Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension

Abstract

Background-LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. Methods and Results-We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (nϭ92), 0.5 mg once daily (nϭ88), 1.0 mg once daily (nϭ86), and 0.5 mg twice daily (nϭ97); eplerenone 50 mg twice daily (nϭ84); or placebo (nϭ77) for 8 weeks. Adrenocorticotropic hormone (250 g IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-␤-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (Ϫ7.1 mm Hg; Pϭ0.0012) and eplerenone 50 mg twice daily (Ϫ7.9 mm Hg; PϽ0.0001) compared with placebo (Ϫ2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (PϽ0.005 or better) and eplerenone (PϽ0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (PϽ0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in Ϸ20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone. Conclusions-Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone-stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00758524.

New drug therapies interfering with the renin–angiotensin–aldosterone system for resistant hypertension

“…32 An 8-week placebo-controlled doseresponse study in patients with stage 1 and 2 essential hypertension reported an optimal decrease in BP with a dose of 1 mg LCI699 o.d., which had an antihypertensive effect similar to that of eplerenone 50 mg b.i.d. 33 However, LCI699 administration was associated with biological signs of partial inhibition of the glucocorticoid axis, as shown by the dose-related increase in both plasma ACTH and in 11-deoxycortisol concentrations, the cortisol precursor, consistent with an inhibition of the CYP11B1 gene product. 31 Nevertheless, the clinical and biological safety and tolerability of LCI699 were similar to those of placebo and eplerenone.…”

“…31 Nevertheless, the clinical and biological safety and tolerability of LCI699 were similar to those of placebo and eplerenone. 33 The effects of LCI699 on the glucocorticoid axis limit the use of higher doses in hypertension because of the loss of selectivity for CYP11B2. Therefore, this aldosterone synthase inhibitor will not be able to replace MR blockade in patients with hypertension, but is now being evaluated at much higher doses in Cushing syndrome.…”

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

“…In early clinical trials, it was observed that while at low doses it is a potent and selective inhibitor of aldosterone synthetase, at higher doses it also inhibits 11b-hydroxylase (CYP11B1 product) (104,105). Following treatment with LCI699, hypertensive patients, either due to primary hyperaldosteronism or essential hypertension, showed a reduction in blood pressure associated with a dose-dependent decrease in plasma and urine aldosterone (up to 80%) and an increase in 11-deoxycorticosterone (104,105,106). At doses of 0.5-1 mg, daily there was an increase in steroid precursors 11-deoxycorticosterone and 11-deoxycortisol and a blunting of the cortisol response to synthetic ACTH, indicating inhibition of 11b-hydroxylase (104,105).…”

Treatment of Cushing's disease: a mechanistic update

“…It also inhibits 11b-hydroxylase (CYP11B1) in a similar manner to the R-enantiomer of fadrozole (FAD286) that blocks the hydroxylation of deoxycortisol to cortisol as well as CYP11B2 blocking the conversion of deoxycorticosterone to corticosterone ( Fig. 2) (Calhoun et al 2011). LCI699 is currently under investigation as a treatment for CD (Tritos et al 2011, Feelders & Hofland 2013.…”