Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases: results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies

Abstract

ObjectivesThe phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases.MethodsMANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21–65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for ‘reversibility’. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints.ResultsAcross both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ−1.7% (95% CI −9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events.ConclusionsResults suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

What benefit–risk trade-offs are acceptable to rheumatoid arthritis patients during treatment selection? Evidence from a multicountry choice experiment

“…While few data on the effects of advanced treatments for inflammatory rheumatic diseases on semen parameters are available, recent data indicated that filgotinib, a preferential JAK1 inhibitor, does not appear to have a negative impact on this aspect of health based on data from the recent MANTA and MANTA/RAy clinical trials. 39 …”

“…While few data on the effects of advanced treatments for inflammatory rheumatic diseases on semen parameters are available, recent data indicated that filgotinib, a preferential JAK1 inhibitor, does not appear to have a negative impact on this aspect of health based on data from the recent MANTA and MANTA/RAy clinical trials. 39 While a number of studies have examined preferences of rheumatologists for DMARDs, 21 22 40 41 patient preference data that is suitable for characterising bDMARDs and tsDMARDs is limited. However, findings of this study complement existing evidence.…”

JAK inhibitors for inflammatory bowel disease: recent advances

“…Gilead Sciences and Galapagos curtailed plans to pursue FDA authorisation despite subsequent safety trials showing no effect on semen parameters or sex hormones. 17 Filgotinib is not approved for CD. Despite the favourable results of the phase II CD study (FITZROY), the induction cohorts of a large phase III study (DIVER-SITY) of 1374 patients with moderate to severely active CD failed to meet the coprimary endpoints of *Definition of clinical remission was similar across the UC trials and was defined as a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0.…”

Efficacy and safety of filgotinib for ulcerative colitis: A real‐world multicenter retrospective study in Japan

“…Regarding the safety profile of filgotinib, although preclinical animal data showed that filgotinib affects the male reproductive organs, 4 a recent human study showed no significant effects on semen parameters in male patients with active IBD and other IMIDs 5 . While all JAK inhibitors increase herpes zoster infection risk, a systematic review and network meta‐analysis showed that such risks with filgotinib were lower than tofacitinib and upadacitinib in patients with IBD 6 .…”