美国礼来公司Zvonko Milicevic团队研究了新型三重GIP、GLP-1和胰高血糖素受体激动剂LY3437943治疗2型糖尿病患者的疗效与安全性。相关论文于2022年10月27日发表在《柳叶刀》杂志上。

使用多受体激动剂治疗2型糖尿病患者的高血糖和肥胖可改善短期和长期预后。LY3437943是一种对胰高血糖素、葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）受体具有激动剂活性的单肽，目前正在开发用于治疗2型糖尿病和肥胖及相关合并症。在一项为期12周的研究中，研究组分析了2型糖尿病患者每周多次服用LY3437943的安全性、药代动力学和药效学。

在临床1b期阶段，研究组在美国的四个中心进行了一项概念验证、双盲、安慰剂对照、随机、多剂量递增试验，招募患有2型糖尿病至少3个月的成年人（20–70岁），其糖化血红蛋白A1c（HbA1c）值为7.0–10.5%、体重指数为23–50 kg/m²、体重稳定（前3个月变化<5%）。参与者被随机分配在12周内每周皮下注射一次LY3437943、安慰剂或1.5 mg杜拉鲁肽。

共研究了五个递增剂量队列，每个队列随机分组，每个队列至少有9名参与者接受LY3437943，3名参与者接受安慰剂，1名参与者接受1.5 mg杜拉鲁肽。两个最高剂量队列中的最高剂量通过逐步递增获得。主要结局是研究LY3437943的安全性和耐受性，其次是描述药效学和药代动力学。对接受至少一剂研究药物的所有参与者进行安全性分析，并对接受至少1剂研究药物且具有可评估数据的所有参与者的药效学和药代动力学进行分析。

2019年12月18日至2020年12月28日，研究组共筛选了210人，其中72人入组，接受了至少一剂研究药物，并纳入了安全性分析。15名参与者服用安慰剂，5名参与者服用杜拉鲁肽1.5 mg，对于LY3437943，9名参与者服用0.5 mg，9名服用1.5 mg，11名服用3 mg，11名服用3/6 mg，12名服用3/6/9/12 mg。29名参与者提前终止了研究。33名（63%）、3名（60%）和8名（54%）分别接受LY3437943、杜拉鲁肽1.5 mg和安慰剂治疗的参与者报告了治疗引发的不良事件，其中胃肠道疾病是最常见的治疗引发不良事件。

LY3437943的药代动力学与剂量成正比，其半衰期约为6天。第12周，安慰剂校正后的三个最高剂量LY3437943组的平均日血糖与基线相比显著降低（3 mg组的最小二乘平均差为2.8 mmol/L；3/6 mg组为-3.1 mmol/L；3/6/9/12 mg组为-2.9 mmol/L）。在三个最高剂量组中，安慰剂校正后的sHbA1c也显著降低（3 mg组为-1.4%；3/6 mg组为-1.6%；3/6/9/12 mg组为-1.2%）。使用LY3437943进行安慰剂校正后的体重减少似乎是剂量依赖性的（3/6/9/12 mg组的体重减少达-8.96 kg）。

在这项早期研究中，LY3437943显示出可接受的安全性，其药代动力学表明适合每周给药一次。该发现以及葡萄糖和体重显著下降的药效学发现，为临床2期的开发提供了支持。

附：英文原文

Title: LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial

Author: Shweta Urva, Tamer Coskun, Mei Teng Loh, Yu Du, Melissa K Thomas, Sirel Gurbuz, Axel Haupt, Charles T Benson, Martha Hernandez-Illas, David A D’Alessio, Zvonko Milicevic

Issue&Volume: 2022-10-27

Abstract:

Background

Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study.

Methods

In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20–70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7·0–10·5%, body-mass index of 23–50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802.

Findings

Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference –2·8 mmol/L [90% CI –4·63 to –0·94] for 3 mg; –3·1 mmol/L [–4·91 to –1·22] for 3/6 mg; and –2·9 mmol/L [–4·70 to –1·01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (–1·4% [90% CI –2·17 to –0·56] for 3 mg; –1·6% [–2·37 to –0·75] for 3/6 mg; and –1·2% [–2·05 to –0·45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to –8·96 kg [90% CI –11·16 to –6·75] in the 3/6/9/12 mg group).

Interpretation

In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development.

DOI: 10.1016/S0140-6736(22)02033-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02033-5/fulltext