Filgotinib Efficacy and Safety - 3 Years Later Save

Filgotinib, the rheumatoid arthritis (RA) oral drug that never made it to the U.S. market but is sold across Europe, Great Britain, and Japan, remained effective for 3 years for most registration trial participants who continued in a long-term extension study, researchers said.

In the so-called FINCH 4 study, ACR20 responses (20% reduction in symptoms by American College of Rheumatology criteria) were evident at week 156 for 45.8% to 67.3% of the 2,729 participants, depending on which dosage and schedule they had been assigned, according to Maya H. Buch, PhD, of the University of Manchester in England, and colleagues writing in RMD Open.

Smaller proportions achieved greater degrees of response, as is typical for RA treatments. For example, ACR50 responses (50% symptom reduction) were seen at week 156 in 25.5% to 53.8% of participants, and 21.8% to 44.3% reached DAS28-CRP (disease activity score in 28 joints modified by C-reactive protein level) values under 2.6, indicating low disease activity. "Boolean remission 1.0" -- a score of 1 or less on a 10-point, patient-reported global assessment -- was met by 7.3% to 26.4% of patients at the last evaluation.

In addition, no particular issues with adverse events stood out in the extension. "Safety data were consistent with the known safety profile of filgotinib" as determined in the original placebo-controlled, randomized trials, Buch and colleagues wrote.

Filgotinib is a Janus kinase (JAK) inhibitor that is more selective for the JAK1 form than others in its family. First-generation JAK inhibitors, namely tofacitinib (Xeljanz), block multiple JAK species. It was thought that greater selectivity for JAK1 (and to some extent JAK2) would cut down on unwanted side effects, and trial data supported it.

But when the drug's initial developers, Gilead Sciences and Galapagos, took it to the FDA for approval in 2020, the agency balked, citing possible "impact on sperm parameters." Officials told the firms that no approval would be forthcoming until they completed a pair of controlled studies called MANTA and MANTA-RAy that were examining the issue. Other potential toxicities were seen at a high 200-mg dose and the FDA expressed concern about that as well.

Findings from those studies, first reported in early 2021, showed no difference in sperm production between the drug and placebo. But Gilead had already called it quits on filgotinib, leaving it to Galapagos to develop further. Regulators in Europe, Britain, and Japan were less concerned about the sperm issue and approved the drug under the brand name Jyseleca.

Now the market for JAK inhibitors has become quite crowded. Besides tofacitinib, baricitinib (Olumiant) and upadacitinib (Rinvoq) are approved -- the latter also selective for JAK1/2. Earlier this year, Galapagos sold the filgotinib business to the Italian firm Alfasigma. It does not appear to have been a huge hit: the announcement indicated that just 20,000 patients across Europe were regular users.

There has been no indication of further interest in bringing the drug to U.S. patients, which U.S. clinicians may regret, insofar as additional drug options (and market competition) are usually welcomed. Of note, the efficacy and safety profile now available for the drug, at least in the manufacturer-sponsored studies, suggest that filgotinib is at least as good as other marketed JAK inhibitors.

Study Details

FINCH 4 included patients from three earlier randomized trials: FINCH 1, in patients with active RA despite methotrexate treatment; FINCH 2, enrolling patients failing biologic agents such as tumor necrosis factor (TNF) inhibitors; and FINCH 3, with patients not previously receiving methotrexate. All were placebo-controlled, and FINCH 1 also included an arm assigned to the anti-TNF agent adalimumab (Humira). Each study also tested two filgotinib doses, 100 and 200 mg.

In the extension, all patients received open-label filgotinib at 100 or 200 mg, plus whatever old-line anti-rheumatic drug they may have received in the randomized trials.

Mean age for FINCH 4 participants was 54, and 80% were women. Disease duration averaged 7.3 years (median 4.3). Mean DAS28-CRP values when entering the original trials averaged 20.7; at FINCH 4 baseline, 71% had values below 3.2.

Treatment-emergent adverse events (TEAEs) were common in the study, seen in 86% and 85% of those on the 200- and 100-mg doses, respectively. TEAEs of grade 3 or higher were recorded for 22% of patients in each dosage group. About 19% had TEAEs rated as serious. About two-thirds of all TEAEs, however, were considered unrelated to filgotinib.

Sperm parameters were not examined in FINCH 4, presumably because most patients weren't men and the issue had its own placebo-controlled studies. The most common in the "serious" category were infections, seen in 5% to 6% of participants. Some 3% to 4% suffered shingles attacks. Malignancies and cardiovascular events each occurred in roughly 2% to 3% of patients.

"In terms of drug retention, it was observed that approximately 63% of patients remained on the study drug at the time of the analyses," Buch and colleagues noted. Treatment interruptions tied to TEAEs were not uncommon, occurring in 36% to 40% of patients, although only about 11% of patients stopped filgotinib altogether because of such events.