The MANTA and MANTA-RAy studies have significantly influenced the regulatory path and commercial prospects of filgotinib, providing crucial safety data that both supported European approval and contributed to its commercial limitations in the United States.

Positive Study Outcomes Supporting Safety Profile

The MANTA and MANTA-RAy phase 2 studies demonstrated that filgotinib 200 mg had no measurable negative impact on male reproductive health [3]. The studies found numerically similar proportions of filgotinib-treated versus placebo-treated patients experienced ≥50% decrease in sperm concentration (6.7% vs 8.3%), with no clinically relevant changes in semen parameters or sex hormones [3]. These findings provided important evidence that the testicular toxicity observed in earlier animal studies did not translate to human males [6]. The totality of data from both studies showed no evidence that the concerning results observed in rats and dogs were replicated in men with inflammatory diseases [3].

European Regulatory Success and Label Update

These positive safety findings directly contributed to regulatory success in Europe, where filgotinib had already received approval for rheumatoid arthritis and ulcerative colitis [3]. Galapagos received a positive CHMP opinion for updating the European label for Jyseleca (filgotinib) based on the testicular function safety data from the MANTA/RAy studies [11]. This label update strengthened filgotinib's safety profile in Europe, potentially supporting its continued use and commercial prospects in that region [12].

US Regulatory Impact and Market Withdrawal

Despite the positive study outcomes, the MANTA and MANTA-RAy results came too late to salvage filgotinib's prospects in the United States [8]. The FDA had specifically requested these study data in their Complete Response Letter, citing concerns about potential impact on sperm parameters and the overall benefit/risk profile of the 200 mg dose [8]. Even though the studies were fully recruited with topline results anticipated in the first half of 2021, Gilead announced in December 2020 that it would no longer pursue FDA approval for filgotinib in rheumatoid arthritis treatment in the US [10]. This decision effectively ended filgotinib's commercial prospects in the world's largest pharmaceutical market.

Impact on Development Programs and Indication Expansion

The data from the MANTA and MANTA-RAy studies allowed development programs in other indications to continue, particularly in Europe [3]. Filgotinib (200 mg once daily) received approval in the European Union, the UK, and Japan for the treatment of adults with moderately to severely active ulcerative colitis [3]. Additionally, investigations into the efficacy and safety of filgotinib continued for Crohn's disease in the phase 3 DIVERSITY trial program and for axial spondyloarthritis in the phase 3 OLINGUITO programme [3].

Methodological Precedent for Future Studies

The MANTA and MANTA-RAy studies represent a landmark clinical trial program that established a methodological reference point for future studies on medication effects on male reproductive parameters [3]. As the first large-scale, placebo-controlled evaluation of potential impacts of an advanced therapy for IBD and rheumatoid diseases on semen parameters, the study design and execution provide valuable insights for assessing similar concerns with other medications [5].

Commercial Repositioning Between Partners

Following the US regulatory setback, Galapagos assumed sole responsibility in Europe for filgotinib in rheumatoid arthritis, where both 200 mg and 100 mg doses are approved [9]. This represented a significant commercial repositioning between Gilead and Galapagos, with implications for the future marketing and revenue potential of the drug.

In conclusion, while the MANTA and MANTA-RAy studies provided reassuring safety data about filgotinib's effects on male reproductive health, these findings came too late to salvage its prospects in the US market but were instrumental in supporting its continued development and marketing in Europe and other regions.

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Bibliography

[1] Effects of Filgotinib on Semen Parameters and Sex Hormones in Male ... https://ard.bmj.com/content/82/8/1049.

[2] ---. 2 May 2023, https://ard.bmj.com/content/early/2023/05/02/ard-2023-224017.abstract.

[3] ---. https://www.sciencedirect.com/science/article/abs/pii/S0003496724423406.

[4] Filgotinib Drops out of US Arthritis Race: Gilead Ends Bid for FDA ... 16 Dec. 2020, https://www.healio.com/news/rheumatology/20201216/filgotinib-drops-out-of-us-arthritis-race-gilead-ends-bid-for-fda-approval.

[5] Galapagos Announces Full Year 2022 Results and Outlook for 2023. 23 Feb. 2023, https://www.globenewswire.com/news-release/2023/02/23/2614774/0/en/Galapagos-announces-full-year-2022-results-and-outlook-for-2023.html.

[6] Galapagos Receives Positive CHMP Opinion for Jyseleca® European ... 3 Oct. 2022, https://www.glpg.com/press-releases/galapagos-receives-positive-chmp-opinion-for-jyseleca-european-label-update-based-on-testicular-function-safety-data-from-manta-ray-studies/.

[7] GALAPAGOS REPORTS PRIMARY ENDPOINT FOR THE ... 4 Mar. 2021, https://www.glpg.com/press-releases/galapagos-reports-primary-endpoint-for-the-ongoing-filgotinib-manta-and-manta-ray-safety-studies/.

[8] Gilead and Galapagos Announce New Commercialization And ... 15 Dec. 2020, https://www.gilead.com/news/news-details/2020/gilead-and-galapagos-announce-new-commercialization-and-development-agreement-for-jyseleca-filgotinib.

[9] Gilead Receives Complete Response Letter for Filgotinib for The ... 18 Aug. 2020, https://www.gilead.com/news/news-details/2020/gilead-receives-complete-response-letter-for-filgotinib-for-the-treatment-of-moderately-to-severely-active-rheumatoid-arthritis.

[10] MANTA and MANTA-RAy Safety Readouts Boost Jyseleca’s ... 9 Mar. 2021, https://www.clinicaltrialsarena.com/marketdata/manta-and-manta-ray-safety-readouts-boost-jyselecas-prospects-in-the-us/.

[11] Rationale and Design of Trials Evaluating Effects of Filgotinib On ... 25 May 2022, https://pmc.ncbi.nlm.nih.gov/articles/PMC9239965/.

[12] ---. 25 May 2022, https://pubmed.ncbi.nlm.nih.gov/35614292/.