Non‐Clinical Pharmacology and Safety Evaluation of TH9507, a Human Growth Hormone‐Releasing Factor Analogue

Abstract

TH9507, an analogue of human growth hormone-releasing factor (hGRF(1-44)NH 2 ) minimally modified by addition of a trans -3-hexenoyl moiety to Tyr 1 of the amino acid sequence, was found to be resistant to dipeptidyl aminopeptidase-IV deactivation. Compared to natural hGRF(1-44)NH 2 , the modification slowed the in vitro degradation of the peptide in rat, dog and human plasma and prolonged the in vivo plasma elimination kinetics of immunoreactive TH9507. Plasma growth hormone and insulin-like growth factor-1 (IGF-1) markedly increased in pigs, rats and dogs after daily repeat intravenous or subcutaneous injections of TH9507 at doses up to 600 µ g /kg. Subchronic toxicity studies in rats and dogs with TH9507 treatment for up to 4 months showed a significant, but not dose-related, increase in body weight gain associated with increased biomarker response. Although TH9507 was well tolerated by both rats and dogs, a more pronounced anabolic effect and more evident (reversible) adverse effects (liver and kidney findings, anaemia, clinical chemistry changes, organ weight effects) were observed in dogs after repeat daily subcutaneous injections, which were attributed to prolonged exposure to supraphysiological levels of growth hormone and/or IGF-1. In both rats and dogs, toxicokinetic evaluations indicated that exposure to immunoreactive TH9507 was dose related after both routes of administration. The apparent elimination t 1/2 in dogs ranged from 21 to 45 min. In conclusion, TH9507 is a modified hGRF peptide having enhanced potency and duration of action. The adverse treatment-related effects in dogs appear to be associated with sustained exposure to supraphysiological levels of growth hormone and IGF-1 induced by prolonged TH9507 treatment.

Strategic Approaches to Optimizing Peptide ADME Properties

“…Even though Nacetylation and C-amidation are known to increase stability against exopeptidases, it was found to improve resistance against endopeptidases for EFK17 (EFKRIVQRIKDFLRNLV) peptide when applied in conjunction with amino acid substitutions (78). Tesamorelin has a hexenoyl group attached to the N-terminus tyrosine residue and has a much longer half-life (1 h) than the natural growth hormone-releasing hormone (GHRH, 6.8 min) (79).…”

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

“…Its advantage over that of classical GRF is that it has been stabilized, and therefore it maintains its biological activity in plasma (600). Tesamorelin markedly increases levels of both GH and IGF-1 (618,620,621), thus resulting in the physiologic effects of these two anabolic agents. Moreover, tesamorelin seems to increase both baseline and pulse GH secretion (622).…”

“…Current doses are 2 mg administered daily via subcutaneous injection. This ensures an 8-hour period of GH release, and side effects appear to be minor (618). However, the high price of this therapy is still a limiting factor for its widespread use (620).…”

“…Tesamorelin is a GRF analog composed of a 44-amino acid sequence (618,619). Its advantage over that of classical GRF is that it has been stabilized, and therefore it maintains its biological activity in plasma (600).…”

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

“…However, the pharmacokinetic properties of GHRH did not warrant further development, partly due to its DPP-IV-mediated rapid clearance. Synthetic analogues of GHRH were explored to address this, leading to the development of TH9507 (tesamorelin) where the addition of a hexenoyl moiety attached to the amino terminus resulted in a molecule found to be resistant to DPP-IV cleavage (55).…”