| 词条 | Filgotinib |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 461425696 | 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 | image = Filgotinib.svg | width = | tradename = | Drugs.com = | MedlinePlus = | licence_EU = | licence_US = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration = Oral | bioavailability = | protein_bound = | metabolism = | elimination_half-life = 6 hours[1] | excretion = | IUPHAR_ligand = 7913 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 28189566 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 1206161-97-8 | ATC_prefix = L01 | ATC_suffix = XE18 | ATC_supplemental = | PubChem = 49831257 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 3XVL385Q0M | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D10871 | synonyms = GLPG0634 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 3301607 | chemical_formula = | C=21 | H=23 | N=5 | O=3| S=1 | molecular_weight = 425.50402 g/mol | smiles = O=C(C1CC1)NC2=NN3C(C4=CC=C(CN5CCS(CC5)(=O)=O)C=C4)=CC=CC3=N2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | 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_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = RIJLVEAXPNLDTC-UHFFFAOYSA-N }} Filgotinib (code name GLPG0634) is a drug which is currently under investigation for the treatment of rheumatoid arthritis (RA) and Crohn's disease. It was developed by the Belgian-Dutch biotech company Galapagos NV. Mechanism of actionFilgotinib is a Janus kinase inhibitor with selectivity for subtype JAK1 of this enzyme. It is considered a promising agent as it inhibits JAK1 selectively. Less selective JAK inhibitors (e.g. tofacitinib) 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.[1] 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 RA. 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.[2] It is however still to be seen to what extent JAK2 inhibition should be avoided. Clinical trialsThe efficacy of filgotinib is currently being studied in a phase2b program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn's disease patients. Phase 1 studyIt was shown in phase 1 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.[3] Phase 2 study: Proof of concept (2011)In November 2011 Galapagos released the results of their phase 2 study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 RA patients were treated who showed a suboptimal clinical response to methotrexate treatment.[4] 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] DARWIN 1 trialThe DARWIN 1 trial was a 24-week double blind placebo-controlled trial with 599 rheumatoid arthritis patients enrolled. All participants had moderate to severe RA and showed an insufficient response to standard methotrexate treatment. The trial compared three dosages of filgotinib as a once or twice per day regimen.[6] During the trial all participants remained on their methotrexate treatment. The trial completed in Feb 2015 and the results were released in July 2015.[7][8] Galapagos announced that the drug met key efficacy endpoints, showed ARC70 responses up to 39%, and maintained its safety profile.[8][9] DARWIN 2 trialThe 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.[10] The recruitment of DARWIN trial 2b ended in November 2014.[11] In August 2015, Galapagos announced that the study confirmed previous results.[12] DARWIN 3 trialPatients who completed DARWIN 1 and 2 were eligible for DARWIN 3. On November 2017, the company announced consistent safety findings and durable activity at week 84 in the trial.[13] The estimated study completion timeframe is May 2019.[14] FINCH Phase 3 trialsFINCH 1 looks at patients where first-line treatment with methotrexate (MTX) is not working. It compares filgotinib versus adalimumab/Humira versus a placebo.[15] 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. MANTADue to concerns over testicular toxicity in males, the MANTA study is examining the safety of the drug in the context of treating ulcerative colitis.[16] Despite these concerns, the FDA allowed a 200-mg daily dose for males in the Phase III FINCH trials.[17] Time line
References1. ^1 {{cite journal |last=Namour |first=Florence |last2=Diderichsen |first2=Paul Matthias |last3=Cox |first3=Eugène |last4=Vayssière |first4=Béatrice |last5=Van der Aa |first5=Annegret |last6=Tasset |first6=Chantal |last7=Van't Klooster |first7=Gerben |date=2015-02-14 |journal=Clin Pharmacokinet |volume=Epub ahead of print|issue=8 |pages=859–874 |title=Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection |doi=10.1007/s40262-015-0240-z|pmid=25681059 |pmc=4513223 }} {{Extracellular chemotherapeutic agents}}{{Cytokine receptor modulators}}2. ^{{cite journal |last=Van Rompaey |first=L |last2=Galien |first2=R |last3=Van der Aar |first3=E |last4=Clement-Lacroix |first4=P |last5=Van der Aar |first5=E |last6=Nelles |first6=L |last7=Smets |first7=B |last8=Lepescheux |first8=L |last9=Cristophe |first9=T |last10=Conrath |first10=K |last11=Vandeghinste |first11= N |last12=Vayssiere |first12=B |last13=De Vos |first13=S |last14=Fletcher |first14=S |last15=Brys |first15=R |last16=Van’t Klooster |first16=G |last17=Feyen |first17=J |last18=Menet |first18=C |date=2013-10-01 |journal=J. 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