Cibinetide: a synthetic 11 amino acid peptide

Introduction

Cibinetide, also known as ARA 290 and helix B surface peptide (HBSP), is a synthetic 11 amino acid peptide derived from the structure of the B helix of erythropoietin (EPO), with marked anti-apoptotic, anti-inflammatory and anti-permeability effects, recapitulating the effects of the endogenous EPO. Unlike EPO, it is not haematopoietic and, thus, is free of the possible side effects of EPO, which can be life-threatening (reviewed by Reid and Lois). In an experimental model of DR, cibinetide administered systemically inhibited vascular leakage and edema and protected against retinal blood vessel and neuroglial degeneration. Additionally, cibinetide led to improvements in metabolic control in both preclinical and clinical studies[1].

Uses

Cibinetide (ARA 290; helix B surface peptide) has high affinity and selectivity for the IRR. Despite a short plasma half-life, cibinetide triggers sustained biological effects when concentrations exceed the low nanomolar affinity of the receptor. Notably, in a mouse model of diabetic SNFL, daily administration of cibinetide reversed neuronal dystrophy. In neuropathic states the transient receptor potential vanilloid-1 (TRPV1) ion channel, a key integrator of nociception and neurogenic inflammation, undergoes upregulation and sensitization in peripheral small nerve fibers and central pain pathways. Recent data demonstrate that cibinetide antagonizes the TRPV1 channel of small nerve fibres and relieves mechanical hypersensitivity. Three prior clinical studies have shown that cibinetide reduces neuropathic symptoms and may promote nerve fibre repair in patients with sarcoidosis or diabetes-related SNFL.

Mechanism of action

ARA290 (cibinetide) mediates tissue protection by reducing inflammatory and fibrotic responses via signalling via a heterodimeric receptor composed of EPOR and CD131, the β common cytokine receptor, which also forms receptor complexes with the α receptor subunits specific for GM-CSF, IL-3, and IL-5[2].

The β-common-receptor acts in conjunction with the EPO receptor to form a heterocomplex that is rapidly up-regulated locally following tissue injury, initiating a local anti-inflammatory response, inhibition of death signals and anti-apoptosis that aids in preventing tissue damage. Chronic treatment with ARA290 reduces systemic inflammation by decreasing susceptibility to diet-induced insulin resistance, neuropathic pain in patients with type 2 diabetes and sarcoidosis associated small nerve loss. Additionally, ARA290 administration to rats improves survival following myocardial infarction, reduces organ dysfunction in mice during hemorrhagic shock, and suppresses the development of atherosclerosis in hyperlipidemic rabbits.

[1] Noemi Lois. “A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema.” Journal of Clinical Medicine (2020).

[2] Nolan M Winicki. “A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan.” Frontiers in Cardiovascular Medicine 9 (2022): 1096887.

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