title: A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile.
abstract: BACKGROUND
  Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect.
  
  
  OBJECTIVE
  To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092.
  
  
  METHODS
  Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies.
  
  
  RESULTS
  SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects.
  
  
  CONCLUSIONS
  SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.
authors.affiliation: Departments of Medical and Science (M.H.R.), Clinical Pharmacology (M.W.B.O.), Development Drug Metabolism and Pharmacokinetics (L.A.), Quantitative Clinical Pharmacology (S.K.), and Biostatistics (M.S.), Novo Nordisk A/S, DK 2880 Bagsværd, Denmark.
authors.forename: Michael Højby
authors.initials: MH
authors.lastname: Rasmussen
authors.forename: Minna W Brændholt
authors.initials: MW
authors.lastname: Olsen
authors.forename: Lene
authors.initials: L
authors.lastname: Alifrangis
authors.forename: Søren
authors.initials: S
authors.lastname: Klim
authors.forename: Mette
authors.initials: M
authors.lastname: Suntum
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006130:Growth Disorders / Q000188:drug therapy* / Q000378:metabolism; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D007279:Injections, Subcutaneous; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D055666:Lipopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012709:Serum Albumin / Q000378:metabolism*; D055815:Young Adult
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D055666:Lipopeptides; C000594654:NNC0195-0092; D010919:Placebos; D012709:Serum Albumin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I