FDA rejects Gilead's would-be blockbuster filgotinib over toxicity concerns

The FDA has rejected Gilead’s filing for approval of filgotinib in rheumatoid arthritis. With the FDA asking to see data from an ongoing clinical trial, Gilead is unlikely to be able to refile until toward the middle of next year, pushing it still further behind its rivals for the JAK inhibitor market.

In disclosing the complete response letter, Gilead said the FDA has requested data from two ongoing clinical trials, MANTA and MANTA-RAy, that are assessing the effect of the 200-mg dose of JAK1 inhibitor filgotinib on sperm concentrations. The FDA has also “expressed concerns regarding the overall benefit/risk profile of the filgotinib 200 mg dose,” according to Gilead.

Gilead said MANTA and MANTA-RAy are fully enrolled and are expected to deliver top-line data in the first half of next year. The need to wait on results from the trials before refiling suggests it may be the midpoint of 2021 before Gilead goes back to the FDA. That timeline implies an early 2022 approval, should it gain the FDA green light.

The delay is a significant setback for a drug that analysts at Jefferies tip to generate annual sales of $3 billion in rheumatoid arthritis and the same again in other indications. That forecast had already been called into question by doubts about Gilead’s ability to take share from AbbVie, which won approval for its JAK1 drug Rinvoq one year ago. Rinvoq generated $149 million in the second quarter.

Gilead and filgotinib partner Galapagos have framed safety as a positive differentiator for filgotinib over other JAK1 inhibitors, which so far have all come with a black box warning. However, the effect of the drug on sperm is a long-standing concern.  

Analysts speculated that the testicular toxicity concerns may have factored into AbbVie’s decision to drop filgotinib in 2015 and focus on Rinvoq. Five years later, AbbVie’s decision looks set to pay off. 

The sperm toxicity concern dates back to toxicology studies of the 200-mg dose in rats and dogs. The results, and the FDA’s response to them, led Galapagos to limit the maximum daily dose at U.S. sites in its phase 2 DARWIN clinical trial program to 100 mg. Gilead and Galapagos subsequently got the green light to enroll a 200-mg cohort in their phase 3 program.

To allay the toxicity concerns, Galapagos ran further preclinical tests, monitored men enrolled in its clinical trials and, with Gilead, initiated the MANTA and MANTA-RAy studies. The work and talks with the FDA led Gilead and Galapagos to think they could seek approval without MANTA and MANTA-RAy data.  

“Neither of them are needed to … gate filing,” Walid Abi-Saab, chief medical officer at Galapagos, told attendees at an R&D event in November. “Once they become available, then they will be used, whether it will be … during the review process or afterwards.”  

The FDA has taken a different view. If the toxicity trials are free from red flags, Gilead could be clear to refile for approval of the 200-mg dose next year. Yet, that plan could be undermined by the FDA’s “concerns regarding the overall benefit/risk profile of the filgotinib 200 mg dose.” Jefferies analysts said they “understand [the FDA’s concern] does not just relate to male toxicity.”

What that means for filgotinib and Gilead’s interest in it remains unclear. Gilead placed a big bet on Galapagos last year when it paid $5.1 billion to expand its alliance well beyond filgotinib. In a post to discuss the FDA rejection, Galapagos CEO Onno van de Stolpe said Gilead’s continues “to believe in the risk/benefit profile of filgotinib,” adding that he is “convinced that Gilead has the know-how and experience to determine appropriate next steps, and guide us through this process.”

However, some analysts are questioning whether Gilead should remain committed to filgotinib. With a series of deals pivoting Gilead toward oncology, Jefferies analyst Michael Yee raised the question of whether fourth-in-class autoimmune drug filgotinib is the best use of the big biotech’s money. 

“We do believe there is a reasonable debate amongst investors as to how much investment GILD should make into filgo anyway—and if they backed off of filgo investments … would this actually be a potential positive to GILD margins and ROI to invest in other areas,” Yee wrote in a note to investors.