title: Pharmacological inhibition of myostatin and changes in lean body mass and lower extremity muscle size in patients receiving androgen deprivation therapy for prostate cancer.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  Four weekly s.c. 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.
authors: Department of Medical Sciences (D.P.) and Biostatistics (E.R.), Amgen Inc (D.P.), Thousand Oaks, California 91320; Department of Medicine (C.S.H.), University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; Carolina Urologic Research Center, (N.D.S.), Myrtle Beach, South Carolina 29579; Urological Associates of Lancaster (P.S.), Lancaster, Pennsylvania 17604; and Massachusetts General Hospital Cancer Center (M.R.S.), Boston, Massachusetts 02114.
authors: Desmond
authors: D
authors: Padhi
authors: Celestia S
authors: CS
authors: Higano
authors: Neal D
authors: ND
authors: Shore
authors: Paul
authors: P
authors: Sieber
authors: Erik
authors: E
authors: Rasmussen
authors: Matthew R
authors: MR
authors: Smith
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000097:blood; D015992:Body Mass Index; D004311:Double-Blind Method; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects*; D007866:Leg; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D055435:Myostatin / Q000037:antagonists & inhibitors*; D010919:Placebos; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: C000594655:AMG 745; D000726:Androgen Antagonists; D057134:Antibodies, Neutralizing; D007141:Immunoglobulin Fc Fragments; C525911:MSTN protein, human; D055435:Myostatin; D010919:Placebos; D011993:Recombinant Fusion Proteins