Leveraging a Clinical Phase Ib Proof‐of‐Concept Study for the GPR40 Agonist MK‐8666 in Patients With Type 2 Diabetes for Model‐Informed Phase II Dose Selection

GPR40 mediates free fatty acid–induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK‐8666, a partial GPR40 agonist, after once‐daily multiple dosing in type 2 diabetes patients. This double‐blind, multisite, parallel‐group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14‐day treatment. The results showed no serious adverse effects or treatment‐related hypoglycemia. One patient (150‐mg group) showed mild‐to‐moderate transaminitis at the end of dosing. Median MK‐8666 T(max) was 2.0–2.5 h and mean apparent terminal half‐life was 22–32 h. On Day 15, MK‐8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer‐term assessment is projected at 500 mg based on exposure–response analysis. In conclusion, MK‐8666 was generally well tolerated with robust glucose‐lowering efficacy.