Long-acting PYY3−36 analogue with semaglutide for obesity: from preclinical assessment through randomized clinical studies

IF 4.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Obesity Pub Date : 2025-07-08 DOI:10.1002/oby.24329

Birgitte S. Wulff, Adam Paul Chambers, Cynthia Karenina Osorto Contreras, Katrine Kirkeby, Anders Rasmussen Rinnov, Riia K. Sustarsic, Søren Østergaard, John E. Laabs, Patrick M. O'Neil

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引用次数: 0

Abstract

Objective

The hormone peptide YY (PYY; cleaved into Y₂-selective form PYY_3-36) is an attractive candidate for use as a complementary pharmacotherapy for obesity along with glucagon-like peptide-1 (GLP-1) receptor agonists. This series of studies investigated a novel long-acting PYY_3-36 analogue (PYY1875) alone and as an add-on to semaglutide for treatment of obesity.

Methods

Weight loss and food intake were first investigated in obese male rats, followed by phase 1 and 2 clinical studies investigating efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of PYY1875 as monotherapy and in combination with semaglutide in participants with overweight or obesity.

Results

PYY1875 induced additional body weight loss in semaglutide-treated obese rats. In the phase 1 study, all doses of PYY1875 alone and coadministered with semaglutide were tolerated. In the phase 2 study, a modest but not clinically meaningful treatment effect of PYY1875 1.0 mg versus placebo as an add-on to semaglutide 2.4 mg was observed. However, gastrointestinal-related adverse events were common with the 1.0-mg PYY1875 dose, and the 2.0-mg PYY1875 dose escalation regimen was not tolerated (both as add-ons to semaglutide).

Conclusions

PYY1875 showed modest efficacy as an add-on to semaglutide for weight management in people with obesity, but the treatment was not well tolerated.

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联合西马鲁肽治疗肥胖症的长效PYY3 -36类似物：通过随机临床研究的临床前评估

目的：探讨激素肽YY (PYY；PYY3-36)与胰高血糖素样肽-1 （GLP-1）受体激动剂一起作为肥胖的补充药物治疗是一种有吸引力的候选药物。这一系列研究研究了一种新的长效PYY3-36类似物（PYY1875）单独使用，并作为西马鲁肽的附加治疗肥胖。方法：首先研究肥胖雄性大鼠的体重减轻和食物摄入情况，然后进行1期和2期临床研究，调查PYY1875作为单药治疗和与西马鲁肽联合治疗超重或肥胖参与者的疗效、安全性、耐受性、药代动力学和药效学。结果：PYY1875诱导西马鲁肽治疗的肥胖大鼠额外体重减轻。在1期研究中，PYY1875单独和与semaglutide共给药的所有剂量均耐受。在2期研究中，观察到PYY1875 1.0 mg与安慰剂相比，作为semaglutide 2.4 mg的附加治疗效果适度但没有临床意义。然而，胃肠道相关不良事件在1.0 mg PYY1875剂量组中很常见，而2.0 mg PYY1875剂量递增方案是不耐受的（两者都是作为semaglutide的附加方案）。结论：PYY1875作为西马鲁肽的附加治疗对肥胖患者的体重管理显示出适度的疗效，但治疗耐受性不佳。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Obesity 医学-内分泌学与代谢

CiteScore

11.70

自引率

1.40%

发文量

261

审稿时长

2-4 weeks

期刊介绍： Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.