Gilead and Galapagos, developers of filgotinib, the potential fourth-to-market Janus kinase (JAK) inhibitor for rheumatoid arthritis (RA) in the US, had high hopes their drug would become the best-in-class agent from a safety standpoint and beat out competitors. However, these hopes came crashing down upon receipt of the FDA’s decision in the form of a Complete Response Letter (CRL), announced by the companies on 18 August. Stocks for both companies plummeted by Wednesday morning, 19 August, 5% for Gilead and 28% for Galapagos, because of the news the night prior. Furthering the blow to Galapagos, the company will not receive $100M in milestone payments this year from Gilead, which was promised upon approval of the drug.

While concerns surrounding the JAK inhibitors class having received an overall negative view of its safety profile have remained a pertinent issue across the autoimmune space, filgotinib had hoped to differentiate itself as the safest JAK, a sentiment stemming from a lower rate of adverse events from cross-trial comparisons. Gilead’s filing in the US and EU was based on data from its Phase III program, consisting of three trials labelled FINCH 1, FINCH 2, and FINCH 3. While analysts and industry stakeholders attempt to reconcile the news and decode the rationale behind the FDA’s decision, Gilead stated two concerns in its press release. Notably, the agency voiced concerns over the risk-benefit of the higher dose of 200mg and also requested data from the company’s Phase II MANTA and MANTA-RAy trials, which are ongoing and were not included in its regulatory filing. The additional trials initiated in 2017 and aimed to determine testicular toxicity by measuring sperm parameters, a concern that appeared in preclinical animal models. The FDA’s request will likely push filgotinib’s approval in the US to H1 2022, assuming that topline results from the MANTA trials are acceptable and that there are no other roadblocks for the drug. GlobalData expects that filgotinib will receive regulatory approval from the European Medicines Agency (EMA) in Q3 this year, having received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in July 2020.

JAK inhibitors have had a checkered past with regulators, and the FDA has issued a boxed warning on all three approved agents in RA for the risk of serious infections, tuberculosis, lymphoma, and thrombosis. Feedback on the higher dosage of filgotinib was not necessarily a surprise, as this has come up before, in 2012 for Pfizer’s Xeljanz during its FDA regulatory review and again in 2018 for Eli Lilly’s Olumiant, when only the low dose gained approval after an initial rejection of the drug. During FDA review of Pfizer’s new drug application (NDA) for Xeljanz, the agency requested more safety analyses, which were submitted in August 2012 and subsequently pushed back its approval by three months. While both 5mg and 10mg doses were ultimately approved for Xeljanz in the US, only the 5mg pill was initially approved in the EU, and the agency warns that Xeljanz must be used with caution for patients at increased risk of blood clots, especially when used at the 10mg twice-daily maintenance dose. AbbVie neglected to file for approval of the higher dosage of Rinvoq, likely taking cues from its competitors and the FDA’s track record with them. At this point, it is unclear whether Gilead will choose to continue with the higher dosage of filgotinib or if the company will choose to withdraw that part of the application, and whether it will pose a problem during the regulatory review if Gilead elects to pursue it.

While news of the CRL shocked stakeholders across the industry, the biggest loss was for Gilead and Galapagos with significant impact to filgotinib’s anticipated arrival to the RA market, potentially dashing hopes that safety would be a differentiating factor and key to becoming best-in-class, despite an eight-year lag over its first competitor. It is still possible for recovery of filgotinib, as safety concerns have plagued JAK inhibitors since the start. Experts interviewed by GlobalData have long called for head-to-head studies within the class, and this may be just the strategy that filgotinib needs to quell concerns and bring it back to the lead in terms of safety in the minds of stakeholders. While a head-to-head trial would be a risky strategy, competitors are making headway over filgotinib, and with billions of dollars on the line, it may be one worth taking.

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