Results from a phase 1 multiple ascending dose study demonstrating safety and selectivity of aldosterone synthase inhibitor CIN-107
Authors: Freeman M , Bond M , Murphy B , Isaacsohn J 
Published: October 2022

Abstract

Background
CIN-107 is a highly potent, selective, and competitive small molecule inhibitor of aldosterone synthase that is a potential treatment for disorders associated with elevated aldosterone levels, including hypertension and primary aldosteronism. This randomized, double-blind, placebo-controlled phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of CIN-107 in healthy volunteers.

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. Cohorts 1 and 2 also underwent an adrenocorticotropic hormone (ACTH) challenge to increase aldosterone and cortisol levels to evaluate the specificity of CIN-107 for targeting 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 plasma aldosterone, cortisol, and electrolytes. Safety assessments included physical examination, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations.

Results
54 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 (Table 1). Plasma concentrations of CIN-107 increased proportionally with ascending doses. CIN-107 was rapidly absorbed, with peak concentrations observed within 4 hours after dosing. The concentration of plasma CIN-107 declined in an apparent biphasic manner with a half-life of 26 to 31 hours. A dose-dependent reduction of plasma aldosterone was observed with CIN-107 doses ≥1.5 mg, regardless of normal or low salt diet. Decreases in plasma aldosterone were observed starting on Day 1 and were sustained, with levels reduced by approximately 51–73% on Day 10 (Figure 1). The inhibition of aldosterone synthase by CIN-107 had no impact on plasma cortisol. CIN-107 resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels, as would be expected from the observed reduction in aldosterone.

Conclusions
Oral administration of CIN-107 was safe and well tolerated in all subjects 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 and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase and 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.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): CinCor Pharma Inc