Filgotinib

Last updated

Filgotinib
Filgotinib.svg
Clinical data
Trade names Jyseleca
Other namesGLPG0634, GS-6034 [1]
Routes of
administration 		By mouth
Drug class Janus kinase inhibitor
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [2]
  • EU:Rx-only [3] [4]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life 6 hours [5]
Identifiers
  • N-(5-{4-[(1,1-dioxido-1λ6,4-thiazinan-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H23N5O3S
Molar mass 425.51 g·mol−1
3D model (JSmol)
  • O=C(Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1)C1CC1
  • InChI=1S/C21H23N5O3S/c27-20(17-8-9-17)23-21-22-19-3-1-2-18(26(19)24-21)16-6-4-15(5-7-16)14-25-10-12-30(28,29)13-11-25/h1-7,17H,8-14H2,(H,23,24,27) Yes check.svgY
  • Key:RIJLVEAXPNLDTC-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). [3] It was developed by the Belgian-Dutch biotech company Galapagos NV. [6]

Contents

The most common side effects include nausea (feeling sick), upper respiratory tract infection (nose and throat infection), urinary tract infection and dizziness. [3]

Filgotinib was approved for medical use in both the European Union and Japan in September 2020. [3] [6] [7]

Medical uses

Filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease‑modifying anti‑rheumatic drugs (DMARDs). [3] Filgotinib may be used as monotherapy or in combination with methotrexate (MTX). [3]

Mechanism of action

Filgotinib is a Janus kinase inhibitor with selectivity for subtype JAK1 of this enzyme. [8] It is considered a promising agent as it inhibits JAK1 selectively, similar to already marketed upadacitinib. [9] Less selective JAK inhibitors (e.g. tofacitinib and baricitinib) are already being marketed. [9] They show long-term efficacy in the treatment of various inflammatory diseases. [10] However, their lack of selectivity leads to dose-limiting side effects. [5] It is thought that inhibition of all JAK isoenzymes is beneficial in rheumatoid arthritis. [11] [12] However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits. [12] This is the rationale for the development of newer and more selective inhibitors like filgotinib. [8] [9] [12]

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1. [8] Inhibition of JAK2 may also contribute to the efficacy against rheumatoid arthritis. [11] Nonetheless it is thought that JAK2 inhibition might lead to anemia and thrombopenia by interference with erythropoietin and thrombopoietin and granulocyte-macrophage colony-stimulating factor. [13] [14] Therefore, one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. [8] [11] Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2. [15] [8]

History

Research

Clinical trials

The efficacy of filgotinib was studied from January 2013 to May 2015 in a Phase IIb program (DARWIN trial 1, 2) with involvement of 790 rheumatoid arthritis patients. [10] [24]

Phase I study

It was shown in Phase I studies that the pharmacokinetics of filgotinib metabolism is independent of hepatic CYP450 enzymatic degradation. The drug metabolism is however mediated by carboxylesterases. There is no interference reported with the metabolism of methotrexate nor with any of the investigated transport proteins. [25]

Phase II study: Proof of concept (2011)

In November 2011 Galapagos released the results of their Phase II study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 rheumatoid arthritis patients were treated who showed a suboptimal clinical response to methotrexate treatment. [26] Three groups of twelve patients were treated either with 200 mg filgotinib in a single dose, 200 mg divided in two doses or placebo. The primary end-point was the ACR20 score, which monitors improvements in the symptomatology of the patient. After the scheduled 4 weeks of treatment, 83% of the respondents showed an improved ACR20-score. Half of the treated patients showed a complete (or near complete) remission of the disease. There were no reports of anemia nor changes in lipidemia. The company stated in their press release that filgotinib is the first selective JAK1 inhibitor that shows clinical efficacy. As a result of this study, the company stated that "GLPG0634 shows one of the highest initial response rates ever reported for rheumatoid arthritis treatments". [5] [27]

DARWIN 1 trial

The DARWIN 1 trial was a 24-week double blind placebo-controlled trial with 599 rheumatoid arthritis patients enrolled. All participants had moderate to severe rheumatoid arthritis and showed an insufficient response to standard methotrexate treatment. The trial compared three dosages of filgotinib as a once or twice per day regimen. [28] During the trial all participants remained on their methotrexate treatment. The trial completed in Feb 2015 and the results were released in July 2015. [29] [30] Galapagos announced that the drug met key efficacy endpoints, showed ACR70 responses up to 39%, and maintained its safety profile. [30] [31]

DARWIN 2 trial

The DARWIN 2 trial was a double blind placebo-controlled trial with 280 rheumatoid arthritis patients enrolled who show an insufficient response to standard methotrexate treatment. In contrast to the previous DARWIN 1 trial, methotrexate was discontinued. Therefore, this trial investigates filgotinib as a second-line monotherapy. [32] The recruitment of DARWIN trial 2b ended in November 2014. [33] In August 2015, Galapagos announced that the study confirmed previous results. [34]

DARWIN 3 trial

Patients who completed DARWIN 1 and 2 were eligible for DARWIN 3. In November 2017, the company announced consistent safety findings and durable activity at week 84 in the trial. [35] The original estimated study completion timeframe is May 2019, but it the study was extended due to promising results and was concluded on January 19, 2023. [36] Patients received filgotinib 200 mg/day, except 15 men who received filgotinib 100 mg/day, the main goal of the trial was safety and tolerability. Filgotinib was well tolerated in patients with RA for up to 8 years. Safety and efficacy profiles were maintained in patients previously receiving either filgotinib plus methotrexate or filgotinib monotherapy. [37]

FINCH Phase III trials

FINCH 1 looks at patients where first-line treatment with methotrexate (MTX) is not working. It compares filgotinib versus adalimumab/Humira versus a placebo. [38] FINCH 2 looks at patients where a biologic is not working. FINCH 3 looks at filgotinib as a first-line treatment unlike previous studies that investigated the drug as a second-line treatment.

FINCH 2 trial revealed patients with active rheumatoid arthritis who had an inadequate response or intolerance to one or more DMARDs, filgotinib showed significance in treatment response compared with placebo. [39]

MANTA

Due to concerns over testicular toxicity in males, the MANTA study is examining the safety of the drug in the context of treating ulcerative colitis. [40] Despite these concerns, the FDA allowed a 200-mg daily dose for males in the Phase III FINCH trials. [41] The study was terminated in October, 2024 due to poor enrollment numbers, the study was unable to recruit a sufficient number of suitable candidates. [40]

References

  1. ↑ "Pipeline". Gilead Sciences. 27 July 2020. Retrieved 27 July 2020.
  2. ↑ "Jyseleca 100 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 1 October 2020. Retrieved 4 October 2020.
  3. 1 2 3 4 5 6 7 "Jyseleca EPAR". European Medicines Agency (EMA). 26 May 2020. Retrieved 4 October 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ "Jyseleca Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  5. 1 2 3 Namour F, Diderichsen PM, Cox E, Vayssière B, Van der Aa A, Tasset C, et al. (August 2015). "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection". Clinical Pharmacokinetics. 54 (8): 859–874. doi:10.1007/s40262-015-0240-z. PMC   4513223 . PMID   25681059.
  6. 1 2 3 "European Commission Grants Marketing Authorization for Jyseleca (Filgotinib) for the Treatment of Adults With Moderate to Severe Active Rheumatoid Arthritis" (Press release). Gilead Sciences. 25 September 2020. Retrieved 4 October 2020– via Business Wire.
  7. 1 2 "Jyseleca (Filgotinib) Approved in Japan for Rheumatoid Arthritis". Gilead Sciences. 25 September 2020. Retrieved 4 October 2020– via Business Wire.
  8. 1 2 3 4 5 Namour F, Anderson K, Nelson C, Tasset C (June 2022). "Filgotinib: A Clinical Pharmacology Review". Clinical Pharmacokinetics. 61 (6). Springer Link: 819–832. doi:10.1007/s40262-022-01129-y. PMC   9249714 . PMID   35637376.
  9. 1 2 3 Vuyyuru SK, Yuan Y, Jairath V (December 2024). "Upadacitinib Versus Filgotinib in Ulcerative Colitis: Is the Evidence Sufficient to Inform Treatment Decisions?". United European Gastroenterology Journal. 12 (10). © John Wiley & Sons, Inc: 1344–1345. doi:10.1002/ueg2.12709. PMC   11652334 . PMID   39535345.
  10. 1 2 3 4 5 6 Dhillon S, Keam SJ (December 2020). "Filgotinib: First Approval". Drugs. 80 (18). Springer: 1987–1997. doi:10.1007/s40265-020-01439-0. PMC   7858213 . PMID   33237566.
  11. 1 2 3 Westhovens R (1 February 2023). "Filgotinib in rheumatoid arthritis". Expert Review of Clinical Immunology. 19 (2). Taylor & Francis: 135–144. doi:10.1080/1744666X.2023.2149495. PMID   36396615.
  12. 1 2 3 Goldman B (23 July 2019). Genovese M (ed.). "Novel rheumatoid arthritis drug succeeds in clinical trial". Autoimmune Conditions. Stanford School of Medicine . Retrieved 7 September 2025.
  13. ↑ Stetka J, Usart M, Kubovcakova L, Rai S, Nageswara Rao T, Sutter J, et al. (9 February 2023). "Iron is a modifier of the phenotypes of JAK2 -mutant myeloproliferative neoplasms". Blood. 141 (17) blood.2022017976. Elsevier Inc.: 2127–2140. doi:10.1182/blood.2022017976. PMID   36758212.
  14. ↑ Wlassits R, Müller M, Fenzl K, Lamprecht T, Erlacher L (February 2024). "JAK-Inhibitors – A Story of Success and Adverse Events". Open Access Rheumatology: Research and Reviews. 16. Dovepress: 43–53. doi: 10.2147/OARRR.S436637 . PMC   10906274 . PMID   38435420.
  15. ↑ Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, et al. (October 2013). "Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases". Journal of Immunology. 191 (7): 3568–3577. doi: 10.4049/jimmunol.1201348 . PMID   24006460.
  16. ↑ Conrath K (25 March 2016). "Previous clinical trials for filgotinib for RA". Galapagos. Vol. R&D, no. Rheumatoid Arthritis. The Galapagos Group. Retrieved 7 September 2025.
  17. ↑ Vanhoutte F, Mazur M, Voloshyn O, Stanislavchuk M, Van der Aa A, Namour F, et al. (October 2017). "Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials". Arthritis & Rheumatology. 69 (10). Wiley: 1949–1959. doi:10.1002/art.40186. PMC   5656813 . PMID   28622463.
  18. ↑ "AbbVie to Advance Once-Daily ABT-494 to Phase 3 in Rheumatoid Arthritis by Year-End". AbbVie (Press release). Archived from the original on 8 January 2018. Retrieved 9 January 2018.
  19. ↑ "Gilead Submits Filgotinib New Drug Application to U.S. Food and Drug Administration Under Priority Review for Rheumatoid Arthritis Treatment". Gilead Sciences, Inc. (Press release). 19 December 2019. Retrieved 27 July 2020.
  20. 1 2 "Jyseleca: Pending EC decision". European Medicines Agency (EMA). 23 July 2020. Archived from the original on 27 July 2020. Retrieved 27 July 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  21. ↑ "Gilead and Galapagos Announce Positive European CHMP Opinion for Jyseleca (Filgotinib) for the Treatment of Adults With Moderate to Severe Rheumatoid Arthritis" (Press release). 24 July 2020. Retrieved 27 July 2020.
  22. ↑ "Gilead and Galapagos Announce Positive European CHMP Opinion for Jyseleca (Filgotinib) for the Treatment of Adults With Moderate to Severe Rheumatoid Arthritis". Gilead Sciences, Inc. (Press release). 24 June 2020. Retrieved 27 July 2020.
  23. ↑ "FDA rejects Gilead's would-be blockbuster filgotinib over toxicity concerns". 19 August 2020.
  24. ↑ Kavanaugh A, Westhovens RR, Winthrop KL, Lee SJ, Tan Y, An D, et al. (August 2021). "Safety and Efficacy of Filgotinib: Up to 4-year Results From an Open-label Extension Study of Phase II Rheumatoid Arthritis Programs". The Journal of Rheumatology. 48 (8): 1230–1238. doi:10.3899/jrheum.201183. PMID   33526618.
  25. ↑ Florence N, Julie D, Van der Aa A, Tasset C, van't Klooster G (2014). "Phase 1 and Phase 2 Data Confirm That GLPG0634, a Selective JAK1 Inhibitor, Has a Low Potential for Drug-Drug Interactions". Meeting Abstracts. 2014 ACR/ARHP Annual Meeting. American College of Rheumatology. 1481.
  26. ↑ Frédéric Vanhoutte M (15 August 2012). "Safety and Preliminary Efficacy of GLPG0634 in Methotrexate-refractory Active Rheumatoid Arthritis Patients". ClinicalTrials.gov. Chisinau, Moldova: National Library of Medicine . Retrieved 7 September 2025.
  27. ↑ Vanhoutte F, Mazur M, Voloshyn O, Stanislavchuk M, Van der Aa A, Namour F, et al. (October 2017). "Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials". Arthritis & Rheumatology. 69 (10). Wiley: 1949–1959. doi:10.1002/art.40186. PMC   5656813 . PMID   28622463.
  28. ↑ Westhovens R, Taylor PC (17 November 2020). "Dose-finding Study of GLPG0634 as add-on to Methotrexate in Active Rheumatoid Arthritis Participants (DARWIN1) (DARWIN1)". ClinicalTrials.gov. National Library of Medicine . Retrieved 7 September 2025.
  29. ↑ "Galapagos reports that the last patient in DARWIN 1 has completed 12 weeks of treatment" (PDF) (Press release). Archived from the original (PDF) on 26 February 2015. Retrieved 26 February 2015.
  30. 1 2 "Galapagos' selective JAK1 inhibitor filgotinib meets key efficacy endpoints, shows ACR70 responses up to 39%, and maintains safety profile after 24 weeks of treatment in DARWIN 1 Phase 2B study" (Press release). Galapagos NV. 29 July 2015 – via GlobeNewswire.
  31. ↑ Westhovens R, Taylor PC, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, et al. (June 2017). "Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)". Annals of the Rheumatic Diseases. 76 (6): 998–1008. doi: 10.1136/annrheumdis-2016-210104 . PMID   27993829.
  32. ↑ "Galapagos completes recruitment for Darwin 1 study with GLPG0634 (filgotinib) in RA" (Press release). Galapagos NV. Archived from the original on 26 February 2015. Retrieved 26 February 2015– via GlobeNewswire.
  33. ↑ "Galapagos completes recruitment for Darwin 2 monotherapy study with GLPG0634 (filgotinib) in RA" (Press release). Galapagos NV. 24 November 2014. Retrieved 26 February 2015– via GlobeNewswire.
  34. ↑ "DARWIN 2 24-week monotherapy data in RA confirm previous results and support best-in-class potential for filgotinib" (Press release). Galapagos NV. 10 August 2015 – via GlobeNewswire.
  35. ↑ "Consistent safety findings and durable activity with filgotinib treatment of rheumatoid arthritis patients up to week 84 in DARWIN 3 study" (Press release). Galapagos NV. 5 November 2017 – via GlobeNewswire.
  36. ↑ Westhovens R, Genovese M, Kavanaugh A, Winthrop K, Alten K (6 April 2024). "Long-term Follow-up Study of GLPG0634 in Active Rheumatoid Arthritis Participants (DARWIN3)". ClinicalTrials.gov. National Library of Medicine . Retrieved 7 September 2025.
  37. ↑ Westhovens R, Winthrop KL, Kavanaugh A, Greenwald M, Dagna L, Cseuz R, et al. (January 2025). "Safety and efficacy of filgotinib in patients with rheumatoid arthritis: final results of the DARWIN 3 long-term extension study". RMD Open. 11 (1) e004857. © 2025 BMJ Publishing Group Ltd. doi:10.1136/rmdopen-2024-004857. PMC   11784233 . PMID   39884731.
  38. ↑ "Filgotinib program in RA - Galapagos Annual Report 2016". Galapagos. Retrieved 8 January 2018.
  39. ↑ Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, Bartok B, Matzkies F, et al. (July 2019). "Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial". JAMA. 322 (4): 315–325. doi:10.1001/jama.2019.9055. PMC   6652745 . PMID   31334793.
  40. 1 2 Reinisch W, Hellstrom W, Dolhain R, Sikka S (9 October 2024). "Study to Evaluate the Testicular Safety of Filgotinib in Adult Males With Moderately to Severely Active Inflammatory Bowel Disease (MANTA)". ClinicalTrials.gov. National Library of Medicine . Retrieved 7 September 2025.
  41. ↑ "Galapagos, Gilead include high dose in PhIII RA trial after talk with FDA". FierceBiotech. 25 May 2016. Retrieved 8 January 2018.
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