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Clinical Trial
. 2017 Sep;10(5):404-411.
doi: 10.1111/cts.12479. Epub 2017 Jul 20.

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

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
Clinical Trial

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

A W Krug et al. Clin Transl Sci. 2017 Sep.

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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Figures

Figure 1
Figure 1
Mean fasting plasma glucose concentrations over time by treatment group (mean ± standard error).
Figure 2
Figure 2
Mean plasma concentration profiles for MK‐8666 following administration of daily oral doses of 50 mg, 150 mg, and 500 mg for 1 day or 14 days to fasted adults with type 2 diabetes (mean ± SE). (a) Linear scale. (b) Semilogarithmic scale.
Figure 3
Figure 3
MK‐8666 mean simulated fasting plasma glucose lowering (placebo‐corrected reduction from baseline) vs. dose from translational PK/PD model, with observed mean (90% CI) study results.
Figure 4
Figure 4
Pharmacokinetic/pharmacodynamic model 12‐week HbA1c dose–response predictions for MK‐8666.14 The number of subjects per dose was 200, and 1,000 simulations were run with uncertainty in population mean parameters and no variability. The shaded region is the confidence interval of the mean.
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