LY3298176，一种新型的双重GIP和GLP-1受体激动剂，用于治疗2型糖尿病:从发现到临床概念证明。

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Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A

LY3298176，一种新型的双重GIP和GLP-1受体激动剂，用于治疗2型糖尿病:从发现到临床概念证明。

Mol Metab. 2018年12月;18:3-14。doi: 10.1016 / j.molmet.2018.09.009。Epub 2018年10月3日

PubMed ID

30473097 (PubMed视图

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摘要

目的:开发了一种新型的双重GIP和GLP-1受体激动剂LY3298176，以确定GIP的代谢作用是否增加了2型糖尿病(T2DM)中选择性GLP-1受体激动剂的临床疗效。方法:LY3298176是一种具有双重GIP和GLP-1受体激动剂活性的脂肪酸修饰肽，设计每周一次皮下给药。LY3298176在体外，通过表达重组或内源性肠促胰岛素受体的细胞系的信号和功能分析，以及在小鼠体内，通过体重、食物摄入、胰岛素分泌和血糖谱进行了鉴定。1期随机、安慰剂对照、双盲研究由三部分组成:单剂量上升(SAD;剂量0.25-8 mg)和4周多次上升剂量(MAD;在健康受试者(HS)中进行剂量0.5-10 mg的研究，随后进行为期4周的多剂量1期b概念验证(POC;剂量0.5- 15mg)用于T2DM患者(ClinicalTrials.gov编号:NCT02759107)。滴定法测定剂量高于5mg，杜拉鲁肽(DU)作为阳性对照。主要目的是研究LY3298176的安全性和耐受性。 RESULTS: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity. CONCLUSIONS: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

引用本文的药物库数据

药物

Tirzepatide

药物靶点

药物	目标	种类	生物	药理作用	行动
Tirzepatide	抑胃多肽	蛋白质	人类	是的	受体激动剂	细节
Tirzepatide	胰高血糖素样肽1受体	蛋白质	人类	是的	受体激动剂	细节

药物载体

药物	航空公司	种类	生物	药理作用	行动
Tirzepatide	血清白蛋白	蛋白质	人类	未知的	粘结剂	细节