Pharmacodynamic effects of highly selective aldosterone synthase inhibitor vicadrostat in cynomolgus monkeys: Contrasting effects of once versus twice daily dosing.

Abstract

Novel inhibitors of aldosterone synthase (CYP11B2) hold promise as treatments for cardiorenal conditions including chronic kidney disease, heart failure, and hypertension. The inadequacy of rodent models and the failure of recombinant systems to reliably recapitulate the properties of the native human enzyme have hindered research in this area. Thus, we developed in vitro and in vivo models based on nonhuman primates. This approach led to the discovery of vicadrostat (BI 690517), an inhibitor with an in vitro IC₅₀ of 19 nM against human aldosterone synthase, 250-fold selective against the highly homologous cortisol synthase (CYP11B1), and with drug-like chemical and pharmacokinetic properties. In an acute in vivo model in cynomolgus monkeys, vicadrostat displayed an IC₅₀ against aldosterone production of 25 nM, with >2000-fold selectivity against synthesis of cortisol. The pharmacodynamic effects of repeated administration were determined in cynomolgus using doses estimated to mimic a likely therapeutic intervention in humans. Vicadrostat significantly lowered plasma aldosterone, with no effect on cortisol. Effects on precursor steroids were observed, with little effect on electrolytes. Importantly, a clear difference between dosing regimens emerged, indicating that once daily dosing (partial-day coverage) resulted in a sustained effect, whereas dosing twice daily (full-day coverage) induced a counteractive increase in aldosterone synthesis that resulted in a loss of effect on overall daily aldosterone levels. These studies were key to the design of early clinical trials with vicadrostat and illustrate the value of establishing a physiologically relevant pharmacodynamic model in reducing the scope of necessary human investigation. SIGNIFICANCE STATEMENT: The standard of care for chronic kidney disease is inadequate to prevent gradual loss of renal function in many patients. Here, the study describes key preclinical studies with the novel aldosterone synthase inhibitor vicadrostat that were instrumental in the design of early clinical studies and provide insight into predicted and unpredicted pharmacodynamic effects. These observations will inform further development of vicadrostat and related drugs for the treatment of kidney disease and other metabolic disease-related morbidities.