Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions

Namour, Florence; Desrivot, Julie; Aa, Annegret Van der; Harrison, P.; Tasset, Chantal; Klooster, Gerben van't

doi:10.2174/1872312810666151223103353

Cited by 52 publications

(43 citation statements)

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“…After oral administration, Filgotinib is metabolized to an active metabolite form which is Jak1 selectivity inhibitor (Namour et al, 2015). The main enzyme(s) that are involved in the metabolism of filgotinib are carboxylesterase1 (CES1) and carboxylesterase2 (CES2), which are localized mainly in the liver and intestine, respectively (Namour, 2015; Namour et al, 2016). It has been shown that CES2 is the major enzyme accountable for the formation of its active metabolite and CES1 could also form the active metabolite (Namour et al, 2016).…”

Section: Clinical Developmentsmentioning

confidence: 99%

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

Hosseini

Gharibi

Marofi

et al. 2020

Journal Cellular Physiology

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Many cytokines are crucial drivers of cancers and autoimmune conditions. These proteins bind to receptors and signal their responses through Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Genetic variations in the JAK-STAT pathway are correlated with the increased risk of cancers, autoimmunity as well as inflammatory diseases. Targeting JAKs and STATs can be a safe and efficacious strategy for treating these diseases. Tofacitinib, as the first JAK inhibitor, is approved for rheumatoid arthritis therapy. Also, many other JAK inhibitors have been proven or are in various phases of clinical trials for various diseases. At present, small-molecule JAK inhibitors are considered as a novel category of drugs in the treatment of cancer and immune-mediated diseases. K E Y W O R D S autoimmune diseases, cancer, Janus kinase inhibitors, novel treatment strategy

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Section: Clinical Developmentsmentioning

confidence: 99%

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

Hosseini

Gharibi

Marofi

et al. 2020

Journal Cellular Physiology

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“…Filgotinib (GLPG0634/GS-6034) is a potent and selective inhibitor of JAK1,7 which is currently under investigation for the treatment of RA and inflammatory bowel disease 7–10. The efficacy and safety of filgotinib in patients with RA has previously been investigated in two short-term phase IIa studies, as add-on treatment to MTX, which suggested that filgotinib has the potential to be effective when administered as a once-daily dosing regimen .…”

Section: Introductionmentioning

confidence: 99%

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)

Kavanaugh

Kremer

Ponce³

et al. 2016

Ann Rheum Dis

196

133

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ObjectivesTo evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX).MethodsIn this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12.ResultsOverall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported.ConclusionsOver 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated.Trial registration numberNCT01894516.

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“…Filgotinib and its metabolite are not substrates of cytochrome P450 or major drug transporters, with the exception of P-glycoprotein, and neither food nor acid-reducing agents have clinically relevant effects on their PK. 8,10 Neither moderate hepatic impairment nor mild-tomoderate renal impairment significantly impact the PK of filgotinib. 7,16,17 The increase in C max of filgotinib (2.1-fold) and metabolite (1.9-fold) with increasing the dose from 200 to 450 mg was greater than the anticipated C max increase that would take place as a result of drug-drug interactions or organ dysfunction in the target patient population, supporting the appropriateness of selecting 450 mg as the supratherapeutic dose for evaluation in this study.…”

Section: Discussionmentioning

confidence: 99%

“…6 Filgotinib is primarily metabolized by carboxylesterase isoform 2, resulting in the loss of the cyclopropyl carboxylic acid group and formation of its major, circulating metabolite, which is predominantly excreted in the urine (>80%). 7,8 The metabolite also exhibits selective JAK1 inhibition, with approximately 16-to 20-fold higher exposure and longer half-life (23-27 hours for the metabolite versus 5-6 hours for filgotinib) but ß19-fold lower potency than filgotinib. 7,9,10 In phase 2 studies, filgotinib has shown clinical efficacy, rapid onset of activity, and a favorable safety and tolerability profile both as monotherapy and in combination with methotrexate in subjects with moderate to severe rheumatoid arthritis, [11][12][13] and in subjects with moderate to severe Crohn's disease.…”

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confidence: 99%

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects

Anderson

Yan

Zheng

et al. 2019

Clinical Pharm in Drug Dev

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Filgotinib, a selective inhibitor of Janus kinase 1, is being developed for the treatment of chronic inflammatory diseases. Electrocardiograms evaluated the effect of filgotinib on the corrected QT (QTc) interval in 52 healthy subjects who received each of 4 treatments: filgotinib 200 mg (therapeutic dose), 450 mg (supratherapeutic dose), and placebo, each administered once daily for 7 days, and a single dose of moxifloxacin 400 mg (positive control). Plasma samples were collected for pharmacokinetic analysis. The QTc interval was calculated using Fridericia's correction factor (QTcF) or an individual correction factor (QTcI). The relationship between plasma concentrations of filgotinib and its major metabolite and time-matched, baseline-adjusted, placebo-corrected QTc ( QTc) was evaluated. Filgotinib did not prolong QTcF or QTcI and using an appropriate mixed-effect model, the upper limit of the 2-sided 90% confidence interval for QTc for each filgotinib dose (200 and 450 mg) remained below 10 milliseconds at all postdose time points. There were no clinically relevant relationships between QTc interval and plasma concentrations of filgotinib or its major metabolite. Filgotinib, administered at 200 or 450 mg, was generally well tolerated. Results of this thorough QT study demonstrate that filgotinib and its major metabolite are not associated with QTc interval prolongation.

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Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions

Abstract: the collective in vivo and in vitro data on drug-metabolizing enzymes and on key drug transporters, support co-administration of filgotinib with commonly used RA drugs to patients without the need for dose adjustments.

Cited by 52 publications

References 0 publications

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

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)

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects

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