Pharmacological Inhibition of Myostatin and Changes in Lean Body Mass and Lower Extremity Muscle Size in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer
Pharmacological Inhibition of Myostatin and Changes in Lean Body Mass and Lower Extremity Muscle Size in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer
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DOI：
10.1210/jc.2014-1271
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发表时间：
2014-10-01
影响因子：
5.8
通讯作者：
Smith, Matthew R.
中科院分区：
文献类型：
--
作者：
Padhi, Desmond;Higano, Celestia S.;Smith, Matthew R.
背景：肌肉生长抑制素是肌肉生长的负调节剂。雄激素剥夺（ADT）与肌肉损失和体脂增加有关，目前可用的疗法治疗这种并发症的疗效有限。抗肌生长抑制素肽体 (AMG 745/Mu-S) 显着减轻睾丸切除小鼠的肌肉损失并减少脂肪积累。 目的：本研究的目的是评估 AMG 745 在接受 ADT 治疗非转移性前列腺癌的男性中的安全性、药代动力学和肌肉功效。 方法：这是一项针对 AMG 745 进行的随机、盲法、安慰剂对照、多剂量、1 期研究， 28天。通过双 X 射线吸收测定法评估的去脂体重 (LBM) 相对于基线的百分比变化的终点是预先设定的。 结果：不良事件发生率（AMG 745 与安慰剂）如下：腹泻（13% vs 9%）、疲劳（13% vs 4%）、挫伤（10% vs 0%）和注射部位瘀伤（6% vs 4%）。暴露量从 0.3 mg/kg 线性增加至 3 mg/kg。与安慰剂组相比，第 29 天 AMG 745 使 3 mg/kg 组的 LBM 显着增加 2.2%（+/- 0.8% SE，P = 0.008）；在探索性脂肪量分析中，观察到减少了 -2.5%（+/- 1.0% SE，P = 0.021）。在第 29 天后 1 个月的随访中，肌肉和脂肪的药效学变化得以维持。结论：每周四次皮下注射 AMG 745 的耐受性良好，并且与接受 ADT 治疗非转移性前列腺癌的男性 LBM 增加和脂肪减少相关。结果支持在肌肉损失和萎缩的临床环境中进一步研究 AMG 745。
Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice.Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer.Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified.Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (+/- 0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of -2.5% (+/- 1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29.Conclusion: Four weekly sc doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.