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

Summary

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 Crohn's 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 Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's 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 Crohn's 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 Crohn's disease compared with placebo, and had an acceptable safety profile.

Funding

Galapagos.

Introduction

Crohn's disease is a chronic inflammatory bowel disease characterised by progressive transmural damage leading to complications. Chronic inflammation of the gastrointestinal tract, most commonly the proximal colon and distal small intestine, leads to symptoms including abdominal pain, diarrhoea, weight loss, and chronic fatigue, as well as progressive damage to the bowel.1, 2 The course of Crohn's disease can be modified by treatment. Whereas the primary goal of therapy for Crohn's disease is to achieve clinical remission, the importance of patient-reported outcomes and endoscopic response are increasingly recognised and are now accepted as valid coprimary endpoints by regulatory agencies.³ Management of the disease has benefited from the development of monoclonal antibodies targeting tumour necrosis factor alpha (TNFα), including infliximab, adalimumab, or certolizumab pegol. These are commonly used in combination with thiopurines or methotrexate. However, not all patients respond to anti-TNF agents and many of those who do will eventually become secondary non-responders. Only 10% of patients with Crohn's disease achieve prolonged clinical remission and 50% require surgery within 10 years of diagnosis.⁴ There is therefore a need for novel disease-modifying treatments with an alternative mechanism of action that are safe and well tolerated.

Janus kinases (JAKs) are intracellular cytoplasmic tyrosine kinases that transduce cytokine-mediated activation of membrane receptors, via phosphorylation of signal transducers and activators of transcription (STATs).⁵ There are four known JAK subtypes (JAK1, JAK2, JAK3, and TYK2) and blocking cytokine signalling via inhibition of the JAK–STAT pathway is a promising therapeutic option for inflammatory disease.⁶ Tofacitinib, a pan-JAK inhibitor that blocks JAK1 and JAK3, and to a lesser extent JAK2, is approved for the treatment of moderate-to-severe rheumatoid arthritis.⁷ It has also shown preliminary efficacy in ulcerative colitis, another type of inflammatory bowel disease.⁸ However, in randomised phase 2a⁹ and 2b¹⁰ studies in Crohn's disease, tofacitinib did not differ significantly from placebo with respect to clinical remission. Therefore, it is unclear whether JAK inhibition is a viable therapeutic option for Crohn's disease.

Research in context

Evidence before this study

We searched PubMed using the terms “Crohn's disease” and “treatment” and “(moderate to severe)” for articles published between Jan 1, 2000, and Aug 6, 2016, restricted to the English language. We found 353 articles, of which 77 were clinical trials in adults. These studies show that anti-tumour necrosis factor agents have been the mainstay of Crohn's disease treatment in recent decades, but that many patients either fail to respond or become secondary non-responders. The scale of this clinical problem has also been confirmed by a systematic review published by the European Crohn's and Colitis Organisation (ECCO). Given that only 10% of patients with Crohn's disease are thought to achieve prolonged clinical remission, there is an urgent need for novel disease-modifying treatments with an alternative mechanism of action. Inhibition of members of the Janus kinase (JAK) family has shown efficacy in phase 3 studies in ulcerative colitis, an inflammatory bowel disease related to Crohn's disease. We did the first randomised, placebo-controlled, phase 2 study of the efficacy and safety of a novel JAK1-selective inhibitor, filgotinib (GLPG0634, GS-6034), in patients with moderate-to-severe Crohn's disease.

Added value of this study

Whereas previous studies in Crohn's disease have recruited patients on the basis of clinical symptoms or endoscopies read by local physicians, our study (FITZROY) is the first double-blind, placebo-controlled study to use centrally read endoscopies to ensure the selective recruitment of patients with active disease including mucosal ulceration. In the intention-to-treat population, a significantly greater proportion of patients achieved clinical remission (defined as a Crohn's Disease Activity Index [CDAI] <150) with filgotinib 200 mg once a day than with placebo. Filgotinib was superior to placebo in CDAI-100 response and in mean change from baseline in quality of life, as revealed by the Inflammatory Bowel Disease Questionnaire score and subscores. Beneficial effects were additionally seen on D'Haens histopathology scores, the Simplified Endoscopy Score for Crohn's Disease scale, and biomarkers of inflammatory activity.

Implications of all the available evidence

The FITZROY study provides the first evidence for the efficacy and safety of the JAK1 inhibitor filgotinib for the treatment of moderate-to-severe Crohn's disease with mucosal ulceration. Filgotinib could represent the first new oral treatment for Crohn's disease in many years, and phase 3 trials with the compound are underway.

Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered inhibitor of JAK1, with about a 30 times selectivity for JAK1 over JAK2 in human whole blood,¹¹ and 50 times selectivity for JAK1 over JAK3. Filgotinib has an elimination half-life of 6 h; it gives rise to an active metabolite, with a terminal elimination half-life of 21–27 h.¹² Both the parent molecule and the active metabolite contribute to the clinical activity of filgotinib, and maximum pharmacodynamic effects are achieved at 200 mg filgotinib daily.¹² Filgotinib showed good efficacy in patients with active rheumatoid arthritis in two phase 2b studies, with beneficial effects on signs, symptoms, and patient-reported outcomes.13, 14

The FITZROY study examined the efficacy and safety of daily filgotinib for the treatment of active moderate-to-severe Crohn's disease, in patients with mucosal ulceration identified by centrally read endoscopies at enrolment. The impact of filgotinib on biomarkers of inflammatory activity was also examined.