Gilead Halts Three Filgotinib Trials Amid FDA Safety Concerns Over JAK1 Inhibitor

Compiled by Fan Dongdong

Recently, Gilead Sciences has suspended patient enrollment in clinical trials for three indications of filgotinib, pending feedback from the U.S. FDA. Just prior to the suspension, the FDA decided to refuse approval of the application for the JAK1 inhibitor for the treatment of rheumatoid arthritis due to concerns regarding drug toxicity.

Gilead stated that it will meet with the FDA in the fourth quarter to discuss the relevant Complete Response Letter (CRL). Dr. Merdad Parsey, Chief Medical Officer of Gilead, said in conversations with investors on Wednesday evening that trials of filgotinib for treating patients with psoriatic arthritis, ankylosing spondylitis, and uveitis have currently been halted. Gilead indicated that the decision to pause the trials was made based on the belief that discussions with the FDA will inform the broader development plan for filgotinib.

This drug is a highly selective JAK1 inhibitor, initially discovered and developed by Galapagos. In late 2015, Gilead Sciences entered into a $2 billion collaboration agreement with Galapagos to jointly develop filgotinib. The two companies initiated Phase 2 trials of filgotinib for the treatment of uveitis in 2017, followed by the launch of two Phase 3 trials of filgotinib in patients with active psoriatic arthritis in 2019.

In recent days, Gilead has updated the status of all three trials to “Active, Not Recruiting.” In July this year, Gilead submitted two Phase 3 clinical trial applications for ankylosing spondylitis. Neither of these trials has yet begun patient recruitment; enrollment is expected to commence only after Gilead receives feedback from the FDA.

The FDA’s feedback could have a significant impact on filgotinib, which had been widely regarded as a potential blockbuster JAK1 inhibitor. When asked whether the FDA’s decision might lead to the abandonment of plans to launch filgotinib in the United States, Parsey stated, “That option is possible.” Currently, Parsey favors a more segmented approach; even if the rheumatoid arthritis trials are halted by the FDA, filgotinib will still proceed with clinical trials in inflammatory bowel disease.

At present, the future development of Gilead’s filgotinib will depend on whether the FDA can be satisfied with the trial evidence. When publicly disclosing the Complete Response Letter (CRL), Gilead stated that the FDA had requested clinical trial data from two studies (MANTA and MANTA-RAy), as the agency expressed concerns regarding the “overall benefit/risk profile for sperm” associated with the 200 mg dose of filgotinib.

Data from two safety clinical trials are scheduled to be released in the first half of next year, but reports suggest that even with these results, the FDA’s concerns may not be fully addressed. Jefferies analysts stated, “The FDA’s concerns extend beyond the potential for male reproductive toxicity associated with filgotinib.” Previously, due to toxicology data from rat and dog studies involving filgotinib, Galapagos restricted its U.S. Phase II trial to a 100 mg dose of filgotinib, raising concerns about the potential impact of the higher 200 mg dose on male sperm.

Should filgotinib encounter regulatory setbacks in the future, its performance in the U.S. market will be adversely affected. Furthermore, during the period in which Gilead Sciences provides additional trial evidence as required by the FDA, AbbVie’s JAK1 inhibitor, Rinvoq, is expected to further strengthen its market position in the United States.

Notably, the side effects of JAK inhibitors have remained an unavoidable issue for major pharmaceutical manufacturers. In July this year, the FDA added a boxed warning to Pfizer’s Xeljanz label, indicating that use of the drug may increase the risk of fatal blood clots. Due to safety concerns, Eli Lilly’s Olumiant has been approved by the FDA only at a low dose of 2 mg, and its labeling also warns patients of potential risks of serious infections, cancer, and blood clots. AbbVie’s Rinvoq was not exempt either, with its label likewise carrying warnings about the risk of serious blood clots.

Reference Source: Gilead stops 3 filgotinib trials pending FDA feedback on faltering JAK1 inhibitor