Introduction Filgotinib (FIL), an oral, selective Janus kinase 1 (JAK1) inhibitor that blocks cytokine signalling by inhibiting STAT phosphorylation, which previously demonstrated efficacy in rheumatoid arthritis, is being evaluated in active Crohn’s disease (CD).

Method 174 patients with moderate-to-severe CD and ulcerations confirmed by centrally read endoscopy were randomised 3:1 to 200 mg FIL or placebo (PBO) QD for 10 weeks. Thereafter, patients continued to receive FIL 200 mg, 100 mg or PBO QD for another 10 weeks. Immunosuppressive agents had to be discontinued, and steroid dosage was kept stable until Week 10 (W10). Key efficacy and safety data, and phosphorylation of STAT3 in intestinal biopsies from the 10 week induction period are presented.

Results Mean baseline characteristics were similar between the FIL and PBO group. The primary endpoint (clinical remission CDAI <150 at W10) was met (FIL 47%, PBO 23%, p=0.0077). Significantly more FIL-patients showed clinical response (CDAI improvement ≥100 points) (FIL 59%, PBO 41%, p=0.0453) and improved quality of life (IBDQ mean changes from baseline) (FIL 33.8, PBO 17.6, p=0.0046) at W10. Numerically more FIL-patients had their CRP normalised (FIL 27%, PBO 14%) and showed at least 50% improvement in SES-CD score (FIL 25%, PBO 14%). Histopathology scores on biopsies at W10 decreased significantly more with FIL versus PBO (FIL −3.5, PBO: −0.6; p=0.0359). Filgotinib was well-tolerated; (S)AEs and early discontinuation rates were similar between groups.

pSTAT3 levels were significantly reduced at W10 in FIL-patients (−36% (95% CI: −51%, −17%)). However, in patients in clinical remission at W10, pSTAT3 levels were significantly reduced irrespective of treatment (PBO −62% (95% CI: −83%, −16%) and FIL −42% (95% CI: −57%,−21%)). In patients without clinical remission, pSTAT3 levels numerically decreased with FIL (−28% (95% CI: −51%,+7%)) and not with PBO (+12% (95% CI:−21%,+94%).

Conclusion Filgotinib is the first JAK inhibitor to demonstrate clinical efficacy in CD, as demonstrated by induction of clinical remission and response, and is associated with a significant reduction in pSTAT3 levels, suggesting that pSTAT3 behaves both as a pharmacodynamic marker for filgotinib and a disease activity marker.

Disclosure of Interest S. Keshav Conflict with: Abbvie, ChemoCentryx, GSK, Merck, Conflict with: Abbvie, Allergan, Astra-Zeneca, Boehringer Ingelheim, ChemoCentryx, Dr Falk Pharma, Ferring, Gilead, GSK, Merck, Mitsubishi Tanabe Pharma, Pharmacosmos, Pfizer, Takeda, Vifor Pharma, J. Goh: None Declared, A. Hart: None Declared, S. Levison: None Declared, S. McLaughlin Conflict with: AbbVie, Conflict with: AbbVie, A. Van der Aa Conflict with: Galapagos NV, R. Galien Conflict with: Galapagos SASU, Y. Pan Conflict with: Gilead Sciences Inc, L. Meuleners Conflict with: Galapagos NV, C. Jamoul Conflict with: Galapagos NV, C. Tasset Conflict with: Galapagos NV, P. Harrison Conflict with: Galapagos NV, S. Vermeire Conflict with: AbbVie, Galapagos, MSD, Takeda, Conflict with: AbbVie, Galapagos, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer,Mundipharma, Hospira, Celgene, Second genome, Janssen, Conflict with: AbbVie