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.

中文翻译：

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34-OR：联合激活素 A 和肌肉生长抑制素阻断对身体成分的影响——1 期试验


简介：临床前数据表明肌肉生长抑制素和激活素 A 是肌肉质量的重要负调节剂。 Trevogrumab（一种单克隆抗体 [mAb]）结合并阻断肌肉生长抑制素信号传导，而 garetosmab（一种 mAb）结合并阻断激活素 A、AB 和 AC 信号传导。在此，评估了单独或联合施用 Trevogrumab 和 garetosmab 对健康参与者身体成分的影响。方法：这项第一阶段双盲安慰剂对照研究将健康男性和绝经后女性随机分配到研究的单剂量或多剂量部分。对于单剂量，女性接受：trevogrumab 6 mg/kg (n=6)；加瑞妥单抗 10 mg/kg (n=6)； Trevogrumab 6 mg/kg 和加瑞托单抗的组合（1 mg/kg，n=6；3 mg/kg，n=6；10 mg/kg，n=12）；或安慰剂（PBO；n=12）。对于多剂量，女性接受：每 4 周 10 mg/kg 的 garetosmab（第 4 周；n=6）或 PBO（n=2）；组合 Trevogrumab 6 mg/kg 和加瑞妥单抗 10 mg/kg，每 2 周一次 (n=6) 或 PBO (n=4)。在多剂量部分，男性接受 garetosmab 10 mg/kg Q4W (n=8) 或 PBO (n=8)。结果：trevogrumab 6 mg/kg + garetosmab 10 mg/kg 组大腿肌肉体积 (TMV) 较基线增加 7.7%（名义值 P<0.001，与 PBO 相比），trevogrumab 6 mg/kg 组大腿肌肉体积 (TMV) 较基线增加 4.6%（名义值 P<0.05 与 PBO 相比）单次给药后8周。 Trevogrumab 6 mg/kg + 加瑞妥单抗 10 mg/kg 组的总脂肪量和机器人脂肪量 (AFM) 较基线有所下降（-4.6% 和 -6.7%；与 PBO 相比，两者名义 P<0.05）。多次给药后，TMV 在 3 剂 trevogrumab 6 mg/kg + garetosmab 10 mg/kg 后最初增加，但在第 28 周时降至与 PBO 相似的水平； AFM 和内脏脂肪量较基线分别减少 14.3% 和 20.1%（与 PBO 相比，名义 P<0.05）。在任何积极治疗组中均未发现安全问题。 结论：曲沃鲁单抗和加瑞妥单抗的联合给药导致健康受试者 TMV 和瘦体重呈剂量依赖性、大于累加性增加，同时减少脂肪量。披露 D. Gonzalez Trotter：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. S. Donahue：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. C. Wynne：员工； NZCR。股票/股东； NZCR。 S. Ali：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. P. Parasoglou：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. A. Boyapati：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. K. Mohammadi：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. B.J. Musser：员工；再生元制药公司股票/股东； Merck Sharp & Dohme Corp. P. Meier：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. J. Mastaitis：员工； Regeneron Pharmaceuticals Inc. E. Gasparino：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. J. Trejos：员工；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. J.D. Davis：员工；再生元制药公司股票/股东；再生元制药公司 G.A.赫尔曼：雇员；再生元制药公司股票/股东； Regeneron Pharmaceuticals Inc. R. Pordy：员工；再生元制药公司 (Regeneron Pharmaceuticals Inc.) 资助再生元制药公司 (Regeneron Pharmaceuticals, Inc.)