OR09-6 Selective and Durable Suppression of Aldosterone Production in Non-Human Primates by a Novel Aldosterone Synthase Inhibitor

Primary aldosteronism (PA) is a common form of secondary hypertension driven by the autonomous production of aldosterone. Often described as low-renin hypertension, PA is a major public health concern given its prevalence and associated cardiovascular and renal pathology. Compared to patients with essential hypertension, patients with PA are at greater risk for stroke, coronary artery disease, atrial fibrillation, and heart failure. Aldosterone excess is also linked to vascular inflammation, fibrosis and oxidative stress. Aldosterone is produced in the adrenal glands by the enzyme CYP11B2 (aldosterone synthase). CYP11B2 belongs to the cytochrome P450 family of enzymes that also control cortisol (CYP11B1) and sex steroid synthesis (e.g. CYP17, CYP19). Thus, to safely suppress aldosterone synthesis in states of excess, a selective CYP11B2 inhibitor is required. SE-6440 is a novel CYP11B2 inhibitor; it is >200-fold selective over the closely related CYP11B1 enzyme as well as related adrenal and liver cytochrome P450 enzymes. Herein we describe the pharmacology of SE-6440 in non-human primate models of steroidogenesis using two different physiological inducers of aldosterone synthesis (Angiotensin II and ACTH). In monkeys, an i.v. bolus of Angiotensin II stimulates aldosterone synthesis and transiently elevates plasma aldosterone levels. Single oral doses of SE-6440 at 1 and 0.2 mg/kg suppressed aldosterone production in a dose-related manner to 3% and 26% that of vehicle-treated animals, respectively, without effect on cortisol synthesis. To determine if this selective inhibitory effect on aldosterone was durable, we dosed monkeys for 14-days with SE-6440 at 0.6 and 0.12 mg/kg orally once daily. Prior to SE-6440 treatment, animals received an i.v. bolus of ACTH to stimulate adrenal steroidogenesis. This ACTH stimulation test mimics that used clinically to diagnose adrenal insufficiency. Following ACTH administration, plasma aldosterone and cortisol pathway steroids were then measured for 8 hours. Each animal was used as its own control when ACTH was similarly administered on day 7 and day 14 of treatment with SE-6440. SE-6440 reduced plasma aldosterone levels, relative to pre-treatment levels, in a dose-related manner. The 0.6 mg/kg dose significantly inhibited aldosterone synthesis and yielded plasma aldosterone levels 13% and 15% that of control on days 7 and 14, respectively, while the 0.12 mg/kg daily dose reduced plasma aldosterone levels to 46% and 49% that of control on days 7 and 14, respectively. In both dose groups, there was no inhibition of CYP11B1 enzyme activity, based on the plasma cortisol, deoxycortisol, and DOC concentrations. These data demonstrate that, regardless of the stimulus, SE-6440 selectively inhibits aldosterone formation without affecting cortisol synthesis and that this inhibition is durable when administered orally once daily for 14 days.