Designing a Mixed Agonist-Antagonist Peptide: A Case Study of OCE-205 in Advanced Liver Disease
Geoff Harris
Founder Ocelot Bio, Ocelot Bio
Systemic hemodynamic complications are a hallmark of decompensated liver cirrhosis. As liver fibrosis progresses, portal blood flow is impeded, leading to portal hypertension. This, in turn, leads to reflex splanchnic arteriolar vasodilation, further exacerbating portal hypertension in a vicious cycle. Ultimately, these hemodynamic disruptions manifest as tissue edema, fluid accumulation in the abdomen (ascites), and hypoperfusion of multiple organs, particularly the kidneys. Hypoperfusion of the kidneys can result in hepatorenal syndrome-acute kidney injury (HRS-AKI), a reversible form of renal failure. Treatments for these hemodynamic complications may include dietary modifications, diuretics, and albumin infusion. While indicated in HRS-AKI, the use of vasoconstrictors in this patient population is challenging, as striking the right balance between efficacy and safety related to excess vasoconstriction (ischemia-lack of blood flow) limits their use until late in disease progression.
To improve the benefit-risk ratio of vasoconstrictor therapy in advanced liver disease, OCE-205 was designed as a selective cyclic vasopressin V1a receptor agonist linked to a selective linear V1a antagonist. The agonist domain of OCE-205 causes desired vasoconstriction of the splanchnic vasculature, thereby reducing portal blood flow and pressure and improving patient systemic hemodynamics. The antagonist domain of OCE-205 was designed to prevent the full activation of V1a-mediated vasoconstrictive effects that drive safety concerns with other agents. The molecule is thought to bind in either orientation but only binds a single receptor at a time, therefore, mimicking the effect of a selective partial agonist. Further, at therapeutic concentrations, OCE-205 does not activate the vasopressin V2 receptor, which causes undesired water retention.
In preclinical disease models of cirrhosis, desired hemodynamic changes were demonstrated, and ascites improved. Two (2) phase 1 studies in healthy volunteers showed that both the pharmacokinetic and pharmacodynamic effects of OCE-205 are consistent with a mixed agonist-antagonist mechanism. Most adverse events were treatment related, generally mild or moderate in severity, and attributable to the drug’s expected pharmacologic effect.
These data suggest that OCE-205 is a suitable candidate for further development in HRS-AKI and for refractory ascites. A phase 2 study in HRS-AKI is underway (NCT05309200).
Geoff has a BS in biology from UCSD and a DVM and PhD from UC Davis. He has worked in the pharmaceutical industry for nearly 20 years and is the founder of Ocelot Bio, a VC backed pharmaceutical company.