121-OR: Safety, Tolerability, and Metabolic Effects of Once-Weekly GL0034 (Utreglutide) in Individuals with Obesity—A Multiple Ascending Dose Study

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-121-or

RAJAMANNAR THENNATI, VINOD S. BURADE, MUTHUKUMARAN NATARAJAN, PRADEEP SHAHI, RAVISHANKARA NAGARAJA, SUDEEP K. AGRAWAL, THIERRY DUVAUCHELLE, ADOLFO GARCIA-OCANA, GUY A. RUTTER, RICHARD E. PRATLEY, BERNARD THORENS, TINA VILSBØLL

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Abstract

Introduction & Objective: GL0034 (GL), a once weekly glucagon-like peptide 1 receptor agonist, previously demonstrated significant reductions in body weight (BW) up to Day 22 in a single ascending dose study in individuals with obesity. This phase 1 study assessed the safety, tolerability and metabolic effects of GL after multiple ascending doses. Methods: Individuals with BMI ≥28 kg/m2 (N=24) were randomized (9:3) to subcutaneous GL, fixed doses (4 × 680 µg; cohort 1); or increasing doses (680, 900, 1520, 2000 µg; cohort 2) or placebo, once weekly for four weeks. Safety, tolerability and key metabolic parameters were assessed. Results: Most common adverse events (AE) were gastrointestinal (GI) with dose-dependent nausea, decreased appetite and vomiting. One individual with a GI related serious AE rapidly recovered upon treatment with intravenous rehydration. On Day 23, reduction was observed in all parameters from baseline (BL) with significant reductions in glucose area under the curve and HbA1c in both groups. In cohorts 1 & 2, BW reduction versus BL was 2.9 kg and 4.6 kg respectively on Day 29 (Table). Conclusions: In individuals with obesity, once weekly GL dosing for four weeks, demonstrated clinically relevant reductions in glucose, insulin, HbA1c, lipids and BW with an overall good tolerability. Disclosure R. Thennati: None. V.S. Burade: None. M. Natarajan: None. P. Shahi: None. R. Nagaraja: None. S.K. Agrawal: None. T. Duvauchelle: Consultant; Sun Pharmaceutical Industries Ltd. A. Garcia-Ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.A. Rutter: Advisory Panel; Sun Pharmaceutical Industries Ltd. R.E. Pratley: Other Relationship; Bayer AG, Dompé, Endogenex, Inc., Gasherbrum Bio, Inc., Hengrui (USA) Ltd., Intas Pharmaceuticals Ltd., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sun Pharmaceutical Industries Ltd. Consultant; AbbVie Inc., AstraZeneca. Other Relationship; Bayer HealthCare Pharmaceuticals, Inc., Biomea Fusion, Carmot Therapeutics, Inc., Corcept Therapeutics, Fractyl Health, Inc., Genprex. Consultant; Getz Pharma. Other Relationship; Lilly USA LLC, Sanofi. Consultant; Scholar Rock, Inc. B. Thorens: Advisory Panel; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Consultant; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Mundipharma. Advisory Panel; Novo Nordisk, Lilly Diabetes, Sanofi. Speaker's Bureau; Bayer Inc., Gilead Sciences, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. Research Support; Lilly Diabetes.

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121-OR：肥胖症患者每周一次服用GL0034（乌曲鲁肽）的安全性、耐受性和代谢作用--一项多剂量递增研究

引言& 目的：GL0034 (GL)是一种每周一次的胰高血糖素样肽1受体激动剂，之前在一项针对肥胖症患者的单次递增剂量研究中，该药在第22天之前都能显著降低体重（BW）。这项 1 期研究评估了 GL 在多次升剂量后的安全性、耐受性和代谢效应。研究方法：将体重指数≥28 kg/m2的患者（24 人）随机（9:3）分配到皮下注射 GL，固定剂量（4 × 680 µg；组别 1）；或递增剂量（680、9000、1520、2000 µg；组别 2）或安慰剂，每周一次，连续四周。对安全性、耐受性和主要代谢参数进行了评估。结果显示最常见的不良反应（AE）是胃肠道反应（GI），包括剂量依赖性恶心、食欲下降和呕吐。一名患者出现了与胃肠道相关的严重不良反应，经静脉补液治疗后迅速恢复。第 23 天，观察到所有参数都比基线（BL）有所下降，两组的血糖曲线下面积和 HbA1c 都显著降低。第 29 天，第 1 组和第 2 组的体重与基线相比分别减少了 2.9 千克和 4.6 千克（见表）。结论：在肥胖症患者中，每周一次 GL 给药，持续四周，可显著降低血糖、胰岛素、HbA1c、血脂和体重，总体耐受性良好。披露 R. Thennati：无。V.S. Burade：无。M. Natarajan：无。P. Shahi：无：P. Shahi: None.R. Nagaraja: None.S.K. Agrawal：无。T. Duvauchelle：太阳制药工业有限公司顾问。A. Garcia-Ocana：顾问；太阳制药工业有限公司G.A. Rutter：顾问团；太阳制药工业有限公司R.E. Pratley：其他关系；拜耳股份公司、Dompé、Endogenex, Inc.、Gasherbrum Bio, Inc.、恒瑞（美国）有限公司、Intas Pharmaceuticals Ltd.、礼来公司、Merck Sharp & Dohme Corp.、诺和诺德公司、辉瑞公司、Rivus Pharmaceuticals Inc.、太阳制药工业有限公司。顾问；艾伯维公司、阿斯利康公司。其他关系；Bayer HealthCare Pharmaceuticals, Inc.、Biomea Fusion、Carmot Therapeutics, Inc.、Corcept Therapeutics、Fractyl Health, Inc.、Genprex。顾问；Getz Pharma。其他关系；礼来美国有限责任公司、赛诺菲。顾问；Scholar Rock, Inc.B. Thorens：顾问; Sun Pharmaceutical Industries Ltd.T. Vilsbøll：顾问; AstraZeneca.顾问团；勃林格殷格翰公司。Speaker's Bureau; Mundipharma.顾问团；诺和诺德、礼来糖尿病、赛诺菲。Speaker's Bureau; Bayer Inc.、Gilead Sciences, Inc.顾问团；太阳制药工业有限公司研究支持；礼来糖尿病

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.