It does this by blocking the action of enzymes known as Janus kinases (JAKs). Online ahead of print. Galapagos delivered in 2017 [media release]. Rheumatology (Oxford). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. 0550]. It’s anticipated that approvals will start to come through in the second half of 2020, Fierce Biotech reports. Combe B, Kivitz A, Tanaka Y, et al. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. European Medicines Agency. Bodyweight, gender, race, age, mild renal impairment [creatinine clearance (CLCR) ≥ 60 mL/min), and mild or moderate hepatic impairment (Child-Pugh A or B) did not have a clinically relevant effect on the pharmacokinetics of filgotinib or GS-829845 [3]. Poźniak M, Porębska N, Krzyścik MA, Sokołowska-Wędzina A, Jastrzębski K, Sochacka M, Szymczyk J, Zakrzewska M, Otlewski J, Opaliński Ł. Mol Med. AbbVie and Galapagos extend GLPG0634 collaboration to include Crohn's disease [media release]. Filgotinib significantly decreased levels of circulating biomarkers associated with active AS disease, including proinflammatory cytokines and chemokines, cell adhesion molecules, and markers of matrix remodelling [40]. Filgotinib treatment results in reduction of biomarkers associated with disease in patients with ankylosing spondylitis [abstract no. J Immunol. Serious infection and herpes zoster were infrequent in all treatment groups [41, 42]. Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis. Patients who had completed 24 weeks’ treatment in DARWIN 1 or DARWIN 2 were eligible to enter the ongoing, open-label, long-term extension study DARWIN 3 (NCT02065700), during which all patients received filgotinib 200 mg/day (apart from 15 males who received a 100 mg/day dosage) [31]. 2018;33(Suppl 4):63–4. FR120]. Efficacy and safety of filgotinib as maintenance therapy for patients with moderately to severely active ulcerative colitis: results from the phase 2b/3 SELECTION study [abstract no. Galapagos was to fund and complete a phase 2 program in Crohn's disease and AbbVie was responsible for funding and performing clinical development beyond phase 2 and completing regulatory and commercialization activities [10]. Gladman DD, Coates LC, Van den Bosch F, et al. Filgotinib is extensively metabolized, primarily by carboxylesterase (CES) 2, and to a lesser extent by CES1, to form the main circulating metabolite GS-829845 [3]. Analysis of the JAK1 selectivity of GLPG0634 and its main metabolite in different species, healthy volunteers and rheumatoid arthritis patients [abstract no. JAKs are cytoplasmic tyrosine kinases that associate with cytokine receptors and transduce cytokine signalling via phosphorylation of STATs [2]. In vitro, filgotinib and GS-829845 are inhibitors of OATP1B1 and OATP1B3. J Gastroenterol Hepatol. Coates LC, Mease PJ, Gladman DD, et al. European Medicines Agency validates marketing application for filgotinib for the treatment of ulcerative colitis [media release]. Filgotinib decreases inflammatory markers associated with endoscopic improvement in moderate to severely active Crohn’s disease [abstract no. Article continues below advertisement The cytotoxic conjugate of highly internalizing tetravalent antibody for targeting FGFR1-overproducing cancer cells. 2020;59(7):1495–504. The phase 3, randomized, double-blind, placebo-controlled trial SEALION2-NAÏVE (NCT04483700) plans to evaluate the efficacy and safety of filgotinib in patients with active AS who are naïve to biologic DMARDs. The mean change from baseline in HAQ-DI scores was greater with filgotinib 200 mg combination therapy and filgotinib 200 mg monotherapy than with methotrexate(nominal p < 0.05), while there was no significant difference between the filgotinib 100 mg combination therapy and methotrexate groups [26]. In January 2016, the company reported closing of the deal and entry into force [13]. Four different types of JAKs (JAK1, JAK2, JAK3 and TYK2) and seven mammalian STAT family members have been identified (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) [2]. 22 Feb 2018. https://www.glpg.com. 2020. The tolerability profile of filgotinib was consistent with its mechanism of action and no new safety concerns were identified [46]. The Janus kinase (JAK)-signal transducer of activation (STAT) signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) [1]. Gut. Impact of filgotinib on structural lesions in the sacroiliac joints at 12 weeks in patients with active axial spondyloarthritis: magnetic resonance imaging data from the double-blind, randomized TORTUGA trial [abstract no. Filgotinib: First Approval. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. European medicines agency validates marketing application for Filgotinib for the treatment of Ulcerative Colitis . In September 2020, filgotinib received its first approvals in the EU and Japan. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated … 2015;66:311–328. The preparation of this review was not supported by any external funding. 2019;78(Suppl 2):78. Despite EU and Japan approvals, forecast for Gilead and Galapagos’ Jyseleca (filgotinib) in the US less sunny than once hoped . Galapagos. NCI CPTC Antibody Characterization Program, Banerjee S, Biehl A, Gadina M, et al. Ann Rheum Dis. Would you like email updates of new search results? Also planned is the phase 3, randomized, double-blind, placebo-controlled SEALION1-IR study (NCT04483687), which will assess the efficacy and safety of filgotinib in patients with active AS who have an inadequate response to biologic DMARDs. Credit: Shutterstock. In in vitro assays, the main metabolite of filgotinib, GS-829845, was approximately 10-fold less active than filgotinib, while exhibiting a similar JAK1 preferential inhibitory activity [3]. Helliwell P, Van den Bosch F, Coates LC, et al. Patient-reported outcomes withy filgotinib, including physical function (HAQ‐DI), pain (VAS), fatigue (FACIT‐F) and SF-36 PCS, also improved rapidly (weeks 2–4), with benefits sustained at week 12 [28]. Galapagos and Gilead Sciences entered into a global partnership in December 2015, for the development and commercialization of filgotinib for the treatment of inflammatory diseases, including RA [4, 12]. In human cellular assays, filgotinib preferentially inhibited JAK1/JAK3-mediated interleukin (IL)-2, IL-4 and IL-15 signalling, JAK1/2-mediated IL-6 signalling and JAK1/TYK2-mediated type I interferon signalling downstream of the heterodimeric cytokine receptors, with functional selectivity over cytokine receptors that signal via pairs of JAK2 or JAK2/TYK2 [3, 18]. The phase 3, randomized, double-blind, placebo-controlled, DIVERSITY trial (NCT02914561) is recruiting patients with moderately to severely active Crohn’s disease. The 52-week randomized, double-blind, active-controlled phase 3 FINCH 3 trial (NCT02886728) showed that filgotinib significantly improved signs and symptoms of disease, physical function and HRQOL, and slowed radiographic progression in methotrexate-naïve patients with moderately to severely active RA [3, 25]. What does this signal for Galapagos, Gilead, and other biotechs working in inflammatory disease? In vitro studies showed that CES2, the main enzyme involved in the metabolism of filgotinib, can be inhibited by medicinal products such as fenofibrate, carvedilol, diltiazem or simvastatin; however, the clinical relevance of this interaction is unknown [3]. In December 2017, Galapagos decided to opt-in on the co-promotion of filgotinib with collaboration partner Gilead Sciences in UK, Germany, France, Italy, Spain, Belgium, the Netherlands and Luxembourg, once filgotinib was approved for commercial sale [14]. Filgotinib — which is approved under the tradename Jyseleca for RA in Europe and Japan — has been plagued in the United States by lingering concerns regarding its testicular toxicity. Permissions team. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. In addition to the ongoing phase 2 DARWIN 3 (NCT02065700) and EQUATOR 2 (NCT03320876) studies, several phase 2 and 3 studies are underway, including the phase 3 FINCH 4 (NCT03025308) long-term extension study in patients with RA, which is evaluating the long-term safety and tolerability of filgotinib in patients who had previously completed FINCH 1, 2 or 3. Galapagos had retained co-promotion rights in Belgium, the Netherlands and Luxembourg [4, 9]. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Patients were randomized to receive filgotinib 100 mg or 200 mg once daily (n = 480 and 475), adalimumab 40 mg every 2 weeks (n = 325) or placebo (n = 475) in addition to stable background treatment with methotrexate. Careers. Patients receiving filgotinib reported significantly greater and clinically meaningful improvements in patient-reported outcomes at week 16, including improvements in the PsA Impact of Disease 9 questionnaire (PsAID9) [35], Patient’s Global Assessment of Disease Activity, pain, HAQ-DI, FACIT-F and SF-36 PCS (all p < 0.01), but not in the SF-36 Mental Summary (MCS) [36]. SAT0158]. Acta Clin Belg. In: UEG Week Online. The study will evaluate the safety and efficacy of filgotinib during induction and maintenance treatment of patients who are biologic-naïve and biologic-experienced. CAS  The most common side effects include nausea, upper respiratory tract infection, urinary tract infection and dizziness. GlobalData expects that filgotinib will receive regulatory approval from the European Medicines Agency (EMA) in Q3 this year, having received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in July 2020. About the FINCH Program . Significantly higher proportions of patients receiving filgotinib 200 mg maintenance therapy also achieved 6-month corticosteroid-free clinical remission, sustained clinical remission, MCS remission, endoscopic remission and histologic remission at week 58 compared with placebo (p < 0.025) [42]. At week 12, significantly (p ≤ 0.001) more patients in the filgotinib 100 mg and 200 mg groups than in the placebo group achieved American College of Rheumatology 20 (ACR20; 70% and 77% vs. 50%; primary endpoint). NDA New Drug Application, RA rheumatoid arthritis, UC ulcerative colitis. Genovese M, Westhovens R, Meuleners L, et al. volume 80, pages 1987–1997 (2020)Cite this article, A Correction to this article was published on 02 February 2021. In the EU, filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs). 2020. LB19]. Further in vivo investigation of drug-drug interactions between filgotinib and OATP substrates is ongoing. Mod Rheumatol. In: 21st Annual Congress of the European League Against Rheumatism. In FITZROY, similar proportions of placebo and filgotinib 100 mg or 200 mg recipients with Crohn’s disease experienced at least one treatment-emergent adverse event; 9% of filgotinib (14/152) and 4% of placebo (3/67) recipients experienced a serious treatment-emergent adverse event. At week 12, significantly (p < 0.0001) more patients achieved ACR20 responses in all filgotinib groups [50 mg: 67% (48/72); 100 mg: 66% (46/70); 200 mg: 73% (50/69)] versus placebo [29% (21/72)] (primary endpoint), with an onset of response as early as week 1 of treatment with filgotinib 200 mg group [29]. A prespecified interim analysis at week 52 showed sustained efficacy in patients continuing treatment with filgotinib 200 mg once daily (n = 54); of the patients who achieved ACR20, ACR50 and ACR70 responses at week 16, 85%, 93% and 77% maintained these at week 52 [37]. The European Commission and Japan's Ministry of Health, Labor and Welfare approved filgotinib, marketed under the name Jyseleca, for rheumatoid arthritis. Enhanced material for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.13191509. Keshav S, Roblin X, D’Haens G, et al. Drugs 2020. https://doi.org/10.1080/17843286.2020.1812830. Filgotinib, the active substance in Jyseleca reduces the activity of the immune system. 19 Jan 2016. https://www.glpg.com, Galapagos. In September 2020, filgotinib received its first approvals in the EU and Japan. The most common adverse reactions with filgotinib 200 mg once daily in the placebo-controlled safety analysis set (up to week 12; n = 777) in trials in patients with RA were nausea (3.5%), upper respiratory tract infection (URTI; 3.3%), urinary tract infection (UTI; 1.7%) and dizziness (1.2%) [3, 20]. P/0045/2019: EMA decision of 29 January 2019 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for filgotinib (EMEA-001619-PIP03-16) (PDF/205 KB) Adopted. van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V, Nadashkevich O, Abi-Saab W, Tasset C, Meuleners L, Besuyen R, Hendrikx T, Mozaffarian N, Liu K, Greer JM, Deodhar A, Landewé R. Lancet. European Medicines Agency. However, Galapagos retained exclusive rights in Belgium, the Netherlands and Luxembourg [16]. There were no clinically relevant differences in exposures when filgotinib was administered with a high-fat or low-fat meal compared with the fasted state; therefore, filgotinib can be administered with or without food. Epub 2018 Oct 22. In September 2020, filgotinib received its first approvals in the EU and Japan. Filgotinib and GS-829845 exposures (area under the concentration-time curve; AUC) and Cmax were similar between healthy adult subjects and patients with RA and values were dose proportional over the therapeutic range. The original version of this article was revised due to a retrospective Open Access order. In September 2020, filgotinib received its first approvals in the EU and Japan. Biggioggero M, Becciolini A, Crotti C, Agape E, Favalli EG. Permissions team, https://doi.org/10.1007/s40265-020-01439-0, An oral, ATP-competitive, reversible JAK1 preferential inhibitor being developed by Galapagos NV and Gilead Sciences for the treatment of inflammatory autoimmune diseases, Received its first approval on 24 September 2020 in the EU and Japan, Approved for the treatment of RA in adults who have responded inadequately to, or who are intolerant to, one or more DMARDs, Filgotinib hydrochloride; G-146034; G-146034-101; GLPG-0634; GS-6034; Jyseleca, 2 ring heterocyclic compounds; amides; anti-inflammatories; antirheumatics; cyclopropanes; pyridines; skin disorder therapies; small molecules; thiamorpholines; triazoles; urologics, Modulates the JAK-STAT pathway by preventing the phosphorylation and activation of STATs, Preferentially inhibits the activity of JAK1 over JAK2, JAK3 and TYK2, Inhibited JAK1/JAK3-mediated IL-2, IL-4 and IL-15 signalling, JAK1/2-mediated IL-6 signalling and JAK1/TYK2-mediated type I interferon signalling in human cellular assays, Dose-dependently inhibited IL-6-induced STAT1 phosphorylation in human whole blood assays, Peak plasma concentration reached in 2–3 h, Filgotinib and GS-829845 (main metabolite) steady state reached in 2–3 and 4 days, respectively, Mean terminal half-lives of filgotinib and GS-829845 approximately 7 and 19 h, respectively, Nausea, upper respiratory tract infection, urinary tract infection, dizziness, Filgotinib, adalimumab, placebo, methotrexate. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Lancet. Bethesda, MD 20894, Copyright In Japan, filgotinib is indicated for the treatment of RA in patients who had an inadequate response to conventional therapies (including prevention of structural damage to joints). for details of this license and what re-use is permitted. Gilead’s oral JAK inhibitor filgotinib wins EU approval. Key milestones in the development of filgotinib.…, Key milestones in the development of filgotinib. Lancet. In many cases, RA is difficult to deal with and diagnose. In a pooled analysis of placebo-controlled studies (FINCH 1 and 2 and DARWIN 1 and 2), the incidence of infection during 12 weeks’ treatment with filgotinib 200 mg was 18.1% compared with 13.3% with placebo; no opportunistic infections (excluding tuberculosis) were reported during this period [3]. First patients treated with filgotinib in Japan and the EU in 2020. Jyseleca: EPAR - public assessment report.

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