A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese adults with type 2 diabetes mellitus
Ryosuke Ono 1, Kenichi Furihata 2, Yoshihiko Ichikawa 1, Yoshiomi Nakazuru 1, Arthur Bergman 3, Donal N Gorman 4, Aditi R Saxena 3

Aims: This research investigated the security, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), that is a novel, dental small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes (T2DM).

Materials and techniques: This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on dieting and exercise. Participants received two times-daily dental doses of placebo or multiple climbing doses of danuglipron titrated to 40, 80 or 120 mg two times daily over 8 days. The main effects were the security and tolerability of danuglipron. Secondary and exploratory outcomes incorporated plasma pharmacokinetics, glycaemic parameters and the body weight.

Results: Within the 37 participants randomized, the most typical treatment-emergent adverse occasions were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse occasions were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady condition (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference as high as -67.89 (-88.98, -46.79) mg/dl] as well as on Day 57 for fasting plasma glucose [as much as -40.87 (-53.77, -27.98) mg/dl], glycated haemoglobin [as much as -1.41% (-2.01%, -.82%)] and the body weight [as much as -1.87 (-3.58, -.17) kg].

Conclusions: In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady condition and robustly reduced glycaemic parameters and the body weight after 8 days of dosing, having a safety profile in conjuction with the mechanism of action.