Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Translational Medicine, Novartis Institutes for BioMedical Research, Basel, Switzerland.
J Cachexia Sarcopenia Muscle. 2020 Dec;11(6):1525-1534. doi: 10.1002/jcsm.12639. Epub 2020 Dec 2.
Bimagrumab prevents activity of myostatin and other negative regulators of skeletal muscle mass. This randomized double-blind, placebo-controlled study investigated safety, pharmacokinetics (PK), and pharmacodynamics of bimagrumab in healthy older and obese adults.
A cohort of older adults (aged 70-85 years) received single intravenous infusions of bimagrumab 30 mg/kg (n = 6) or 3 mg/kg (n = 6) or placebo (n = 4) and was followed for 20 weeks. A second cohort of obese participants [body mass index (BMI) 30-45 kg/m , aged 18-65 years] received a single intravenous infusion of bimagrumab 30 mg/kg (n = 6) or placebo (n = 2) and was followed for 12 weeks. Outcomes included the safety, tolerability, and PK of bimagrumab, in both cohorts. Measures of pharmacodynamics were performed in the older adult cohort to evaluate the effects of bimagrumab on thigh muscle volume (TMV), total lean body mass (LBM), total fat body mass, and muscle strength.
All 24 randomized participants completed the study. The older adults had a mean (±SD) age of 74.5 ± 3.4 years and BMI of 26.5 ± 3.5 kg/m . The obese participants had a mean (±SD) age of 40.4 ± 11.8 years, weight of 98.0 ± 11.3 kg, and BMI of 34.3 ± 3.9 kg/m . Adverse events in both cohorts were mostly mild. In older adults, most commonly reported adverse events were upper respiratory tract infection, rash, and diarrhoea (each 3/16, 19%). Obese participants reported muscle spasms and rash (both 5/8, 63%) most often. Non-linearity was observed in the PK concentration profiles of both cohorts due to target-mediated drug disposition. Bimagrumab 3 and 30 mg/kg increased mean (±SD) TMV (Week 4: 5.3 ± 1.8% and 6.1 ± 2.2%, vs. placebo: 0.5 ± 2.1%, both P ≤ 0.02) and LBM (Week 4: 6.0 ± 3.2%, P = 0.03 and 2.4 ± 2.2%, vs. placebo: 0.1 ± 2.4%), which were maintained longer with higher dose level, while total fat body mass (Week 4: -2.7 ± 2.9% and -1.6 ± 3.0%, vs. placebo: -2.3 ± 3.2%) decreased from baseline in older adults, with no change in muscle strength.
Bimagrumab was safe and well tolerated and demonstrated similar PK in older and obese adults. A single dose of bimagrumab rapidly increased TMV and LBM and decreased body adiposity in older adults. Muscle hypertrophy and fat loss were sustained with extended drug exposure.
比马鲁单抗可抑制肌肉生长抑制素和其他骨骼肌质量负调控因子的活性。这项随机、双盲、安慰剂对照研究旨在探究健康老年和肥胖成年人中单次静脉输注比马鲁单抗的安全性、药代动力学（PK）和药效学。
一组老年受试者（年龄 70-85 岁）接受 30mg/kg（n=6）或 3mg/kg（n=6）或安慰剂（n=4）单次静脉输注比马鲁单抗，并随访 20 周。另一组肥胖受试者[体重指数（BMI）30-45kg/m ，年龄 18-65 岁]接受 30mg/kg（n=6）或安慰剂（n=2）单次静脉输注比马鲁单抗，并随访 12 周。两组的主要终点均为比马鲁单抗的安全性、耐受性和 PK。在老年受试者队列中进行药效学测量，以评估比马鲁单抗对大腿肌肉量（TMV）、总瘦体重（LBM）、总脂肪体重和肌肉力量的影响。
所有 24 名随机受试者均完成了研究。老年受试者的平均（±SD）年龄为 74.5±3.4 岁，BMI 为 26.5±3.5kg/m 。肥胖受试者的平均（±SD）年龄为 40.4±11.8 岁，体重为 98.0±11.3kg，BMI 为 34.3±3.9kg/m 。两组的不良反应大多为轻度。在老年受试者中，最常见的不良反应为上呼吸道感染、皮疹和腹泻（均为 3/16，19%）。肥胖受试者报告肌肉痉挛和皮疹（均为 5/8，63%）最常见。由于靶器官介导的药物处置，两组的 PK 浓度曲线均呈现非线性。3 和 30mg/kg 剂量的比马鲁单抗使 TMV（第 4 周：5.3±1.8%和 6.1±2.2%，安慰剂：0.5±2.1%，均 P≤0.02）和 LBM（第 4 周：6.0±3.2%，P=0.03 和 2.4±2.2%，安慰剂：0.1±2.4%）增加，且高剂量组维持时间更长，而总脂肪体重（第 4 周：-2.7±2.9%和-1.6±3.0%，安慰剂：-2.3±3.2%）从基线下降，肌肉力量无变化。
比马鲁单抗安全且耐受良好，在老年和肥胖成年人中的 PK 特征相似。单次剂量的比马鲁单抗可使老年受试者的 TMV 和 LBM 迅速增加，并减少体脂。肌肉肥大和脂肪减少可随药物暴露时间延长而持续。
Zotero 插件
