Filgotinib Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:461425696
Tradename:Jyseleca
Routes Of Administration:By mouth
Class:Janus kinase inhibitor
Atc Prefix:L04
Atc Suffix:AF04
Legal Uk:POM
Legal Uk Comment:[1]
Legal Eu:Rx-only
Legal Eu Comment:[2] [3]
Legal Status:Rx-only
Elimination Half-Life:6 hours[4]
Index2 Label:as salt
Cas Number:1206161-97-8
Pubchem:49831257
Iuphar Ligand:7913
Drugbank:DB14845
Chemspiderid:28189566
Unii:3XVL385Q0M
Kegg:D10871
Kegg2:D11106
Chembl:3301607
Pdb Ligand:2HB
Synonyms:GLPG0634, GS-6034[5]
Iupac Name:N-[5-[4-[(1,1-Dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-''a'']pyridin-2-yl]cyclopropanecarboxamide
C:21
H:23
N:5
O:3
S:1
Smiles:O=C(Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1)C1CC1
Stdinchi: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)
Stdinchikey:RIJLVEAXPNLDTC-UHFFFAOYSA-N

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

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

Filgotinib was approved for medical use in both the European Union and Japan in September 2020.[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). Filgotinib may be used as monotherapy or in combination with methotrexate (MTX).

Mechanism of action

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

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1. Inhibition of JAK2 may also contribute to the efficacy against rheumatoid arthritis. 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. Therefore, one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2.[8] It is however still to be seen to what extent JAK2 inhibition should be avoided.

History

Research

Clinical trials

The efficacy of filgotinib is being studied in a Phase IIb program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn's disease patients.

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.[15]

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. 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".[16]

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. During the trial all participants remained on their methotrexate treatment. The trial completed in Feb 2015 and the results were released in July 2015.[17] [18] Galapagos announced that the drug met key efficacy endpoints, showed ACR70 responses up to 39%, and maintained its safety profile.[19]

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.[20] The recruitment of DARWIN trial 2b ended in November 2014.[21] In August 2015, Galapagos announced that the study confirmed previous results.[22]

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.[23] The estimated study completion timeframe is May 2019.

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.[24] 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.[25]

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. Despite these concerns, the FDA allowed a 200-mg daily dose for males in the Phase III FINCH trials.[26]

Notes and References

  1. Web site: Jyseleca 100 mg film-coated tablets - Summary of Product Characteristics (SmPC) . (emc) . 1 October 2020 . 4 October 2020.
  2. Web site: Jyseleca EPAR . European Medicines Agency (EMA) . 26 May 2020 . 4 October 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. Web site: Jyseleca Product information . Union Register of medicinal products . 3 March 2023.
  4. Namour F, Diderichsen PM, Cox E, Vayssière B, Van der Aa A, Tasset C, Van't Klooster G . Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection . Clinical Pharmacokinetics . 54 . 8 . 859–74 . August 2015 . 25681059 . 4513223 . 10.1007/s40262-015-0240-z .
  5. Web site: Pipeline . . 27 July 2020 . 27 July 2020.
  6. European Commission Grants Marketing Authorization for Jyseleca (Filgotinib) for the Treatment of Adults With Moderate to Severe Active Rheumatoid Arthritis . Gilead Sciences . Business Wire . 25 September 2020 . 4 October 2020.
  7. Web site: Jyseleca (Filgotinib) Approved in Japan for Rheumatoid Arthritis . Gilead Sciences . Business Wire . 25 September 2020 . 4 October 2020.
  8. Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, Lepescheux L, Christophe T, Conrath K, Vandeghinste N, Vayssiere B, De Vos S, Fletcher S, Brys R, van 't Klooster G, Feyen JH, Menet C . Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases . Journal of Immunology . 191 . 7 . 3568–77 . October 2013 . 24006460 . 10.4049/jimmunol.1201348 . free .
  9. AbbVie to Advance Once-Daily ABT-494 to Phase 3 in Rheumatoid Arthritis by Year-End. AbbVie. 9 January 2018. 8 January 2018. https://web.archive.org/web/20180108175045/https://news.abbvie.com/news/abbvie-to-advance-once-daily-abt-494-to-phase-3-in-rheumatoid-arthritis-by-year-end.htm. dead.
  10. Gilead Submits Filgotinib New Drug Application to U.S. Food and Drug Administration Under Priority Review for Rheumatoid Arthritis Treatment . Gilead Sciences, Inc. . 19 December 2019 . 27 July 2020.
  11. Web site: Jyseleca: Pending EC decision . European Medicines Agency (EMA) . 23 July 2020 . 27 July 2020 . 27 July 2020 . https://web.archive.org/web/20200727102811/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/jyseleca . dead . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. Gilead and Galapagos Announce Positive European CHMP Opinion for Jyseleca (Filgotinib) for the Treatment of Adults With Moderate to Severe Rheumatoid Arthritis . 24 July 2020 . 27 July 2020.
  13. 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. . 24 June 2020 . 27 July 2020.
  14. Web site: FDA rejects Gilead's would-be blockbuster filgotinib over toxicity concerns. 19 August 2020.
  15. Phase 1 and Phase 2 Data Confirm That GLPG0634, a Selective JAK1 Inhibitor, Has a Low Potential for Drug-Drug Interactions . Florence N, Julie D, Van der Aa A, Tasset C, van't Klooster G . 2014 . American College of Rheumatology . Meeting Abstracts . 2014 ACR/ARHP Annual Meeting . 1481.
  16. Galapagos' GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study . 26 February 2015 .
  17. Galapagos reports that the last patient in DARWIN 1 has completed 12 weeks of treatment . 26 February 2015 . 26 February 2015 . https://web.archive.org/web/20150226192947/http://www.glpg.com/files/1914/2467/2531/LPLV_Darwin_1__FINAL.pdf . dead .
  18. 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. Galapagos NV . 29 July 2015. GlobeNewswire .
  19. Westhovens R, Taylor PC, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P . 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 . June 2017 . 27993829 . 10.1136/annrheumdis-2016-210104 . free .
  20. Galapagos completes recruitment for Darwin 1 study with GLPG0634 (filgotinib) in RA . 26 February 2015 . Galapagos NV . GlobeNewswire . 26 February 2015 . https://web.archive.org/web/20150226201828/http://www.euroinvestor.com/news/2014/11/12/galapagos-completes-recruitment-for-darwin-1-study-with-glpg0634-filgotinib-in-ra/13036399 . dead .
  21. Galapagos completes recruitment for Darwin 2 monotherapy study with GLPG0634 (filgotinib) in RA . 24 November 2014 . 26 February 2015 . Galapagos NV . GlobeNewswire .
  22. DARWIN 2 24-week monotherapy data in RA confirm previous results and support best-in-class potential for filgotinib . Galapagos NV . 10 August 2015. GlobeNewswire .
  23. Consistent safety findings and durable activity with filgotinib treatment of rheumatoid arthritis patients up to week 84 in DARWIN 3 study . Galapagos NV . 5 November 2017. GlobeNewswire .
  24. Web site: Filgotinib program in RA - Galapagos Annual Report 2016. Galapagos. 8 January 2018.
  25. Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, Bartok B, Matzkies F, Gao J, Guo Y, Tasset C, Sundy JS, de Vlam K, Walker D, Takeuchi T . 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 . July 2019 . 31334793 . 6652745 . 10.1001/jama.2019.9055 .
  26. Web site: Galapagos, Gilead include high dose in PhIII RA trial after talk with FDA . FierceBiotech . 8 January 2018.

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