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

  • Clin Transl Sci. 2017 Sep;10(5):404-411. doi: 10.1111/cts.12479.
A W Krug  1 ,  P Vaddady  1 ,  R A Railkar  1 ,  B J Musser  1 ,  J Cote  1 ,  Agh Ederveen  2 ,  D G Krefetz  3 ,  E DeNoia  4 ,  A L Free  5 ,  L Morrow  6 ,  M V Chakravarthy  1  7 ,  E Kauh  1 ,  D A Tatosian  1 ,  P A Kothare  1
Affiliations
  • 1. Merck & Co., Inc., Kenilworth, New Jersesy, USA.
  • 2. CBG-MEB, Utrecht, The Netherlands.
  • 3. PRA Health Sciences, Marlton, New Jersey, USA.
  • 4. ICON Development Solutions, San Antonio, Texas, USA.
  • 5. Pinnacle Research Group, Anniston, Alabama, USA.
  • 6. Profil Institute for Clinical Research, Chula Vista, California, USA.
  • 7. Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
PMID: 28727908 DOI: 10.1111/cts.12479
Abstract

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.

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