Vermeire S.*1, Reinisch W.2,3, Wasko-Czopnik D.4, Van Kaem T.5, Desrivot J.6, Vanhoutte F.5, Beetens J.5
1University Hospital Leuven, Gastroenterology, Leuven, Belgium 2McMaster University, Gastroenterology, Hamilton, Canada 3Medical University Vienna, Gastroenterology & Hepatology, Vienna, Austria 4Medical University of Wrocław, Gastroenterology & Hepatology, Wroclaw, Poland 5Galapagos NV, Development, Mechelen, Belgium 6Galapagos SASU, Development, Romainville, France
GPR84, a GPCR activated by medium-chain free fatty acids, is primarily expressed on white blood cells (polymorphonuclear, monocyte/macrophage). GLPG1205 is a potent and selective antagonist of GPR84, inhibiting GPR84-induced neutrophil migration in vitro. In a mouse IBD model (DSS), GLPG1205 dose-dependently decreased disease activity, histological activity, neutrophil influx as well as colonic MPO content.
The efficacy and safety of GLPG1205 in moderate-to-severe UC (Mayo score 6–12 with an endoscopic subcore of ≥2) was evaluated in an exploratory, double-blind study, in 63 patients (aged 18–75) treated for 12 weeks with 100 mg q.d. GLPG1205 or placebo (pbo) in a 2:1 randomization (NCT02337608). A stable background of 5-aminosalicylates, immunosuppressants or steroids was allowed. Mayo scores and biopsies for Geboes scores and myeloperoxidase (MPO) positive cells (immunohistochemistry) were collected at baseline (BL) and week 8. Fecal calprotectin (FC), subscores for partial Mayo and PK were evaluated at BL and week 4, 8 and 12.
Baseline characteristics, including duration of disease (6.9 y), prior and concomitant medication, Mayo score, FC, MPO positive cells were similar in both groups. At primary endpoint (W8), there was no statistically significant difference in Mayo score, Mayo clinical response, clinical remission, mucosal healing, Geboes Index, and histological response (MPO) between GLPG1205 and placebo (see table). Over the total 12-week treatment period, no treatment difference was observed in the partial Mayo score, the Mayo sub-scores or FC changes. GLPG1205 was well tolerated. Worsening of colitis, leading to study discontinuation, was reported by 4 patients (3 GLPG1205, 1 placebo). Patients showed a good drug exposure with average plasma concentrations within the range of exposures observed in healthy subjects.
|Outcome parameter||Time||Placebo||GLPG1205 (100 mg QD)||p-value|
|Mayo score (mean)||BL||8.7||8.7|
|Mayo response (%)1||Week 8||48%||40%||0.6143|
|Mayo remission (%)2||Week 8||5%||5%||0.9084|
|Mucosal healing (%)3||Week 8||10%||5%||0.6261|
|MPO positive cells (median)||BL||5%||7%|
|Fecal calprotectin (median) (mg/kg)||BL||325||335|
1Decrease in Mayo score ≥3 points and ≥30% and a decrease in rectal bleeding ≥1 or an absolute score 0/1. 2Mayo score ≤2 and no individual subscore >1. 3Endoscopy subscore 0 or 1. BL = baseline.
In this 12-week first-in-patient study with a GPR84 antagonist in patients with moderate to severe UC, GLPG1205 was well-tolerated. Compared to placebo, GLPG1205 had no effect on the clinical parameters or on the biomarkers related to the mode of action (FC or MPO). Therefore, our data suggest that inhibition of GPR84-mediated processes on inflammatory cells may not be relevant in the pathophysiology of active UC.