S-16-4: PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY RESULTS FROM A PHASE 1 MULTIPLE ASCENDING DOSE STUDY OF THE SELECTIVE ALDOSTERONE SYNTHASE INHIBITOR CIN-107

Abstract

Objective: To evaluate the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the highly potent, selective small-molecule inhibitor of aldosterone synthase (CIN-107) in a randomized, double-blind, placebo-controlled phase 1 study in healthy volunteers. Design and methods: Subjects were randomized into 5 cohorts to receive CIN-107 or placebo once daily for 10 days. Cohorts 1 and 2 were placed on a low salt diet to stimulate aldosterone production and were administered 2.5 or 5.0 mg oral CIN-107, respectively. They also underwent an adrenocorticotropic hormone challenge to increase aldosterone and cortisol levels to evaluate the specificity of CIN-107 for aldosterone synthase. Cohorts 3, 4, and 5 were placed on a normal salt diet and were administered 1.5, 2.5, or 0.5 mg oral CIN-107, respectively. Blood samples were collected prior to and after dosing on days 1 and 10 for measurement of plasma CIN-107 concentrations to characterize single-dose and steady-state pharmacokinetics. Pharmacodynamic measurements included aldosterone, cortisol, and electrolytes. Safety assessments included physical examination, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations, including renal function. Results: Fifty-four subjects completed the study. There were no deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). All TEAEs in subjects receiving CIN-107 were mild in severity. Plasma concentrations of CIN-107 increased proportionally with ascending doses. CIN-107 was rapidly absorbed, with peak concentrations observed within 4 hours after dosing. Mean half-life was 26–31 hours. A dose-dependent reduction of plasma aldosterone occurred with CIN-107 doses ≧1.5 mg, regardless of normal or low salt diet. Decreases in plasma aldosterone started on Day 1 and were sustained, with levels reduced by approximately 51–73% on Day 10 (Figure 1). CIN-107 had no meaningful impact on plasma cortisol levels. The urine sodium:potassium ratio increased on Day 1 and diminished by Day 10, an effect mediated by greater elimination of sodium on Day 1 compared to Day 10. A mild increase in the blood urea nitrogen:creatinine ratio and a mild reduction in the glomerular filtration rate (<15%) suggest that CIN-107 produced a mild diuretic effect. Conclusions: CIN-107 was safe and well tolerated and resulted in dose-dependent increases in plasma CIN-107 with a half-life that supports once-daily dosing. The dose-dependent decrease in plasma aldosterone, transient increase in sodium excretion, and mild diuretic effect support continued study in ongoing phase 2 clinical trials evaluating the efficacy and safety of CIN-107 for treatment-resistant or uncontrolled hypertension and primary aldosteronism.