title: A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.
abstract: The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis.
  
  
  BACKGROUND
  RANKL is an essential osteoclastic differentiation and activation factor.
  
  
  METHODS
  The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers.
  
  
  CONCLUSIONS
  Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of -81% in the 3.0 mg/kg AMG 162 group compared with -10% in the placebo group; serum NTX changes were -56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to approximately 3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.
authors.affiliation: Amgen Inc., Thousand Oaks, California 91320-1789, USA. Pbekker@amgen.com
authors.forename: Pirow J
authors.initials: PJ
authors.lastname: Bekker
authors.forename: Donna L
authors.initials: DL
authors.lastname: Holloway
authors.forename: Amy S
authors.initials: AS
authors.lastname: Rasmussen
authors.forename: Robyn
authors.initials: R
authors.lastname: Murphy
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Philip T
authors.initials: PT
authors.lastname: Leese
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Holmes
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: Alex M
authors.initials: AM
authors.lastname: DePaoli
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D015331:Cohort Studies; D003094:Collagen / Q000652:urine; D024042:Collagen Type I; D000069448:Denosumab; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood; D010455:Peptides / Q000652:urine; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002352:Carrier Proteins; D024042:Collagen Type I; D008562:Membrane Glycoproteins; D010281:Parathyroid Hormone; D010455:Peptides; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D003094:Collagen; D000469:Alkaline Phosphatase; D002118:Calcium