Luc Meuleners

Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials

JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK‐1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors.

Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial

BACKGROUND The Janus kinase 1 (JAK1) pathway has been implicated in the pathogenesis of psoriatic arthritis. We aimed to investigate the efficacy and safety of filgotinib, a selective JAK1 inhibitor, for the treatment of psoriatic arthritis. METHODS The EQUATOR trial was a randomised, double-blind, placebo-controlled phase 2 trial that enrolled adults from 25 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Patients (aged ≥18 years) had active moderate-to-severe psoriatic arthritis (defined as at least five swollen joints and at least five tender joints) fulfilling Classification for psoriatic arthritis (CASPAR) criteria, active or a documented history of plaque psoriasis, and an insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Patients continued to take csDMARDs during the study if they had received this treatment for at least 12 weeks before screening and were on a stable dose for at least 4 weeks before baseline. Using an interactive web-based system, we randomly allocated patients (1:1) to filgotinib 200 mg or placebo orally once daily for 16 weeks (stratified by current use of csDMARDs and previous use of anti-tumour necrosis factor). Patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was proportion of patients achieving 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 in the full analysis set (patients who received at least one dose of study drug), which was compared between groups with the Cochran-Mantel-Haenszel test and non-responder imputation method. This trial is registered with ClincalTrials.gov, number NCT03101670. FINDINGS Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30·2-59·6], p<0·0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group. INTERPRETATION Filgotinib is efficacious for the treatment of active psoriatic arthritis, and no new safety signals were identified. FUNDING Galapagos and Gilead Sciences.

Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial

BACKGROUND At present, biological disease-modifying anti-rheumatic drugs (DMARDs) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The TORTUGA trial investigated the efficacy and safety of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, for the treatment of patients with active ankylosing spondylitis. METHODS In this completed, randomised, double-blind, placebo-controlled, phase 2 trial, we enrolled adult patients from 30 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Eligible patients had active ankylosing spondylitis and an inadequate response or intolerance to two or more NSAIDs. Patients were randomly assigned (1:1) with an interactive web-based response system to receive filgotinib 200 mg or placebo orally once daily for 12 weeks. Randomisation was stratified by current use of conventional synthetic DMARDs and previous receipt of anti-tumour necrosis factor therapy. The patients, study team, and study sponsor were masked to treatment assignment. The primary endpoint was the change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12, which was assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug). Safety was assessed according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT03117270. FINDINGS Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n=58) or placebo (n=58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was -1·47 (SD 1·04) in the filgotinib group and -0·57 (0·82) in the placebo group, with a least squares mean difference between groups of -0·85 (95% CI -1·17 to -0·53; p<0·0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study. INTERPRETATION Filgotinib is efficacious and safe for the treatment of patients with active ankylosing spondylitis who have not responded to first-line pharmacological therapy with NSAIDs. Further investigation of filgotinib for ankylosing spondylitis is warranted. FUNDING Galapagos and Gilead Sciences.

Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: patient-reported outcomes

BackgroundThe aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies.MethodsPatients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized to daily placebo or filgotinib 50 mg, 100 mg, or 200 mg as add-on therapy to MTX (NCT01888874) or as monotherapy (NCT01894516). At week 12, nonresponders receiving filgotinib 50 mg in both studies or placebo in the add-on study, and all patients receiving placebo as monotherapy, were re-assigned to filgotinib 100 mg. PROs were measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) including Patient Pain assessed by visual analog scale, and the Patient Global Assessment of Disease Activity (Patient Global), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (Version 4), and the 36-Item Short Form Health Survey (SF-36).ResultsAt week 12, improvements in all PROs, apart from the SF-36 mental component in the add-on study, were statistically better with filgotinib than placebo; some improvements were noted as early as the first assessment time point (week 1 or week 4). Filgotinib improved HAQ-DI by 0.58–0.84 points, FACIT-Fatigue by 6.9–11.4 points, Patient Global by 25.2–35.6 mm, and Pain by 24.2–37.9 mm; scores were maintained or improved to week 24. Across all PROs, more patients achieved minimal clinically important differences and normative values with filgotinib 200 mg than placebo. Patients re-assigned to filgotinib 100 mg at week 12 experienced improvements in PROs between weeks 12 to 24.ConclusionsFilgotinib as MTX add-on therapy or as monotherapy demonstrated rapid and sustained (to 24 weeks) improvements in health-related quality of life and functional status in patients with active RA.Trial registrationMTX add-on study: ClinicalTrials.gov, NCT01888874. Registered on 28 June 2013. Monotherapy study: ClinicalTrials.gov, NCT01894516. Registered on 10 July 2013.

O02. FILGOTINIB, AN ORAL JAK1 SELECTIVE INHIBITOR WITH A RAPID ONSET OF ACTION: RESULTS FROM THE DARWIN 1 STUDY IN METHOTREXATE INADEQUATE RESPONSE RHEUMATOID ARTHRITIS PATIENTS

Background: Ankylosing spondylitis/axial spondyloarthritis (AS/Axial SpA) is a chronic inflammatory condition that typically affects younger people and often has a detrimental impact on their ability to work. There is little awareness of the condition among family, friends and employers which makes it difficult for those with AS/Axial SpA to have fulfilled working lives. We aimed to conduct in-depth semi-structured interviews with participants to identify the experiences regarding the disclosure of AS/Axial SpA to employers, colleagues, family and healthcare professionals which also included factors perceived as barriers or facilitators associated with this issue. Methods: Within this qualitative study, using an interpretive phenomenological paradigm, semi-structured interviews were conducted with ten participants with AS/Axial SpA. The interviews were recorded, transcribed and analysed thematically using a Framework analysis. Ethical approval and informed consent were obtained. Results: Analysis led to the following five themes being identified: Coping until diagnosis identifies symptoms that participants struggled to deal with and their personal journeys until being diagnosed that was usually delayed. Opening up about diagnosis describes the different experiences and challenges for participants in disclosing to the different groups. Looking for support provides insights into the different groups of people that participants turn to for support when disclosing their diagnosis and for managing symptoms. Sensing the stigma focuses on the different forms of stigma and the resulting psychosocial impact in their overall lives. Making others aware describes the perceived lack of general awareness about the condition and suggestions from participants on how to address this issue. Conclusion: Participants discussed their diagnosis and symptoms to varying levels with employers, family members, friends and healthcare professionals. They decided on the level of disclosure after assessing the risks and potential benefits. They were able to find support from work colleagues and family but this was sometimes riddled with challenges. In addition, the specialist physiotherapy team were able to offer much needed physical and psychological support. Despite disclosing their diagnosis, participants remained fearful of stigmatisation especially at work, resulting in psychological distress, which was amplified by the lack of awareness about the condition. Employers, healthcare professionals and family members should not underestimate the challenges faced by individuals when deciding whether to disclose this hidden disability. Offering support and encouragement to empower individuals with AS/Axial SpA to successfully disclose their diagnosis should they choose to should be taken into account as a routine element of clinical care. Disclosure statement: J.M.: Other: Speaker fees from AbbVie, Pfizer and UCB. R.S., E.G-C. and J.A.G. have declared no conflicts of interest.

Efficacy of Filgotinib, a Selective jak1 Inhibitor, is Independent of Prior Anti-TNF Exposure: Subgroup Analysis of the Phase 2 Fitzroy Study in Moderate-To-Severe Crohn’s Disease

These three posters from the previously reported FITZROY study will be presented in the session titled “IBD: Controlled Clinical Trials in Humans” to be held on 7 May 2017 from 12:00 PM to 2:00 PM CT. As per DDW policy, the embargo on posters lifts at 9:30 AM CT on the date of presentation. The ePosters will be made available to the public after June 6 2017 at the DDW archive site, ddw.scientificposters.com.

THU0173 Long term safety and efficacy of filgotinib in a phase 2B open label extension study in patients with rheumatoid arthritis: results up to 144 weeks

Background Filgotinib (GLPG0634, GS-6034) is an oral JAK1 selective inhibitor with a favorable safety and efficacy profile in two 24-week Phase 2b studies as add-on to methotrexate (DARWIN 1) or as monotherapy (DARWIN 2) in patients with active rheumatoid arthritis (RA). Three daily doses were tested (50mg, 100mg or 200mg) in comparison to placebo. Objectives To assess long term safety and efficacy of filgotinib 200mg daily in patients from the DARWIN 3 Phase 2 open-label extension study. Methods Patients who completed DARWIN 1 or 2 and enrolled in DARWIN 3 received filgotinib 200mg once daily or 100mg twice daily, depending on prior treatment assignment. The DARWIN 3 data cut off was when the last patient reached extension Week 60. For safety, all data from the first intake of filgotinib in DARWIN 1/2/3 were analysed (up to 144 weeks). Results 877 patients participated in DARWIN 1 or 2, 790 completed and 739 entered DARWIN 3 from 22 countries (82% females, mean age 53y). 559 patients (75.6%) completed Week 60, 9.3% discontinued due to positive Quantiferon, 7.8% due to other adverse events, 6.8% for other reasons and 0.3% due to insufficient response. Overall exposure to filgotinib was 1314 patient-years (PYE). Treatment-emergent adverse events (157.7/100PYE), serious adverse events (5.3/100PYE) and serious infections (1.9/100PYE) occurred at similar rates compared to the core studies, however infections decreased on a percentage basis from 15% (109/739, W0–12) to 5% (25/549, W85–96). 16 cases of Herpes zoster were reported (1.2/100PYE), 6 cases of malignancy (excl. NMSC) (0.5/100PYE) and 1 case of MACE (0.1/100PYE). There was no active case of tuberculosis. Three fatalities were reported (0.2/100PYE). Mean change from baseline (CFB) at Week 96 and CTCAE toxicity grading in lab parameters of special interest are shown in table 1.Table 1. Mean CFB at Week 96 and CTCAE toxicity grading of selected lab parameters Mean CFB CTCAE Grade 3–4 (%) Hb +6.5 g/L 0.4 Neutrophils −1.73 giga/L 1 Lymphocytes −0.19 giga/L 2 Creatinine +8.2 μmol/L 0 ALT +6.1 U/L 0.4 LDL +13% – HDL +23% – Tot chol/HDL −4% – NK cells −0.02 giga/L – Based on an observed case analysis 84% (505/601), 65% (389/601), 44% (267/601) and 51% (299/587) of patients reached ACR20, ACR50, ACR70 and DAS28(CRP) remission at Week 60 respectively. Conclusions With 1314 patient-years of exposure, the safety profile of filgotinib appears consistent with that of previously reported double-blind studies and the clinical response appears durable. References Westhovens R et al. Ann Rheum Dis 2016;0:1–11. Kavanaugh A et al. Ann Rheum Dis 2016;0:1–11. Disclosure of Interest R. Alten Grant/research support from: Galapagos, R. Westhovens Grant/research support from: Roche, Consultant for: Galapagos, Speakers bureau: BMS, A. Kavanaugh Consultant for: Galapagos, Pfizer, AbbVie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, M. Genovese Grant/research support from: Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, Consultant for: Galapagos, Gilead, Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, K. Winthrop Grant/research support from: BMS, Pfizer, Consultant for: pfizer, BMS, lilly, Abbvie, Roche, UCB, Galapagos, Amgen, M. Greenwald Grant/research support from: Abbvie,Amgen, Bristol Myers Squibb, Celgene, Galapagos, Gilead, Lilly, Merck, Pfizer, UCB, Consultant for: Lilly, Pfizer, L. Ponce: None declared, F. Enriquez: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, L. Meuleners Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, P. Harrison Employee of: Galapagos NV, A. Van der Aa Employee of: Galapagos NV