美国礼来公司Paul J. Emmerson团队报道长效GDF15受体激动剂LY3463251的发现、开发和临床机制的证明。该项研究成果于2023年1月10日在线发表在《细胞—代谢》杂志上。

研究人员报道了一种GDF15的类似物——LY3463251，这是一种在GFRAL/RET受体上的强效激动剂，具有延长的药代动力学。在啮齿动物和肥胖的非人灵长类动物中，LY3463251减少了食物摄入量和体重，但没有不适或呕吐的迹象。在一项针对健康参与者的首次人体研究中，单次皮下注射LY3463251显示出安全性和药代动力学特征，这支持进一步的临床开发，但在一部分人中出现剂量依赖性恶心和呕吐。随后在超重和肥胖参与者中进行的为期12周的多剂量递增研究显示，LY3463251诱导食物摄入量和食欲评分明显下降，与适度的体重减轻有关，与恶心和呕吐无关（clinicaltrials.gov: NCT03764774）。这些观察表明，GFRAL/RET系统的激动作用可以调节人类的能量平衡，尽管体重的减少令人惊讶地温和，这表明在利用GDF15系统进行临床减肥应用方面存在挑战。

据介绍，GDF15及其受体GFRAL/RET形成了一个非内稳态的系统，其在临床前物种中调节食物摄入和体重。

附：英文原文

Author: Olivier Benichou, Tamer Coskun, Malgorzata D. Gonciarz, Parag Garhyan, Andrew C. Adams, Yu Du, James D. Dunbar, Jennifer A. Martin, Kieren J. Mather, Richard T. Pickard, Vincent L. Reynolds, Deborah A. Robins, Simbarashe P. Zvada, Paul J. Emmerson

Issue&Volume: 2023-01-10

Abstract: GDF15 and its receptor GFRAL/RET form a non-homeostatic system that regulates food intake and body weight in preclinical species. Here, we describe a GDF15 analog, LY3463251, a potent agonist at the GFRAL/RET receptor with prolonged pharmacokinetics. In rodents and obese non-human primates, LY3463251 decreased food intake and body weight with no signs of malaise or emesis. In a first-in-human study in healthy participants, single subcutaneous LY3463251 injections showed a safety and pharmacokinetic profile supporting further clinical development with dose-dependent nausea and emesis in a subset of individuals. A subsequent 12-week multiple ascending dose study in overweight and obese participants showed that LY3463251 induced significant decreases in food intake and appetite scores associated with modest body weight reduction independent of nausea and emesis (clinicaltrials.gov: NCT03764774). These observations demonstrate that agonism of the GFRAL/RET system can modulate energy balance in humans, though the decrease in body weight is surprisingly modest, suggesting challenges in leveraging the GDF15 system for clinical weight-loss applications.

DOI: 10.1016/j.cmet.2022.12.011

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00548-4