The Food and Drug Administration unexpectedly rejected two major medicines on Tuesday and Wednesday, turning back what would have been the first gene therapy for hemophilia as well as a closely followed anti-inflammatory treatment.
The regulator's decisions were a shocking surprise and, in the case of BioMarin Pharmaceutical's Roctavian, could delay by years hopes for a gene therapy fix to one of the best-known inherited diseases.
Doctors and patients were excited for Roctavian, which is designed to correct the genetic defect that results in missing or reduced clotting protein in the blood of those with severe hemophilia A. An approval would have been a major milestone, capping decades of scientific research that led to Roctavian as well as several other experimental treatments that work similarly.
The FDA's rejection, therefore, could be consequential for other gene therapies from Roche and Sangamo Therapeutics in hemophilia A and UniQure in the less common hemophilia B form.
BioMarin submitted data from two clinical trials to support its application for Roctavian's approval. Results from a smaller, earlier study had shown treatment nearly eliminated bleeds in the 13 patients given high doses of Roctavian, freeing them from taking regular medication to control their disease. Four years later, Roctavian's benefits are still holding up.
A preliminary analysis from a larger, Phase 3 trial were meant to support those early findings, although BioMarin hadn't followed the study participants for as long.
But in a letter to BioMarin, the FDA said it would need two-year follow-up data from a Phase 3 study of Roctavian. The California biotech estimates the last patient in that trial will complete two years of study in November 2021, likely setting up a resubmission and FDA review by mid- or late-2022.
The requirement had not been specified by the agency previously, according to BioMarin.
"We were quite confident," said company CEO Jean-Jacques Bienaime in an interview Wednesday. "We had an agreement with the FDA over a year ago ... regarding the hurdle we'd have to pass for accelerated approval."
"Not only did they move the goalpost for accelerated approval, but they're now apparently moving the goalpost for full approval," he added, noting that BioMarin had designed the Phase 3 trial to assess annualized bleeding rates at one year.
At issue is whether the FDA can rely on the results from the Phase 3 trial to predict a similar long-lasting benefit as was seen in the Phase 1/2 study. Data showed the effectiveness of Roctavian appeared less potent in the later study, and waned over time.
BioMarin said it would meet with the FDA in the coming weeks to discuss next steps. The company's shares lost nearly a third of their value following Wednesday's announcement.
The FDA's decision to reject filgotinib, an arthritis treatment from Gilead and partner Galapagos, was also surprising, if not as dramatic as Roctavian.
Filgotinib is the crown jewel of a sprawling R&D alliance between the Belgian biotech and Gilead, which aimed to use the drug to build a larger business in inflammatory diseases.
Arthritis was the companies' first target, with other studies underway in diseases like ulcerative colitis and inflammatory bowel disease. The drug is part of a competitive class of oral medicines known as JAK inhibitors, several of which have been approved, but come with safety concerns.
Those concerns appear to be part of the reason for the FDA's rejection. According to Gilead, the FDA questioned the risk-benefit profile of a high dose of filgotinib, which was shown to be more effective.
Depending on what those questions are — Gilead didn't specify — approvals for filgotinib in other diseases could now be at higher risk of rejection, wrote RBC Capital Markets analyst Brian Abrahams.
The agency also wants to see data from two ongoing safety studies, dubbed MANTA and and MANTA-RAy, that are evaluating filgotinib's reproductive toxicity in men. The companies previously indicated the results, which aren't expected to be available until next year, were not necessary for approval.
Waiting for more data puts Gilead and Galapagos further behind their would-be competitors, most notably AbbVie and its similar arthritis drug Rinvoq.
Shares in Galapagos dropped 25% Wednesday, while Gilead's fell by 3.5%.