for the drug candidate, but now the agency has issued a complete response letter that could cause a major delay for any future approval, and this has effectively put a red X on what would have been the first-ever approval of a gene therapy for the bleeding disorder.
The removal of an AdComm was seen as being positive at the time, but 3-year data on the drug candidate recently reported has sparked concerns about its durability after factor VIII levels seemed to drop off after 12-18 months, suggesting the patients may need to re-dose to maintain sustained protection against bleeds.
The FDA is citing concerns over durability but BioMarin is contending that this is the first time they have 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,” reads a company 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 company must now finish off that phase 3 and then submit 2 years follow up safety and efficacy data on all of the 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 company will be meeting 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 red rejection by the FDA recently, this one comes just after the agency gave another red X to Gilead’s hopeful candidate filgotinib for rheumatoid arthritis citing safety issues. Both rejections come after public concerns over the FDA possibly lowering the bar for new medications.
“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.”
