Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 101, Issue 8, Pages 2744-2754Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.23229
Keywords
growth hormone; long acting; growth hormone deficiency; pharmacodynamics; pharmacokinetics; safety; hormones; protein delivery; glomerular filtration
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A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor binding without mutations to rhGH by genetically fusing with XTEN amino acid sequences to the N-terminus and the C-terminus of the native hGH sequence. Although in vitro potency of VRS-317 was reduced approximately 12-fold compared with rhGH, in vivo potency was increased because of the greatly prolonged exposure to the target tissues and organs. VRS-317 was threefold more potent than daily rhGH in hypophysectomized rats and fivefold more potent than daily rhGH in juvenile monkeys. In juvenile monkeys, a monthly dose of 1.4?mg/kg VRS-317 (equivalent to 0.26?mg/kg rhGH) caused a sustained pharmacodynamic response for 1 month equivalent to 0.05?mg/kg/day rhGH (1.4?mg/kg rhGH total over 28 days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110?h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14 weeks. VRS-317 also did not cause lipoatrophy in pig and monkey studies. VRS-317 is currently being studied in GH-deficient patients to confirm the observations in these animal studies. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:27442754, 2012
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