Annegret Van der Aa

Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial

BACKGROUND Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohns disease. METHODS We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohns disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohns Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. FINDINGS Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohns disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. INTERPRETATION Filgotinib induced clinical remission in significantly more patients with active Crohns disease compared with placebo, and had an acceptable safety profile. FUNDING Galapagos.

Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects

Aims Free fatty acids (FFA) can act as direct signalling molecules through activation of several membrane‐bound G‐protein coupled receptors. The FFA2 receptor (known as GPR43) is activated by short chain fatty acids (SCFA) such as acetate and has been shown to play a major role in SCFA‐induced neutrophil activation and migration and to contribute in the development and control of inflammation. GLPG0974 is a potent and selective antagonist of the human FFA2. The main objectives of the two phase 1 trials were to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG0974. Methods Two consecutive randomized, double‐blind, placebo‐controlled, single centre trials in healthy subjects were performed. In the first, GLPG0974 was administered as single doses up to 250 mg and in the second, multiple daily doses up to 400 mg for 14 days were evaluated. Non‐compartmental analysis was used to determine GLPG0974 pharmacokinetics while target engagement was investigated through the inhibition of neutrophils in acetate‐simulated whole blood samples using surface expression of CD11b activated epitope as a marker of neutrophil activation. Results The investigation of safety/tolerability and pharmacokinetics in the early development phase showed that GLPG0974 was safe and well tolerated up to a daily dose of 400 mg. GLPG0974 showed good and dose proportional exposure up to 400 mg daily as well as a substantial and sustained inhibition of acetate‐stimulated neutrophil activation. Conclusion Based on these results, a proof‐of‐concept study was initiated to evaluate the safety, tolerability and efficacy of GLPG0974 in patients with mild to moderate ulcerative colitis.

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

Background Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). Objective This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo (part A). An interim analysis after part A would determine whether the dose-finding part (part B) would be performed. Methods In part A, eligible methotrexate (MTX)-refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. Results The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. Conclusions This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA.

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.

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.

Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor

Filgotinib (GS‐6034, formerly GLPG0634) is an oral, selective Janus kinase 1 (JAK1) inhibitor that showed early response and sustained efficacy in patients with rheumatoid arthritis and with Crohns disease. The aim of the present study was to investigate the impact of age and renal impairment (RI) on the pharmacokinetics (PK) of filgotinib and its main metabolite.

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.