34-OR： Activin A 和 Myostatin 联合阻断剂对身体成分的影响--一期试验

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-34-or

DINKO GONZALEZ TROTTER, STEPHEN DONAHUE, CHRIS WYNNE, SHAZIA ALI, PRODROMOS PARASOGLOU, ANITA BOYAPATI, KUSHA MOHAMMADI, BRET J. MUSSER, PRETTY MEIER, JASON MASTAITIS, EVELYN GASPARINO, JESUS TREJOS, JOHN D. DAVIS, GARY A. HERMAN, ROBERT PORDY

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For single-dose, females received: trevogrumab 6 mg/kg (n=6); garetosmab 10 mg/kg (n=6); combination trevogrumab 6 mg/kg and garetosmab (1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=12); or placebo (PBO; n=12). For multiple‑dose, females received: garetosmab 10 mg/kg every 4 weeks (Q4W; n=6) or PBO (n=2); combination trevogrumab 6 mg/kg and garetosmab 10 mg/kg every 2 weeks (n=6) or PBO (n=4). In the multiple dose part, males received garetosmab 10 mg/kg Q4W (n=8) or PBO (n=8). Results: Thigh muscle volume (TMV) increased from baseline 7.7% with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (nominal P&lt;0.001 vs PBO) and 4.6% with trevogrumab 6 mg/kg (nominal P&lt;0.05 vs PBO) 8 weeks after single-dose. Total fat mass and android fat mass (AFM) decreased from baseline with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (-4.6% and -6.7%; both nominal P&lt;0.05 vs PBO). 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引用次数: 0

摘要

导言临床前数据表明，肌生成素和激活素 A 是肌肉质量的重要负性调节因子。Trevogrumab（一种单克隆抗体[mAb]）能结合并阻断肌生成素信号，而 garetosmab（一种 mAb）能结合并阻断激活素 A、AB 和 AC 信号。在此，我们评估了单独或联合使用曲妥珠单抗和加瑞妥单抗对健康参与者身体组成的影响。研究方法这项一期双盲安慰剂对照研究将健康男性和绝经后女性随机分为单剂量或多剂量研究。对于单剂量，女性接受：曲妥珠单抗 6 毫克/千克（n=6）；加瑞妥单抗 10 毫克/千克（n=6）；曲妥珠单抗 6 毫克/千克和加瑞妥单抗组合（1 毫克/千克，n=6；3 毫克/千克，n=6；10 毫克/千克，n=12）；或安慰剂（PBO；n=12）。在多剂量部分，女性接受：每4周一次（Q4W；n=6）或安慰剂（PBO；n=2），加雷托单抗10毫克/千克；每2周一次（n=6）或安慰剂（PBO；n=4），特瑞伏格鲁单抗6毫克/千克和加雷托单抗10毫克/千克的组合。在多剂量部分，男性接受加雷托单抗10毫克/千克，每4周一次（n=8）或PBO（n=8）。结果单剂量8周后，trevogrumab 6 mg/kg + garetosmab 10 mg/kg的大腿肌肉体积（TMV）比基线增加了7.7%（标称P<0.001 vs PBO），trevogrumab 6 mg/kg的大腿肌肉体积（TMV）比基线增加了4.6%（标称P<0.05 vs PBO）。trevogrumab 6 mg/kg + garetosmab 10 mg/kg的总脂肪量和甲状腺脂肪量（AFM）比基线下降（-4.6%和-6.7%；名义P<0.05 vs PBO）。多次给药后，TMV最初在3次给药trevogrumab 6 mg/kg + garetosmab 10 mg/kg后增加，但在第28周时降至与PBO相似的水平；AFM和内脏脂肪量分别比基线减少了14.3%和20.1%（与PBO相比，两者的标称P<0.05）。所有积极治疗组均未发现安全问题。结论trevogrumab和加雷托莫单抗联合用药可导致TMV和瘦体重的剂量依赖性、大于加成的增加，同时降低健康参与者的脂肪量。披露 D. Gonzalez Trotter：雇员；Regeneron Pharmaceuticals Inc.股票/股东；Regeneron Pharmaceuticals Inc.S. Donahue：员工；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.C. Wynne：员工；NZCR.股票/股东; NZCR.S. Ali：员工；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.P. Parasoglou：员工；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.A. Boyapati：员工；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.K. Mohammadi：雇员；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.B.J. Musser：员工；Regeneron Pharmaceuticals Inc.股票/股东; Merck Sharp & Dohme Corp.P. Meier：雇员；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.J. Mastaitis：员工；Regeneron Pharmaceuticals Inc.E. Gasparino：员工；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.J. Trejos：员工；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.J.D. Davis：雇员；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.G.A. Herman：雇员；Regeneron Pharmaceuticals Inc.股票/股东; Regeneron Pharmaceuticals Inc.R. Pordy：雇员；Regeneron Pharmaceuticals Inc.资助Regeneron Pharmaceuticals, Inc.

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34-OR: The Effect of Combined Activin A and Myostatin Blockade on Body Composition—A Phase 1 Trial

Introduction: Preclinical data suggest myostatin and activin A are important negative regulators of muscle mass. Trevogrumab (a monoclonal antibody [mAb]) binds and blocks myostatin signalling, while garetosmab (a mAb) binds and blocks activin A, AB and AC signalling. Here, the effects of administering trevogrumab and garetosmab, alone or in combination, on body composition in healthy participants was assessed. Methods: This Phase 1, double-blind, placebo-controlled study randomized healthy males and postmenopausal females to single-dose or multiple-dose parts of the study. For single-dose, females received: trevogrumab 6 mg/kg (n=6); garetosmab 10 mg/kg (n=6); combination trevogrumab 6 mg/kg and garetosmab (1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=12); or placebo (PBO; n=12). For multiple‑dose, females received: garetosmab 10 mg/kg every 4 weeks (Q4W; n=6) or PBO (n=2); combination trevogrumab 6 mg/kg and garetosmab 10 mg/kg every 2 weeks (n=6) or PBO (n=4). In the multiple dose part, males received garetosmab 10 mg/kg Q4W (n=8) or PBO (n=8). Results: Thigh muscle volume (TMV) increased from baseline 7.7% with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (nominal P<0.001 vs PBO) and 4.6% with trevogrumab 6 mg/kg (nominal P<0.05 vs PBO) 8 weeks after single-dose. Total fat mass and android fat mass (AFM) decreased from baseline with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (-4.6% and -6.7%; both nominal P<0.05 vs PBO). After multiple-dose, TMV initially increased after 3 doses of trevogrumab 6 mg/kg + garetosmab 10 mg/kg but decreased to similar levels as PBO at Week 28; AFM and visceral fat mass decreased from baseline by 14.3% and 20.1%, respectively (both nominal P<0.05 vs PBO). No safety concerns were identified in any active treatment groups. Conclusion: Combined administration of trevogrumab and garetosmab led to dose-dependent, greater‑than‑additive increases in TMV and lean mass, while decreasing fat mass in healthy participants. Disclosure D. Gonzalez Trotter: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. S. Donahue: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. C. Wynne: Employee; NZCR. Stock/Shareholder; NZCR. S. Ali: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. P. Parasoglou: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. A. Boyapati: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. K. Mohammadi: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. B.J. Musser: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Merck Sharp & Dohme Corp. P. Meier: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J. Mastaitis: Employee; Regeneron Pharmaceuticals Inc. E. Gasparino: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J. Trejos: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J.D. Davis: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. G.A. Herman: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R. Pordy: Employee; Regeneron Pharmaceuticals Inc. Funding Regeneron Pharmaceuticals, Inc.

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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.