OCE-205, a Selective V1a Partial Agonist, Reduces Portal Pressure in Rat Models of Portal Hypertension

Abstract

Purpose Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists. Methods We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT). For both models, OCE-205 was administered as a subcutaneous bolus injection. Thirty male Wistar rats were fed a methionine/choline-deficient (MCD) diet to model PHT. Animals received OCE-205 (10, 25, 100, or 500 µg/kg) or intra-arterial terlipressin (100 µg/kg). In a more severe model of PHT, 11 male Sprague Dawley rats had the common bile duct surgically ligated (BDL) and received OCE-205. Portal pressure (PP) and mean arterial pressure (MAP) were measured. Results For PP in the MCD model, MAP increased while PP decreased in rats treated with OCE-205 or terlipressin; the peak changes to MAP were 14.7 and 33.5 mmHg, respectively. Changes in MAP began to plateau after 10 min in the OCE-205 groups, whereas in the terlipressin group, MAP rapidly increased and peaked after 20 min. Across all treatment groups in the BDL model, a dose-related decrease from baseline in PP was observed following OCE-205, plateauing as the dose increased. In all treatment groups, PP change remained negative throughout the 30-min testing period. In both PHT rat models, a reduction in PP was coupled to an increase in MAP, with both plateauing in dose–response curves. Conclusion Data support OCE-205 as a promising candidate for further development. Institutional Protocol Number Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee on July 13, 2011, under protocol FRI-07-0002.

Review article: Recent advances in ascites and acute kidney injury management in cirrhosis

“…In addition, it does not have any affinity for the V2 receptor, and therefore is not associated with water retention and the associated risk for volume overload. In a rat model of cirrhosis and another rat model of portal hypertension without significant liver fibrosis, the use of OCE205 was able to increase the mean arterial pressure to within the desired range for efficacy and safety while decreasing portal pressure in both rat models 124 . Currently, there is a clinical trial assessing the efficacy of various doses OCE205 in patients with HRS‐AKI (NCT05309200).…”