title: Pegylated long-acting human growth hormone possesses a promising once-weekly treatment profile, and multiple dosing is well tolerated in adult patients with growth hormone deficiency.
abstract: BACKGROUND
  Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration.
  
  
  OBJECTIVE
  Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD).
  
  
  METHODS
  Thirty-three adult patients with GHD, age 20-65 yr, body mass index 18.5-35.0 kg/m(2), and glycated hemoglobin of 8.0% or below. Fourteen days before randomization, subjects discontinued daily rhGH. NNC126-0083 (0.01, 0.02, 0.04, and 0.08 mg/kg) was given sc once weekly for 3 wk (NNC126-0083 for six subjects and placebo for two subjects). Blood samples were collected up to 168 h after the first and up to 240 h after the third dosing. Physical examination, antibodies, and local tolerability were assessed.
  
  
  RESULTS
  NNC126-0083 was well tolerated with no difference in local tolerability compared with placebo and with no signs of lipoatrophy. A more than dose-proportional exposure was observed at the highest NNC126-0083 dose (0.16 mg protein/kg). Steady-state pharmacokinetics seemed achieved after the second dosing. A clear dose-dependent pharmacodynamic response in circulating IGF-I levels was observed [from a predose mean (SD) IGF-I SD score of -3.2 (1.7) to peak plasma concentration of -0.5 (1.3), 1.6 (1.3), 2.1 (0.5), and 4.4 (0.9) in the four dose groups, respectively].
  
  
  CONCLUSIONS
  After multiple dosing of NNC126-0083, a sustained pharmacodynamic response was observed. NNC126-0083 has the potential to serve as an efficacious, safe, and well-tolerated once-weekly treatment of adult patients with GHD.
authors.affiliation: Aarhus University Hospital, DK-8000, Aarhus C, Denmark.
authors.forename: Esben
authors.initials: E
authors.lastname: Søndergaard
authors.forename: Marianne
authors.initials: M
authors.lastname: Klose
authors.forename: Mette
authors.initials: M
authors.lastname: Hansen
authors.forename: Birgit Sehested
authors.initials: BS
authors.lastname: Hansen
authors.forename: Marianne
authors.initials: M
authors.lastname: Andersen
authors.forename: Ulla
authors.initials: U
authors.lastname: Feldt-Rasmussen
authors.forename: Torben
authors.initials: T
authors.lastname: Laursen
authors.forename: Michael Højby
authors.initials: MH
authors.lastname: Rasmussen
authors.forename: Jens Sandahl
authors.initials: JS
authors.lastname: Christiansen
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001823:Body Composition; D015992:Body Mass Index; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D013006:Growth Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000172:deficiency* / Q000627:therapeutic use* / Q000031:analogs & derivatives; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D019382:Human Growth Hormone; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C558310:NNC126-0083