Pharmacological Inhibition of Myostatin and Changes in Lean Body Mass and Lower Extremity Muscle Size in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

• Published in: The journal of clinical endocrinology and metabolism 2014-10, Vol.99 (10), p.E1967-E1975
• Main Authors: Padhi, Desmond, Higano, Celestia S, Shore, Neal D, Sieber, Paul, Rasmussen, Erik, Smith, Matthew R
• Format: Article
• Language: English
• Subjects: Adipose Tissue - drug effects; Adipose Tissue - pathology; Adult; Aged; Aged, 80 and over; Androgen Antagonists - administration & dosage; Androgen Antagonists - adverse effects; Androgen Antagonists - pharmacokinetics; Antibodies, Neutralizing - blood; Body Mass Index; Double-Blind Method; Humans; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - adverse effects; Leg; Male; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Myostatin - antagonists & inhibitors; Placebos; Prostatic Neoplasms - drug therapy; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-1271

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.