Endocrine Abstracts

Medical treatment of acromegaly is based on either suppressing pituitary GH secretion or inhibiting GH action by preventing interaction with its receptor in order to suppress the elevated levels of IGF1. AZP-3813 is a 16-amino acid, bicyclic peptide antagonist of the GH receptor (GHR) derived from peptide sequences discovered using a unique, cell-free in vitro transcription-translation system screened against the human GHR, and that was optimized by rational design to increase binding affinity, solubility and half-life. The K_D of AZP-3813 for the human GHR is 1.9 nM, and 18.5 nM for the rat GHR. The circulating half-life of AZP-3813 in the rat is 11.2 h. To examine the ability of AZP-3813 to antagonize the interaction between GH and its receptor in vivo and thereby reduce IGF1 levels, we injected normal, 5-week old (~150g), male Sprague Dawley rats subcutaneously either with vehicle or with AZP-3813 at doses of 0.3, 1, 3, 10 or 30 mg/kg BID or with 10 or 30 mg/kg QD (n=8/group). Blood samples were collected immediately prior to AZP-3813 injection and at 24, 48 and 72 h after injection, and were assayed for total IGF1 content by radioimmunoassay. Twenty-four hours after injection, IGF1 levels were suppressed in a dose-related manner, with maximal and similar degrees of suppression achieved with 30 mg/kg AZP-3813 administered either QD or BID (38.4 + 3.8% and 39.2 + 3.7% decrease from vehicle-treated controls, respectively). By 48 h post-injection, IGF1 levels had returned to the level observed in vehicle-treated control rats. In a follow-up experiment, AZP-3813 was administered subcutaneously daily for 4 days at a dose of 30 mg/kg, either QD or BID. As a comparator, the commercially available GH antagonist, pegvisomant, was also administered subcutaneously for 4 days at a dose of 100 mg/kg QD. Blood samples to be assayed for IGF1 were collected immediately prior to compound injection on all days, and at 24, 48 and 72 h after the last injection. IGF1 was maximally suppressed by AZP-3813 within 24 h after the first injection (47.2 + 2.6% decrease vs vehicle-treated controls), and, with continued treatment, the suppression was maintained through 24 h after the last injection. In contrast, pegvisomant treatment gradually lowered IGF1, reaching a maximal suppression of 32.5 + 3.6% 24 h after the third injection. These results demonstrate that the potent GHR antagonist activity exhibited by AZP-3813 translates to in vivo suppression of IGF1 levels, and support its development as a potential therapy for acromegaly.