P612 Human safety, pharmacokinetics and pharmacodynamics of the GPR84 antagonist GLPG1205, a potential new approach to treat IBD.
F. Vanhoutte1, S. Dupont2, T. Van Kaem1, M.-H. Gouy3, R. Blanqué2, R. Brys4, N. Vandeghinste4, L. Gheyle5, W. Haazen5, G. van 't Klooster1, J. Beetens*1
1Galapagos NV, Development, Mechelen, Belgium, 2Galapagos SASU, Translational Science, Romainville, France, 3Galapagos SASU, Development, Romainville, France, 4Galapagos NV, Therapeutic Area Group, Mechelen, Belgium, 5SGS Life Science Services, Clinical Pharmacology Unit, Antwerpen, Belgium
Free fatty acids (FFAs) have been shown to act as signaling molecules through a family of G protein-coupled receptors, which are involved in the pathophysiology of a variety of diseases, including metabolic and inflammatory disorders. GPR84 is activated by medium chain FFAs. The receptor is primarily expressed on white blood cells (PMN, monocyte/macrophage) consistent with a reported role for GPR84 in inflammation.
GLPG1205 is a potent and selective antagonist of GPR84, inhibiting GPR84 activation in a functional GTPγS binding assay, as well as GPR84-induced neutrophil and macrophage migration. In the DSS mouse IBD model, GLPG1205 dose-dependently prevented disease progression, to a similar extent as sulfasalazine and cyclosporine. The histological score for colon lesions, neutrophil influx as well as colonic MPO content was substantially reduced.
The safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of orally administered GLPG1205 (liquid formulation) were evaluated in healthy volunteers after single dosing (10-800 mg) and multiple ascending dosing for 14 days (50, 100, 200 mg QD) (NCT01887106). TE was assessed by a competitive radiometric displacement assay in whole blood (ex vivo). The bioavailability of a solid formulation (capsule) of GLPG1205 was determined in fasted and fed state after single oral dose administration (NCT02143856).
In healthy volunteers, GLPG1205 was generally safe and well tolerated up to 100 mg QD for 14 days, with no adverse effects on ECG, vital signs or laboratory parameters. The most relevant adverse event was headache. The PK of the compound showed a rapid absorption, a long apparent terminal half-life (> one day) and a dose-proportional increase in exposure from 50 to 100 mg QD. Steady state was reached after 10 days. GLPG1205 showed dose-dependent target engagement, with a similar potency as in in vitro assays. The single-dose PK/TE data demonstrated a clear relationship between drug exposure and TE. At steady state, sustained target occupancy for 24 hours after once daily dosing was observed. Exposure and absorption rate of the capsule was similar to the liquid formulation and no food effect was observed.
GLPG1205, a potent and selective inhibitor of GPR84, is safe and generally well tolerated in healthy volunteers. It shows a favourable PK/PD profile, clearly demonstrating the ability of the compound to antagonize GPR84, a target which might be implicated in several neutrophil- and macrophage-driven inflammatory conditions. At steady state, a sustained 24-hour inhibition was observed. The efficacy and safety of GLPG1205 will be evaluated in Proof of Concept studies in IBD patients.