title: In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone.
abstract: MOD-4023 is a novel long-acting version of human growth hormone (hGH), containing the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG). MOD-4023 is being developed as a treatment for adults and children with growth hormone deficiency (GHD), which would require fewer injections than currently available GH formulations and thus reduce patient discomfort and increase compliance. This study characterizes MOD-4023's binding affinities for the growth hormone receptor, as well as the pharmacokinetic and pharmacodynamics, toxicology, and safety profiles of repeated dosing of MOD-4023 in Sprague-Dawley rats and Rhesus monkeys. Although MOD-4023 exhibited reduced in vitro potency and lower affinity to the GH receptor than recombinant hGH (rhGH), administration of MOD-4023 every 5 days in rats and monkeys resulted in exposure comparable to daily rhGH, and the serum half-life of MOD-4023 was significantly longer. Repeated administration of MOD-4023 led to elevated levels of insulin-like growth factor 1 (IGF-1), and twice-weekly injections of MOD-4023 resulted in larger increase in weight gain with fewer injections and a lower accumulative hGH dose. Thus, the increased half-life of MOD-4023 in comparison to hGH may increase the frequency of protein-receptor interactions and compensate for its decreased in vitro potency. MOD-4023 was found to be well-tolerated in rats and monkeys, with minimal adverse events, suggesting an acceptable safety profile. These results provide a basis for the continued clinical development of MOD-4023 as a novel treatment of GHD in children and adults.
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Hershkovitz
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Ahuva
authors.initials: A
authors.lastname: Bar-Ilan
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Guy
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Yana
authors.initials: Y
authors.lastname: Felikman
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Laura
authors.initials: L
authors.lastname: Moschcovich
authors.affiliation: Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio 45229, United States.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.affiliation: Department of Pediatrics, Oregon Health & Science University , Portland, Oregon 97239, United States.
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Fima
authors.affiliation: OPKO Biologics , Nes Ziona 7414002, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Hart
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D006207:Half-Life; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D010446:Peptide Fragments; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I
keywords: growth hormone; growth hormone deficiency; long acting; pharmacodynamics; pharmacokinetics; recombinant fusion proteins