Additive effect of combined treatment with the small peptide GH receptor antagonist, AZP-3813, and the somatostatin analog, octreotide, in decreasing IGF1 levels in the rat

Guillaume Ravel; Corentin Berardet; Clementine Chalmey; Haruaki Kurasaki; Tatsuya Tomiyama; Patrick Reid; David Duracher; Rakesh Datta; Myriam Aouadi; Michael Culler

doi:10.1530/endoabs.99.P333

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Endocrine Abstracts (2024) 99 P333 | DOI: 10.1530/endoabs.99.P333

ECE2024 Poster Presentations Pituitary and Neuroendocrinology (120 abstracts)

Additive effect of combined treatment with the small peptide GH receptor antagonist, AZP-3813, and the somatostatin analog, octreotide, in decreasing IGF1 levels in the rat

Guillaume Ravel ¹ , Corentin Berardet ¹ , Clémentine Chalmey ¹ , Haruaki Kurasaki ² , Tatsuya Tomiyama ² , Patrick Reid ² , David Duracher ¹ , Rakesh Datta ³ , Myriam Aouadi ¹ & Michael Culler ³

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¹Amolyt Pharma, Écully, France; ²PeptiDream Inc, Kawasaki City, Kanagawa, Japan; ³Amolyt Pharma, Cambridge, Massachusetts, United States

While somatostatin analogs (SSA) are the primary medical therapy for treatment of acromegaly, they fail to normalize insulin-like growth factor 1 (IGF1) levels in the majority of patients when used as monotherapy. Even in patients with controlled IGF1, growth hormone (GH) levels can remain elevated and induce symptoms by interacting with GH receptors throughout the body. AZP-3813 is a 16-amino acid, bicyclic peptide GH receptor antagonist (GHRA) which has been demonstrated to potently decrease IGF1 in both rats and dogs. To examine the effect of adding AZP-3813 to SSA treatment to decrease 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 a dose of 20μg 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 both infusion groups were injected subcutaneously with either vehicle or AZP-3813 at 0.3, 1, 3, 10 or 30 mg/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. Seventy-two hours after initiating OCT infusion, IGF1 was decreased by -10 ± 3.6%, as compared to baseline, while vehicle-infused rats showed a 2 ± 2.8% increase. Injection of AZP-3813 into the vehicle-infused rats produced a dose-related decrease in IGF1 that was significantly different from baseline with doses from 3 to 30 mg/kg, decreasing IGF1 by -13 ± 2.8 to -29 ± 2.0%, respectively. When AZP-3813 was injected into OCT-infused rats, a clear, additive effect was observed with the same 3 to 30 mg/kg doses of AZP-3813 now producing a dose-related decrease in IGF1 ranging from -23 ± 3.3 to -38 ± 3.4%. The magnitude of the decrease in IGF1 obtained with the 3 mg/kg dose of AZP-3813 combined with OCT infusion was not statistically different from the decrease in IGF1 obtained with the 30 mg/kg dose of AZP-3813 alone in vehicle-infused rats; thus, demonstrating a 10-fold increase in the effectiveness of AZP-3813 when combined with OCT. 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 treatment for patients inadequately controlled with SSA monotherapy.