小柯机器人

辉瑞全球研发中心Albert M. Kim研究小组取得一项新突破。他们报道了Danuglipron (PF-06882961) 治疗 2 型糖尿病(T2D)的 1 期临床试验结果，这是一项随机、安慰剂对照、多剂量递增 试验。该研究于2021年6月14日发表于国际学术期刊《自然-医学》杂志。

研究人员研发了 danuglipron (PF-06882961)，这是一种口服小分子胰高血糖素样肽 1 受体 (GLP-1R) 激动剂，并发现它在人源化小鼠模型中具有与注射肽 GLP-1R 激动剂相当的功效。随后，研究人员开展并完成了一项安慰剂对照、随机、双盲、多次递增剂量的 1 期临床研究 (NCT03538743)，在该研究中，研究人员招募了98名有服用二甲双胍史的 T2D患者，并将他们随机分配接受多次剂量递增的danuglipron或安慰剂，治疗周期为28 d、有8个剂量梯度。

主要结果是评估不良事件 (AE)、安全测试、生命体征和 12 导联心电图。大多数具有轻微的AE，最常见的是恶心、消化不良和呕吐。各组实验室值中没有具有临床意义的AE。在第28天使用danuglipron 治疗时，心率通常会增加，但没有报告心率的AE。与安慰剂相比，第28天使用 danuglipron 治疗时收缩压略有下降，舒张压变化相似。没有具有临床意义的心电图结果。在这项 T2D 研究中，danuglipron 通常耐受性良好，其安全性与GLP-1R激动剂一致。

研究人员表示，GLP-1R激动剂有降低血糖和减轻体重的功效，是治疗 2 型糖尿病和肥胖症的一种治疗手段。

附：英文原文

Title: Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial

Author: Aditi R. Saxena, Donal N. Gorman, Ryan M. Esquejo, Arthur Bergman, Kristin Chidsey, Clare Buckeridge, David A. Griffith, Albert M. Kim

Issue&Volume: 2021-06-14

Abstract: Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study (NCT03538743), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism.

DOI: 10.1038/s41591-021-01391-w

Source: https://www.nature.com/articles/s41591-021-01391-w

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