Gasiorek Agnes, Heydorn Arne, Gabery Sanaz, Hjerpsted Julie B, Kirkeby Katrine, Kruse Thomas, Petersen Signe B, Toubro Søren, Vegge Andreas, Key Cassandra
Research and Early Development, Novo Nordisk A/S, Måløv, Denmark.
Development, Novo Nordisk A/S, Søborg, Denmark.
Lancet. 2025 Jun 20. doi: 10.1016/S0140-6736(25)01176-6.
GLP-1 receptor agonists and amylin receptor agonists have shown clinically relevant weight loss and glucose-lowering effects in people with overweight, obesity, and type 2 diabetes. Amycretin is a novel, single-molecule GLP-1 receptor and amylin receptor agonist. We aimed to investigate the safety, tolerability, pharmacokinetic properties, and pharmacodynamic effects of single ascending doses (part A) and multiple ascending doses (parts B and C/D) of amycretin in adult participants with overweight or obesity.
In this phase 1, first-in-human, randomised, double-blind, placebo-controlled multipart study, participants were recruited at a single clinical research unit in San Antonio (TX, USA). Eligible individuals were men or women (including women of childbearing potential) aged 18-55 years at the time of signing informed consent with a BMI of 25·0-34·9 kg/m for parts A and B and a BMI of 27·0-39·9 kg/m for part C/D. For part A, participants were randomly assigned across six treatment groups (single ascending doses of oral amycretin [1 mg, 3 mg, 6 mg, 12 mg, 18 mg (12 + 6 mg per adaptive study design), or 25 mg]) or placebo (6:2 to amycretin groups vs placebo). Part A consisted of a 28-day screening period, a 1-day (single dose) intervention period, and a 21-day follow-up period. In part B, participants were randomly assigned across three treatment groups (multiple ascending doses of oral amycretin [3 mg, 6 mg, or 12 mg once daily]) or placebo (9:3 to amycretin groups vs placebo). Part B consisted of a 28-day screening period, a 10-day intervention period, and a 21-day follow-up period. In part C/D, 60 participants were randomly assigned to one of three dose-escalation treatment groups (multiple ascending doses of oral amycretin in a fixed titration regimen for all participants [part C1: from 3 mg to 50 mg once daily; part C2: from 6 mg to 2 × 50 mg (two tablets in a single daily dose); and part D: from 3 mg to 2 × 25 mg (two tablets in a single daily dose)]), or placebo (16:4 to amycretin groups vs placebo). Part C/D consisted of a 4-week screening period, a 12-week intervention period, and a 3-week follow-up period. The primary endpoint was the number of treatment-emergent adverse events reported from before dosing on day 1 (baseline) until the end-of-study visit on day 22 (part A), day 31 (part B), or day 105 (part C/D). Supportive secondary pharmacokinetic endpoints for parts A-D were area under the amycretin plasma concentration-time curve and maximum plasma concentration. Exploratory pharmacodynamic endpoints in part C/D were change in bodyweight (%) and fasting plasma glucose (mmol/L) from before dosing on day 1 until day 85. The safety analysis set, comprising all participants who were exposed to treatment, was used to analyse the endpoints and assessments related to safety. The full analysis set, comprising all randomly assigned participants, was used to analyse endpoints related to pharmacokinetic and exploratory pharmacodynamic endpoints. This study is registered with ClinicalTrials.gov, NCT05369390.
Between May 11, 2022, and Jan 9, 2024, 144 participants were enrolled in the study (48 participants in part A, 36 participants in part B, and 60 participants in part C/D). Across parts A-D, there were 364 treatment-emergent adverse events in 89 (62%) of 144 participants, all of which were mild or moderate in severity and increased in frequency in a dose-dependent manner. The most common treatment-emergent adverse events were gastrointestinal in nature (180 [49%] of 364 events), observed in 72 (81%) of 89 participants who reported a treatment-emergent adverse event. No deaths were reported. Amycretin plasma concentrations were consistent with dose proportionality across all treatment groups.
In people with overweight or obesity, amycretin appeared safe and tolerable. Results from this first-in-human, phase 1 study support further investigation of the weight loss properties of amycretin.
Novo Nordisk A/S.
胰高血糖素样肽-1（GLP-1）受体激动剂和胰淀素受体激动剂已在超重、肥胖和2型糖尿病患者中显示出具有临床意义的体重减轻和降糖作用。Amycretin是一种新型单分子GLP-1受体和胰淀素受体激动剂。我们旨在研究Amycretin在超重或肥胖成年参与者中单次递增剂量（A部分）和多次递增剂量（B部分和C/D部分）的安全性、耐受性、药代动力学特性和药效学作用。
在这项1期、首例人体、随机、双盲、安慰剂对照的多部分研究中，参与者在美国得克萨斯州圣安东尼奥的一个临床研究单位招募。符合条件的个体为签署知情同意书时年龄在18-55岁的男性或女性（包括有生育潜力的女性），A部分和B部分的体重指数（BMI）为25.0-34.9kg/m²，C/D部分的BMI为27.0-39.9kg/m²。对于A部分，参与者被随机分配到六个治疗组（口服Amycretin的单次递增剂量[1mg、3mg、6mg、12mg、18mg（根据适应性研究设计为12mg+每6mg）或25mg]）或安慰剂组（Amycretin组与安慰剂组的比例为6:2）。A部分包括28天的筛查期、1天（单剂量）干预期和21天的随访期。在B部分，参与者被随机分配到三个治疗组（口服Amycretin的多次递增剂量[3mg、6mg或12mg，每日一次]）或安慰剂组（Amycretin组与安慰剂组的比例为9:3）。B部分包括28天的筛查期、10天的干预期和21天的随访期。在C/D部分，60名参与者被随机分配到三个剂量递增治疗组之一（所有参与者采用固定滴定方案口服Amycretin的多次递增剂量[C1部分：从3mg到50mg，每日一次；C2部分：从6mg到2×50mg（每日单剂量两片）；D部分：从3mg到2×25mg（每日单剂量两片）]）或安慰剂组（Amycretin组与安慰剂组的比例为16:4）。C/D部分包括4周的筛查期、12周的干预期和3周的随访期。主要终点是从第1天给药前（基线）到第22天（A部分）、第31天（B部分）或第105天（C/D部分）的研究结束访视期间报告的治疗中出现的不良事件数量。A-D部分的支持性次要药代动力学终点是Amycretin血浆浓度-时间曲线下面积和最大血浆浓度。C/D部分的探索性药效学终点是从第1天给药前到第85天体重（%）和空腹血糖（mmol/L）的变化。安全性分析集包括所有接受治疗的参与者，用于分析与安全性相关的终点和评估。完整分析集包括所有随机分配的参与者，用于分析与药代动力学和探索性药效学终点相关的终点。本研究已在ClinicalTrials.gov注册，注册号为NCT05369390。
在2022年5月11日至2024年1月9日期间，144名参与者被纳入研究（A部分48名参与者，B部分36名参与者，C/D部分6名参与者）。在A-D部分，144名参与者中有89名（62%）出现364次治疗中出现的不良事件，所有这些不良事件的严重程度均为轻度或中度，且发生率呈剂量依赖性增加。最常见的治疗中出现的不良事件是胃肠道不良事件（364次事件中的180次[49%]），在报告治疗中出现不良事件的89名参与者中的72名（81%）中观察到。未报告死亡病例。所有治疗组的Amycretin血浆浓度与剂量成正比。
在超重或肥胖人群中，Amycretin似乎是安全且可耐受的。这项首例人体1期研究的结果支持对Amycretin的减肥特性进行进一步研究。
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