Additive effects of ALXN2420, a GH receptor antagonist, and octreotide on IGF1 suppression in vivo.

Abstract

Objective: Acromegaly is an endocrine disorder caused by the hypersecretion of growth hormone (GH) by a benign tumor of the pituitary that leads to insulin-like growth factor-1 (IGF1) overproduction. In most patients, somatostatin analogs (SSAs), the current first-line medical therapy for acromegaly, do not normalize IGF1 levels. This study aims to investigate the pre-clinical efficacy of ALXN2420, a novel, small peptide antagonist of the growth hormone receptor (GHR), being developed as a combination therapy to SSAs to further suppress and normalize IGF1 levels.

Design: In vitro and in vivo experiments were performed to investigate the efficacy of ALXN2420 in antagonizing the GHR and in reducing circulating IGF1 levels.

Methods: The binding affinity of ALXN2420 to GHR was determined by Surface Plasmon Resonance (SPR), and inhibition of GH-induced GHR activation was investigated in vitro in primary hepatocytes. The efficacy of ALXN2420 in suppressing IGF1 levels was evaluated in rats and dogs. The ability of ALXN2420 to reduce growth was determined in the juvenile rat model. Ultimately, the effect of combining ALXN2420 with a SSA in suppressing IGF1 was examined in rats.

Results: ALXN2420 bound to the human GHR and inhibited its activation by GH in vitro. In vivo, ALXN2420 administration efficiently reduced IGF1 levels, which was associated with reduced growth in juvenile rats. Importantly, when combined with a SSA, ALXN2420 demonstrated an additive effect on IGF1 reduction.

Conclusion: These results support the investigation of ALXN2420 as a combination therapy for the treatment of patients with acromegaly inadequately controlled by SSAs.