Pfizer Research and Development Japan, Tokyo, Japan.
P-One Clinic, Tokyo, Japan.
Diabetes Obes Metab. 2023 Mar;25(3):805-814. doi: 10.1111/dom.14928. Epub 2022 Dec 19.
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).
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.
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].
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.
本研究旨在评估新型口服小分子胰高血糖素样肽-1 受体激动剂 danuglipron（PF-06882961）在日本 2 型糖尿病（T2DM）患者中的安全性、耐受性、药代动力学和药效学。
这是一项在饮食和运动控制不佳的日本成年 T2DM 患者中进行的、为期 8 周的、1 期、随机、双盲、安慰剂对照、平行分组研究。参与者每日两次口服接受安慰剂或递增剂量的 danuglipron 治疗，剂量分别为 40、80 或 120mg，每天两次。主要终点为 danuglipron 的安全性和耐受性。次要和探索性终点包括血浆药代动力学、血糖参数和体重。
在 37 名随机分组的参与者中，最常见的治疗后不良事件是恶心、呕吐、腹部不适、腹泻和头痛。大多数治疗后不良事件为轻度或中度。在稳态（第 56 天）时，观察到 danuglipron 暴露参数呈剂量依赖性增加。与安慰剂相比，第 56 天，danuglipron 使平均每日血糖[最小二乘均值（90%置信区间），安慰剂校正差值高达-67.89（-88.98，-46.79）mg/dl]，第 57 天，空腹血糖[高达-40.87（-53.77，-27.98）mg/dl]，糖化血红蛋白[高达-1.41%（-2.01%，-0.82%）]和体重[高达-1.87（-3.58，-0.17）kg]显著降低。
在日本 T2DM 成年患者中，danuglipron 在稳态时血浆暴露呈剂量依赖性增加，给药 8 周后可显著降低血糖参数和体重，安全性与作用机制一致。
