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DOP075 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

D'Haens G.1, Schreiber S.2, Petryka R.3, Kuehbacher T.4, Hebuterne X.5, Roblin X.6, Klopocka M.7, Goldis A.8, Wisniewska-Jarosinska M.9, Baranovsky A.10, Sike R.11, Stoyanova K.12, Meuleners L.13, Tasset C.13, Van der Aa A.13, Harrison P.13, Vermeire S.*14

1Academic Medical Center (AMC), Department of Gastroenterology, Amsterdam, Netherlands 2University Medical Center Schleswig-Holstein Kiel, Department of Internal Medicine I, Kiel, Germany 3Vivamed, Warsaw, Poland 4Asklepios Hospital West Hamburg, Department of Gastroenterology, Hamburg, Germany 5CHU Nice Hopital l'Archet, Department of Gastroenterology and Nutrition, Nice Cedex 3, France 6North Hospital, Department of Gastroenterology, Saint Priez en Jarez, France 7NC University in Toruń, Collegium Medicum, Bydgoszcz, Poland 8Dr. Goldis Center for Gastroenterology, Ltd., Timisoara, Romania 9Santa LLC, Santa Familia Research, Prevention and Treatment Centre, Lodz, Poland 10City Clinical Hospital #31, St. Petersburg, Russian Federation 11Szent Margit Hospital, Budapest, Hungary 12PSI Pharma Support EOOD, Sofia, Bulgaria 13Galapagos NV, Mechelen, Belgium 14University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium

Background

Filgotinib is an oral, selective Janus kinase 1 (JAK1) inhibitor. This 20-week Phase 2 study evaluated efficacy and safety of filgotinib in patients with active Crohn's disease (CD). The primary endpoint (CDAI remission at Week 10) was met with an acceptable safety profile. Here, an exploratory subgroup analysis of the first 10 weeks, based upon prior exposure to anti-TNF therapy, is presented.

Methods

174 patients with moderate-to-severely active CD (CDAI: 220 to 450) and ulcerations confirmed by centrally read endoscopy were randomized 3:1 to receive 200mg filgotinib (FIL) or placebo (PBO) QD for 10 weeks. Immunosuppressants were to be discontinued prior to treatment initiation but corticosteroid-treated patients remained on stable doses until Week 10. Patients naïve to anti-TNF therapy as well as patients who were previously exposed to anti-TNF with no response or loss-of-response were included. Endpoints include clinical outcome (CDAI), patient-reported outcomes (PRO: CDAI and IBDQ), histopathology (D'Haens score) and combined clinical-biological response (CDAI and biomarkers).

Results

Baseline characteristics were similar in FIL and PBO groups, including mean disease duration (8.3 years), mean CDAI score (293), mean CRP (15.6mg/L, 41%>10mg/L), oral corticosteroids (51%, mean daily dose 20.8 mg/day). 42% of the patients were anti-TNF naïve, 58% were anti-TNF non-responder. Clinical remission (CDAI<150) was induced at Week 10 in 47% of FIL patients versus 23% on PBO (p=0.0077).

CDAI remission and response were higher in the FIL group versus PBO irrespective of prior anti-TNF therapy. PRO measured by changes from baseline in PRO2 score and general well-being (CDAI component), as well as quality of life assessed by IBDQ improved more in both FIL subgroups compared to PBO. A combined clinical-biological response endpoint confirmed these findings in the subgroup with elevated CRP or faecal calprotectin at baseline. Histopathology at Week 10 showed numerically greater effects after FIL treatment versus PBO for both subgroups (Table 1).

FIL was safe and well tolerated. Similar incidences in SAEs, TEAEs leading to discontinuation and infections were observed in both anti-TNF subgroups, with a somewhat higher incidence of TEAEs in anti-TNF non-responders.

Table 1

Variable/unit/populationAnti-TNF naiveAnti-TNF non-responder
PBO=16FIL=57PBO=28FIL=71
Clinical remission (CDAI<150), %, ITT-NRI13602937
100-points clinical response (CDAI improvement with ≥100 points), %, ITT-NRI44673954
PRO2 score, mean change from baseline, ITT-LOCF (7×(mean daily number of liquid or very soft stools + 7×(mean daily abdominal pain score))−19.8−24.8−13.2−19.5
PRO2 remission (PRO2 ≤28), %, ITT-NRI31612941
CDAI general well-being score, mean change from baseline, ITT-LOCF−0.78−1.08−0.58−0.90
Total IBDQ score, mean change from baseline, ITT-LOCF19.740.816.328.2
Overall total histopathology score, mean change from baseline, ITT-LOCF−0.3−3.9−0.7−3.2
Anti-TNF naiveAnti-TNF non-responder
PBO=9FIL=39PBO=18FIL=54
Combined clinical-biological response, %, ITT-NRI (CDAI score <150 points and CRP decrease >50% and/or fecal calprotectin decraese >50% from baseline)36620

CDAI: Crohn's Disease Activity Index; ITT: Intent-to-treat; NRI: Non-responder imputation; LOCF: Last observation carried forward; IBDQ: Inflammatory Bowel Disease Questionnaire; ITT population = 172 patients (2 pts without post-baseline assessments).

Conclusion

Efficacy of filgotinib was shown in CD patients independently of their prior anti-TNF exposure, and was consistent across all endpoints. The safety profile was also similar. These data suggest a favourable risk/benefit profile, in both anti-TNF naives and anti-TNF non-responders.