OCE-205, a selective V1a receptor mixed agonist-antagonist, for the treatment of hepatorenal syndrome-acute kidney injury: A phase 2 randomized trial

Background and aims: OCE-205 is a mixed agonist-antagonist selective for the vasopressin 1a (V1a) receptor with no vasopressin 2 (V2) receptor activity. Safety and efficacy of OCE-205 were evaluated in patients with hepatorenal syndrome-acute kidney injury (HRS-AKI). Methods: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted at 23 North American centers. Patients received a continuous infusion of OCE-205 at 8, 15, 30 or 50 µg/hr or placebo. Primary endpoint was time to confirmed clinical improvement, defined as serum creatinine (sCr) <1.5 mg/dL, with at least an absolute reduction of ≥0.3 mg/dL, for 2 days. Following terlipressin’s approval, this study was stopped early due to lack of equipoise in conducting a placebo-controlled trial. Results: Baseline characteristics between OCE-205 (n=37) vs. placebo (n=10) groups were: sCr 2.6 vs 2.3 mg/dL, MELD 27.9 vs 25.8, alcohol-related cirrhosis 51.4% vs 60.0%. The primary endpoint was met in 48.6% vs. 30.0% ( p =0.48 by Log-rank test and NS by Bayesian analysis). Bradycardia was the most common adverse event (21.6% vs 0%). Most events were asymptomatic, requiring no intervention. No new/unexpected safety findings, no events of ischemia, and no related events of respiratory failure occurred. Conclusions: OCE-205 was well tolerated, with no evidence of excessive vasoconstriction or related events of ischemia or respiratory failure at any dose level. OCE-205 had a predictable, capped maximal efficacy that improved HRS-AKI in numerically more patients than placebo, though was underpowered for statistical significance. OCE-205 warrants additional investigation as a novel HRS therapy with a favorable benefit/risk profile.