7145 Enhanced Ability of the Small Peptide GH Receptor Antagonist, AZP-3813, to Decrease IGF1 When Combined with the Somatostatin Analog, Octreotide
Authors: Ravel Guillaume , Berardet Corentin , Chalmey Clémentine , Kurasaki Haruaki , Tomiyama Tatsuya , Reid Patrick , Duracher David , Datta Rakesh , Aouadi Myriam , Culler Michael D 
Published: October 2024

Disclosure: G. Ravel: None. C. Berardet: Employee; Self; Amolyt Pharma. C. Chalmey: Employee; Self; Amolyt Pharma. H. Kurasaki: Employee; Self; Peptidream Inc. T. Tomiyama: Employee; Self; Peptidream Inc. P. Reid: Employee; Self; Peptidream Inc. D. Duracher: Employee; Self; Amolyt Pharma. R. Datta: Consulting Fee; Self; Amolyt Pharma. M. Aouadi: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma.

There is a strong rationale for combining a growth hormone (GH) receptor antagonist (GHRA) with somatostatin analog (SSA) therapy for acromegalic patients. While SSAs are the primary medical therapy for treatment of acromegaly, insulin-like growth factor 1 (IGF1) levels fail to normalize with SSA monotherapy in most patients. Even in patients with controlled IGF1, GH levels can remain elevated and induce symptoms by interacting with GH receptors throughout the body. In addition, while GHRAs have no significant effect on the causative pituitary tumor, SSAs can often induce tumor stabilization or shrinkage. AZP-3813 is a 16-amino acid, bicyclic peptide GHRA which has been demonstrated to potently decrease IGF1 in both rats and dogs. In order to examine the effect of combining AZP-3813 with a SSA in decreasing IGF1, 8-week old, male, Sprague Dawley rats were implanted subcutaneously with Alzet model 2002 minipumps containing either vehicle or the SSA, octreotide (OCT), at concentrations required to deliver either 20 or 40μg OCT/kg/day. Blood samples for IGF1 measurement were collected before, and 48 and 72 hours after pump implantation. Immediately following the 72-hour blood collection, rats from each infusion group were injected subcutaneously with either vehicle or AZP-3813 at 0.3, 1, 3, 10 or 30mg/kg (n=7/group). A subsequent blood sample was collected 24 hours after the injection of vehicle or AZP-3813, which also corresponded to 96 hours after pump implantation. Plasma levels of IGF1 were assessed by radioimmunoassay. In rats infused with vehicle, the 0.3mg/kg dose of AZP-3813 had no effect on IGF1 as compared with baseline; however, with higher doses a clear, dose-related decrease in IGF1 was observed ranging from -7 ± 3.0% with 1mg/kg AZP-3813 to -29 ± 2.0% with 30mg/kg. OCT infusion alone at 20μg/kg/day produced a -10 ± 3.6% decrease in IGF1, while injection of AZP-3813 into rats infused with 20μg/kg/day OCT, produced an enhanced, dose-related decrease, ranging from -7 ± 3.8% with 0.3mg/kg AZP-3813 to -38 ± 3.4% with 30mg/kg. A clear additive relationship was observed by focusing on the 3mg/kg dose of AZP-3813, which, alone, decreased IGF1 by -13 ± 2.8% in vehicle-infused rats. When injected into rats infused with OCT, which alone decreased IGF1 by -10 ± 3.6%, a combined decrease of -23 ± 3.3% was observed. The magnitude of the combined decrease was not statistically different from the decrease obtained with 30mg/kg AZP-3813 alone in vehicle-infused rats; thus, demonstrating a 10-fold increase in the effectiveness of AZP-3813 when combined with OCT. Similar results were observed with 40μg/kg/day OCT infusion. These results demonstrate the enhanced efficacy of AZP-3813 in decreasing IGF1 when combined with the SSA, OCT, and support the development of AZP-3813 as an add-on therapy in patients inadequately controlled with SSA treatment.

Presentation: 6/3/2024