In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone

Oren Hershkovitz, Ahuva Bar-Ilan, Rachel Guy, Yana Felikman, Laura Moschcovich, Vivian Hwa, Ronald (Ron) Rosenfeld, Eyal Fima, Gili Hart

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)631-639
Number of pages9
JournalMolecular Pharmaceutics
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Human Growth Hormone
Growth Hormone
Peptides
Injections
Haplorhini
Half-Life
Somatotropin Receptors
Safety
Somatomedins
Chorionic Gonadotropin
Macaca mulatta
Toxicology
Compliance
Weight Gain
Sprague Dawley Rats
Pharmacokinetics
Therapeutics
Serum
In Vitro Techniques
Proteins

Keywords

  • growth hormone
  • growth hormone deficiency
  • long acting
  • pharmacodynamics
  • pharmacokinetics
  • recombinant fusion proteins

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone. / Hershkovitz, Oren; Bar-Ilan, Ahuva; Guy, Rachel; Felikman, Yana; Moschcovich, Laura; Hwa, Vivian; Rosenfeld, Ronald (Ron); Fima, Eyal; Hart, Gili.

In: Molecular Pharmaceutics, Vol. 13, No. 2, 01.02.2016, p. 631-639.

Research output: Contribution to journalArticle

Hershkovitz, O, Bar-Ilan, A, Guy, R, Felikman, Y, Moschcovich, L, Hwa, V, Rosenfeld, RR, Fima, E & Hart, G 2016, 'In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone', Molecular Pharmaceutics, vol. 13, no. 2, pp. 631-639. https://doi.org/10.1021/acs.molpharmaceut.5b00868
Hershkovitz, Oren ; Bar-Ilan, Ahuva ; Guy, Rachel ; Felikman, Yana ; Moschcovich, Laura ; Hwa, Vivian ; Rosenfeld, Ronald (Ron) ; Fima, Eyal ; Hart, Gili. / In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone. In: Molecular Pharmaceutics. 2016 ; Vol. 13, No. 2. pp. 631-639.
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