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

• Published in: Clinical and translational science 2017-09, Vol.10 (5), p.404-411
• Main Authors: Krug, AW, Vaddady, P, Railkar, RA, Musser, BJ, Cote, J, Ederveen, AGH, Krefetz, DG, DeNoia, E, Free, AL, Morrow, L, Chakravarthy, MV, Kauh, E, Tatosian, DA, Kothare, PA
• Format: Article
• Language: English
• Subjects: Accuracy; Adult; Aged; Agonists; Beta cells; Blood Glucose - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Dosage; Dose-Response Relationship, Drug; Drug dosages; Employees; Endpoint Determination; Glucose; Humans; Hypoglycemia; Insulin; Insulin resistance; Insulin secretion; Least-Squares Analysis; Metabolism; Middle Aged; Models, Biological; Patients; Pharmacodynamics; Pharmacokinetics; Proof of Concept Study; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Secretion; Treatment Outcome
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.12479

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 Tmax 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.