Filgotinib

Last updated

Filgotinib
Filgotinib.svg
Clinical data
Trade names Jyseleca
Other namesGLPG0634, GS-6034 [1]
License data
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-Dioxo-1,4-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. It is considered a promising agent as it inhibits JAK1 selectively, similar to already marketed upadacitinib.[ medical citation needed ] Less selective JAK inhibitors (e.g. tofacitinib and baricitinib) are already being marketed.[ medical citation needed ] They show long-term efficacy in the treatment of various inflammatory diseases.[ medical citation needed ] 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.[ medical citation needed ] However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits.[ medical citation needed ] This is the rationale for the development of newer and more selective inhibitors like filgotinib.[ medical citation needed ]

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1.[ medical citation needed ] Inhibition of JAK2 may also contribute to the efficacy against rheumatoid arthritis.[ medical citation needed ] 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.[ medical citation needed ] Therefore, one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option.[ medical citation needed ] 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.[ medical citation needed ]

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.[ citation needed ]

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. [16] [ full citation needed ] 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". [17]

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. [18] [ full citation needed ] During the trial all participants remained on their methotrexate treatment. The trial completed in Feb 2015 and the results were released in July 2015. [19] [20] Galapagos announced that the drug met key efficacy endpoints, showed ACR70 responses up to 39%, and maintained its safety profile. [20] [21]

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. [22] The recruitment of DARWIN trial 2b ended in November 2014. [23] In August 2015, Galapagos announced that the study confirmed previous results. [24]

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. [25] The estimated study completion timeframe is May 2019. [26] [ full citation needed ]

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. [27] 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. [28]

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. [29] [ full citation needed ] Despite these concerns, the FDA allowed a 200-mg daily dose for males in the Phase III FINCH trials. [30]

Related Research Articles

Rheumatology is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatology covers more than 100 different complex diseases, collectively known as rheumatic diseases, which includes many forms of arthritis as well as lupus and Sjögren's syndrome. Doctors who have undergone formal training in rheumatology are called rheumatologists.

<span class="mw-page-title-main">Methotrexate</span> Chemotherapy and immunosuppressant medication

Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.

<span class="mw-page-title-main">Disease-modifying antirheumatic drug</span> Category of drugs

Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal anti-inflammatory drugs and steroids.

<span class="mw-page-title-main">Psoriatic arthritis</span> Long-term inflammatory arthritis

Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

<span class="mw-page-title-main">Anakinra</span> Pharmaceutical drug

Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a slightly modified recombinant version of the human interleukin 1 receptor antagonist protein. It is marketed by Swedish Orphan Biovitrum. Anakinra is administered by subcutaneous injection.

<span class="mw-page-title-main">Leflunomide</span> Chemical compound

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

<span class="mw-page-title-main">Belimumab</span> Pharmaceutical drug

Belimumab, sold under the brand name Benlysta, is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). It is approved in the United States and Canada, and the European Union to treat systemic lupus erythematosus and lupus nephritis.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID‑19. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

Blisibimod is a selective antagonist of B-cell activating factor, being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus. It is currently under active investigation in clinical trials.

<span class="mw-page-title-main">Fostamatinib</span> Chemical compound

Fostamatinib, sold under the brand names Tavalisse and Tavlesse, is a tyrosine kinase inhibitor medication for the treatment of chronic immune thrombocytopenia (ITP). The drug is administered by mouth.

Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.

Olokizumab (OKZ) sold under the name Artlegia, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis and COVID‑19. It is a humanized monoclonal antibody against the interleukin-6 (IL-6). IL-6 is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases. Olokizumab is the first IL-6 inhibitor approved for treatment of rheumatoid arthritis which directly blocks cytokine instead of its receptor. Olokizumab specifically binds to IL-6 at site 3, blocking IL-6's ability to form a hexameric complex. Olokizumab was developed by R-Pharm group, and was launched in 2020.

<span class="mw-page-title-main">Baricitinib</span> Chemical compound

Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.

<span class="mw-page-title-main">ERA-63</span> Chemical compound

ERA-63, also known as ORG-37663, as well as 3-methylene-7α-methyl-17α-ethynylestra-5(10)-en-17β-ol, is a synthetic, steroidal estrogen and a selective agonist of the ERα that was under development for the treatment of rheumatoid arthritis but was never marketed. The drug produced estrogenic effects but failed to show effectiveness for rheumatoid arthritis in a phase IIa clinical study. A large clinical trial also found that prinaberel (ERB-041), a selective ERβ agonist, was ineffective in the treatment of rheumatoid arthritis in spite of activity in preclinical models.

<span class="mw-page-title-main">Upadacitinib</span> Chemical compound (medication)

Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

<span class="mw-page-title-main">Abrocitinib</span> Chemical compound

Abrocitinib, sold under the brand name Cibinqo, is a medication used for the treatment of atopic dermatitis (eczema). It is a Janus kinase inhibitor and it was developed by Pfizer. It is taken by mouth.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

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 © 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 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): 859–74. 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. ↑ 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): 3568–77. doi: 10.4049/jimmunol.1201348 . PMID   24006460.
  9. ↑ "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.
  10. ↑ "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.
  11. 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 © 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" (Press release). 24 July 2020. Retrieved 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. (Press release). 24 June 2020. Retrieved 27 July 2020.
  14. ↑ "FDA rejects Gilead's would-be blockbuster filgotinib over toxicity concerns". 19 August 2020.
  15. ↑ 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.
  16. ↑ Clinical trial number NCT01384422 for "Safety and Preliminary Efficacy of GLPG0634 in Methotrexate-refractory Active Rheumatoid Arthritis" at ClinicalTrials.gov
  17. ↑ "Galapagos' GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study" (PDF) (Press release). Retrieved 26 February 2015.[ permanent dead link ]
  18. ↑ Clinical trial number NCT01888874 for "Dose-finding Study of GLPG0634 as add-on to Methotrexate in Active Rheumatoid Arthritis Patients (DARWIN1)" at ClinicalTrials.gov
  19. ↑ "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.
  20. 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.
  21. ↑ 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.
  22. ↑ "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.
  23. ↑ "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.
  24. ↑ "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.
  25. ↑ "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.
  26. ↑ Clinical trial number NCT02065700 for "Long-term Follow-up Study of GLPG0634 in Active Rheumatoid Arthritis Patients" at ClinicalTrials.gov
  27. ↑ "Filgotinib program in RA - Galapagos Annual Report 2016". Galapagos. Retrieved 8 January 2018.
  28. ↑ 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.
  29. ↑ Clinical trial number NCT03201445 for "Study to Evaluate the Testicular Safety of Filgotinib in Adult Males With Moderately to Severely Active Ulcerative Colitis" at ClinicalTrials.gov
  30. ↑ "Galapagos, Gilead include high dose in PhIII RA trial after talk with FDA". FierceBiotech. Retrieved 8 January 2018.
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