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

by Selleckchem | Sep 24 2023

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

Materials and methods: This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight.

Results: In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (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 of up to -67.89 (-88.98, -46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to -40.87 (-53.77, -27.98) mg/dl], glycated haemoglobin [up to -1.41% (-2.01%, -0.82%)] and body weight [up to -1.87 (-3.58, -0.17) kg].

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

Comments:

The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM).

The study was designed as a phase 1, randomized, double-blind, placebo-controlled, parallel-group trial. Adult Japanese participants with T2DM who had inadequate glycemic control despite diet and exercise were enrolled. The participants were randomly assigned to receive either placebo or escalating doses of danuglipron (40, 80, or 120 mg) orally twice daily for a duration of 8 weeks. The primary objective was to assess the safety and tolerability of danuglipron, while secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters, and body weight.

The study included a total of 37 randomized participants. The most frequently reported treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhea, and headache. These adverse events were generally mild to moderate in intensity. When measured at steady state on Day 56, danuglipron exposure showed dose-proportional increases. On Day 56, significant improvements were observed in mean daily glucose levels, with placebo-adjusted differences ranging up to -67.89 mg/dL (90% confidence interval: -88.98, -46.79). On Day 57, fasting plasma glucose levels decreased by up to -40.87 mg/dL, glycated hemoglobin levels decreased by up to -1.41%, and body weight decreased by up to -1.87 kg.

In conclusion, the study demonstrated that danuglipron exhibited dose-proportional increases in plasma exposure at steady state. Furthermore, it robustly reduced glycaemic parameters (mean daily glucose, fasting plasma glucose, glycated hemoglobin) and body weight after 8 weeks of treatment. The safety profile of danuglipron was consistent with its mechanism of action. These findings suggest that danuglipron may be a promising therapeutic option for Japanese adults with T2DM.