Endocrine Abstracts

Background: Acromegaly is a rare disease typically caused by a benign growth hormone (GH)-secreting pituitary adenoma that stimulates over-production of insulin-like growth factor-1 (IGF1) from the liver. Treatment with somatostatin analog (SSA) monotherapy does not provide optimal control of circulating IGF-1 levels in the majority of patients. AZP-3813, a 16-amino acid, bicyclic GH receptor antagonist (GHRA) binds to the GH receptor and prevents endogenous GH from stimulating the production of IGF-1. In normal animals, AZP-3813 potently decreases circulating levels of IGF-1 and further suppressive effects are observed when combined with the SSA, octreotide. AZP-3813 is being developed as an add-on therapy for the treatment of acromegaly in patients insufficiently controlled with SSAs.

Aim: To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZP-3813 in healthy subjects.

Methods: Randomized double-blind placebo-controlled single and multiple ascending dose studies (SAD and MAD, respectively) are being conducted. In the SAD study, 5 subjects received a single subcutaneous administration of 3 mg AZP-3813 or placebo (3:2) and 8 subjects received 10, 20, 40, 60, 90, 120 mg AZP-3813 or placebo (6:2). In the MAD study, 8 subjects received 10, 20, 40 mg AZP-3813 or placebo (6:2) QD for 14 consecutive days.

Results: Treatment was well tolerated in all subjects with no safety concerns. Cmax and AUC increased in a dose-proportional manner. The half-life of AZP-3813 was estimated to be 18-22 hours. In the SAD study, AZP-3813 induced a dose-related decrease in circulating IGF-1 levels at doses of 10 mg and above with a more prolonged reduction up to 72 hours at higher doses. In the MAD study, AZP-3813 induced a gradual and sustained dose-related decrease in circulating IGF-1 levels at 20 and 40 mg/day, with a larger effect after 2 weeks of dosing as compared to single administration at the same dose, consistent with a cumulative effect of repeated administration. Mean placebo-adjusted % change from baseline for the 20 and 40 mg cohorts were 19% and 44%, respectively. This study is ongoing, and updates on additional MAD cohorts will be reported at the meeting.

Conclusion: These data clearly demonstrate that the novel GHRA, AZP-3813, substantially decreases circulating IGF-1 levels in healthy individuals, thereby supporting further testing in patients with acromegaly.