Endocrine Abstracts

Medical treatment of acromegaly is based on either suppressing pituitary growth hormone (GH) secretion or by inhibiting GH action by preventing interaction with its receptor in order to suppress the elevated levels of insulin-like growth factor 1 (IGF1). AZP-3813 is a 16-amino acid, bicyclic peptide antagonist of the GH receptor (GHR) with K_D of 1.9 nM for the human GHR. Previously, AZP-3813 was demonstrated to suppress IGF1 secretion in juvenile rats in a dose-related manner, and to maintain IGF1 suppression when given daily for extended periods. To examine the ability of AZP-3813 treatment to suppress IGF1 levels in normal dogs, we injected adult, non-fasted, male Beagle dogs subcutaneously with AZP-3813 at doses of 0.1, 1 or 10 mg/kg. Three dogs received a single 0.1 mg/kg dose of AZP-3813 and, after 7 days, the same dogs received a single 10 mg/kg dose of AZP-3813. A second group of three dogs received 1 mg/kg AZP-3813 daily for 5 days. Blood was collected 3 days and immediately before treatment, and at 15 min, 30 min, and 1, 2, 4, 8, 24, 48, 72 and 96 hours after the single injections of 0.1 and 10 mg/kg AZP-3813, and after the first and fifth injections for dogs receiving 1 mg/kg AZP-3813 daily for five days. Pre- and 24 hour post-injection samples were assayed for total IGF1 content by radioimmunoassay, and all samples were analyzed for AZP-3813 content by LC-MS/MS. Maximal blood concentrations (C_max) of AZP-3813 were observed 4 hours following injection, and were 0.72±0.028, 7.2±0.36 and 58.9±2.8 mg/ml for the 0.1, 1 and 10 mg/kg doses, respectively. After the fifth injection of 1 mg/kg, blood levels of AZP-3813 were 8.7±0.34 mg/ml, indicating compound accumulation. Elimination curves for all doses were parallel with a half-life of 14.2±0.47 hours. While the 0.1 mg/kg dose of AZP-3813 was ineffective (-2.2±7.1% decrease from baseline), 24 hours after injection of 1 and 10 mg/kg AZP-3813, IGF1 levels were suppressed by 21.4±2.7% and 27.8±1.5%, respectively. The repeated injection of 1 mg/kg AZP-3813 maintained a similar magnitude of IGF1 suppression through 72 hours following the fifth injection, while suppression of IGF1 was maintained at a similar level through 72 hours after the single injection of 10 mg/kg. These results demonstrate that the potent GHR antagonist activity of AZP-3813 translates to a sustained suppression of IGF1 in normal dogs and further support the development of AZP-3813 as a potential therapy for acromegaly.