Abstract：
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.
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.
摘要：
目的：本研究调查了安全性，耐受性,danugliproon（PF-06882961）的药代动力学和药效学，这是一部小说，口服小分子胰高血糖素样肽-1受体激动剂，日本2型糖尿病（T2DM）参与者。
方法：第一阶段，随机，双盲,安慰剂对照,平行组研究纳入了饮食和运动控制不足的日本2型糖尿病成年参与者.参与者每天两次口服安慰剂或多次递增剂量的danuglipron，在8周内每天两次滴定至40、80或120mg。主要结果是danuglipron的安全性和耐受性。次要和探索性结果包括血浆药代动力学，血糖参数和体重。
结果：在随机分组的37名参与者中，最常见的治疗引起的不良事件是恶心，呕吐,腹部不适,腹泻和头痛。大多数因治疗引起的不良事件为轻度或中度。在稳态下观察到danuglipron暴露参数的剂量成比例的增加(第56天)。在第56天，danuglipron的平均每日葡萄糖[最小二乘平均值（90％置信区间）安慰剂调整差异高达-67.89（-88.98，-46.79）mg/dl]和第57天，观察到空腹血糖[高达-40.87（-53.77，-27.98）mg/dl]的基线显着降低，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]。
结论：在患有T2DM的日本成年人中，在给药8周后，danuglipron在稳态下的血浆暴露量呈剂量比例增加，血糖参数和体重显著降低，具有与作用机制一致的安全性。
方法：第一阶段，随机，双盲,安慰剂对照,平行组研究纳入了饮食和运动控制不足的日本2型糖尿病成年参与者.参与者每天两次口服安慰剂或多次递增剂量的danuglipron，在8周内每天两次滴定至40、80或120mg。主要结果是danuglipron的安全性和耐受性。次要和探索性结果包括血浆药代动力学，血糖参数和体重。
结果：在随机分组的37名参与者中，最常见的治疗引起的不良事件是恶心，呕吐,腹部不适,腹泻和头痛。大多数因治疗引起的不良事件为轻度或中度。在稳态下观察到danuglipron暴露参数的剂量成比例的增加(第56天)。在第56天，danuglipron的平均每日葡萄糖[最小二乘平均值（90％置信区间）安慰剂调整差异高达-67.89（-88.98，-46.79）mg/dl]和第57天，观察到空腹血糖[高达-40.87（-53.77，-27.98）mg/dl]的基线显着降低，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]。
结论：在患有T2DM的日本成年人中，在给药8周后，danuglipron在稳态下的血浆暴露量呈剂量比例增加，血糖参数和体重显著降低，具有与作用机制一致的安全性。
