DOP070. The FFA2 antagonist GLPG0974: opportunity to treat neutrophil-driven inflammation
F. Vanhoutte1, F. Namour2, S. Dupont2, W. Haazen3, M. Petkova3, A. Van der Aa1, G. van 't Klooster1, J. Beetens1, 1Galapagos NV, Clinical Development, Mechelen, Belgium, 2Galapagos SASU, Development, Romainville, France, 3SGS Life Science Services, Clinical Pharmacology Unit, Antwerp, Belgium
Free fatty acids (FFA) act as signalling molecules through several GPCRs including FFA2. FFA2 is a receptor activated by short chain fatty acids (SCFA). FFA2 is expressed on immune cells (neutrophils, monocytes, B lymphocytes), enterocytes, entero-endocrine cells and adipocytes. FFA2 plays a major role in SCFA-induced neutrophil activation and migration. Studies in FFA2 knock-out mice suggest an important contribution to the control of inflammation. In IBD patients, FFA2 expression in colon biopsies was shown to be upregulated and was reduced after successful treatment with infliximab.
GLPG0974 was identified as a potent and selective antagonist of human FFA2. In vitro, it potently inhibits acetate-induced calcium flux in HEK293 cells and human neutrophil migration. In a human whole blood assay, GLPG0974 inhibits acetate-stimulated neutrophil activation, as evidenced by downregulated CD11b activated epitope [AE] expression. It is highly selective for FFA2 over the close homologues FFA1 and FFA3, other non-related GPCRs and a wide range of kinases covering the human kinome.
The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered GLPG0974 were evaluated in healthy volunteers after single dosing (SD) (NCT01496937) and multiple ascending dosing for 14 days (MAD) (NCT01721980). The PD was assessed by flow cytometric measurement of neutrophil activation (CD11b[AE] expression) in whole blood upon ex vivo stimulation by acetate.
Single doses up to 250 mg and multiple doses up to 400 mg daily were safe and well-tolerated. GLPG0974 administered under fed conditions as capsules or oral solution, was slowly absorbed with a median tmax of about 3 h and eliminated with a mean t1/2 of about 5.5 h. The PK was dose proportional over the 50 to 400 mg daily dose range. GLPG0974 substantially inhibited acetate-stimulated neutrophil activation in whole blood. In general, the inhibitory effect peaked at 2 h post dose and the activity was sustained for at least 12 h after dosing. The PK/PD data showed a clear relationship between drug exposure and PD effect, with a maximum effect achieved at a daily dose of around 200 mg.
In healthy volunteers, the potent FFA2 inhibitor GLPG0974 is safe, and shows good PK properties and a dose-dependent inhibition of acetate-induced neutrophil activation. Inhibition of neutrophil migration into the gastro-intestinal tract may prevent neutrophil-induced tissue damage as in ulcerative colitis. A Proof-of-Concept study is ongoing to evaluate the safety and efficacy of GLPG0974 in patients with this condition.