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

Walter Reinisch; Wayne Hellstrom; Radboud J.E.M. Dolhain; Suresh Sikka; René Westhovens; Rajiv Mehta; Timothy Ritter; Ursula Seidler; Oleksandr Golovchenko; Vladimir Simanenkov; Olena Garmish; Sławomir Jeka; Radka Moravcová; Vijay Rajendran; Franck Olivier Le Brun; Sarah Arterburn; Timothy R. Watkins; Robin Besuyen; Dirk Vanderschueren

doi:10.1136/ard-2023-224017

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

Walter Reinisch, Wayne Hellstrom, Radboud J.E.M. Dolhain, Suresh Sikka, René Westhovens, Rajiv Mehta, Timothy Ritter, Ursula Seidler, Oleksandr Golovchenko, Vladimir Simanenkov, Olena Garmish, Sławomir Jeka, Radka Moravcová, Vijay Rajendran, Franck Olivier Le Brun, Sarah Arterburn, Timothy R. Watkins, Robin Besuyen, Dirk Vanderschueren^*

^*Corresponding author for this work

Rheumatology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Objectives: The 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. Methods: MANTA (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. Results: Across 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. Conclusions: Results 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.

Original language	English
Article number	224017
Pages (from-to)	1049-1058
Number of pages	10
Journal	Annals of the Rheumatic Diseases
Volume	82
Issue number	8
DOIs	https://doi.org/10.1136/ard-2023-224017
Publication status	Published - 1 Aug 2023

Bibliographical note

Funding Information:
We would like to thank all investigators, site staff and patients for their contributions to this study (investigators are listed in the supplemental material). We would also like to thank the following study leads for their contributions: Goele Dekkers, William Barchuk, Dick de Vries, Lien Gheyle, Angi Gillen, Afsaneh Mozaffarian and Caroline Tonussi. Medical writing support for the preparation of this manuscript was provided by Frances Thompson, PhD, and Katie Pillidge, PhD, of PharmaGenesis London, London, UK, funded by Galapagos NV (Mechelen, Belgium). Publication coordination was provided by Slavka Baronikova, PhD, of Galapagos NV.

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© 2023 BMJ Publishing Group. All rights reserved.

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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 studiesFinal published version, 1.06 MBLicence: CC BY-NC

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Reinisch, W., Hellstrom, W., Dolhain, R. J. E. M., Sikka, S., Westhovens, R., Mehta, R., Ritter, T., Seidler, U., Golovchenko, O., Simanenkov, V., Garmish, O., Jeka, S., Moravcová, R., Rajendran, V., Le Brun, F. O., Arterburn, S., Watkins, T. R., Besuyen, R., & Vanderschueren, D. (2023). 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. Annals of the Rheumatic Diseases, 82(8), 1049-1058. Article 224017. https://doi.org/10.1136/ard-2023-224017

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title = "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 = "Objectives: The 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. Methods: MANTA (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. Results: Across 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. Conclusions: Results 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.",

author = "Walter Reinisch and Wayne Hellstrom and Dolhain, {Radboud J.E.M.} and Suresh Sikka and Ren{\'e} Westhovens and Rajiv Mehta and Timothy Ritter and Ursula Seidler and Oleksandr Golovchenko and Vladimir Simanenkov and Olena Garmish and S{\l}awomir Jeka and Radka Moravcov{\'a} and Vijay Rajendran and {Le Brun}, {Franck Olivier} and Sarah Arterburn and Watkins, {Timothy R.} and Robin Besuyen and Dirk Vanderschueren",

note = "Funding Information: We would like to thank all investigators, site staff and patients for their contributions to this study (investigators are listed in the supplemental material). We would also like to thank the following study leads for their contributions: Goele Dekkers, William Barchuk, Dick de Vries, Lien Gheyle, Angi Gillen, Afsaneh Mozaffarian and Caroline Tonussi. Medical writing support for the preparation of this manuscript was provided by Frances Thompson, PhD, and Katie Pillidge, PhD, of PharmaGenesis London, London, UK, funded by Galapagos NV (Mechelen, Belgium). Publication coordination was provided by Slavka Baronikova, PhD, of Galapagos NV. Publisher Copyright: {\textcopyright} 2023 BMJ Publishing Group. All rights reserved.",

year = "2023",

month = aug,

day = "1",

doi = "10.1136/ard-2023-224017",

language = "English",

volume = "82",

pages = "1049--1058",

journal = "Annals of the Rheumatic Diseases",

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Reinisch, W, Hellstrom, W, Dolhain, RJEM, Sikka, S, Westhovens, R, Mehta, R, Ritter, T, Seidler, U, Golovchenko, O, Simanenkov, V, Garmish, O, Jeka, S, Moravcová, R, Rajendran, V, Le Brun, FO, Arterburn, S, Watkins, TR, Besuyen, R & Vanderschueren, D 2023, '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', Annals of the Rheumatic Diseases, vol. 82, no. 8, 224017, pp. 1049-1058. https://doi.org/10.1136/ard-2023-224017

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. / Reinisch, Walter; Hellstrom, Wayne; Dolhain, Radboud J.E.M. et al.
In: Annals of the Rheumatic Diseases, Vol. 82, No. 8, 224017, 01.08.2023, p. 1049-1058.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Effects of filgotinib on semen parameters and sex hormones in male patients with inflammatory diseases

T2 - results from the phase 2, randomised, double-blind, placebo-controlled MANTA and MANTA-RAy studies

AU - Reinisch, Walter

AU - Hellstrom, Wayne

AU - Dolhain, Radboud J.E.M.

AU - Sikka, Suresh

AU - Westhovens, René

AU - Mehta, Rajiv

AU - Ritter, Timothy

AU - Seidler, Ursula

AU - Golovchenko, Oleksandr

AU - Simanenkov, Vladimir

AU - Garmish, Olena

AU - Jeka, Sławomir

AU - Moravcová, Radka

AU - Rajendran, Vijay

AU - Le Brun, Franck Olivier

AU - Arterburn, Sarah

AU - Watkins, Timothy R.

AU - Besuyen, Robin

AU - Vanderschueren, Dirk

N1 - Funding Information: We would like to thank all investigators, site staff and patients for their contributions to this study (investigators are listed in the supplemental material). We would also like to thank the following study leads for their contributions: Goele Dekkers, William Barchuk, Dick de Vries, Lien Gheyle, Angi Gillen, Afsaneh Mozaffarian and Caroline Tonussi. Medical writing support for the preparation of this manuscript was provided by Frances Thompson, PhD, and Katie Pillidge, PhD, of PharmaGenesis London, London, UK, funded by Galapagos NV (Mechelen, Belgium). Publication coordination was provided by Slavka Baronikova, PhD, of Galapagos NV. Publisher Copyright: © 2023 BMJ Publishing Group. All rights reserved.

PY - 2023/8/1

Y1 - 2023/8/1

N2 - Objectives: The 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. Methods: MANTA (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. Results: Across 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. Conclusions: Results 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.

AB - Objectives: The 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. Methods: MANTA (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. Results: Across 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. Conclusions: Results 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.

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DO - 10.1136/ard-2023-224017

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AN - SCOPUS:85160233227

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JO - Annals of the Rheumatic Diseases

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Reinisch W, Hellstrom W, Dolhain RJEM, Sikka S, Westhovens R, Mehta R et al. 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. Annals of the Rheumatic Diseases. 2023 Aug 1;82(8):1049-1058. 224017. doi: 10.1136/ard-2023-224017

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

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