Blood pressure and potassium effects of the new direct aldosterone synthase inhibitor, lci699, in patients with primary aldosteronism: 9d.03

Objective: Aldosterone synthase inhibition with LCI699 is a new therapeutic option aimed at decreasing hormone concentrations in both plasma and tissues. We report the first administration of LCI699 to patients with primary aldosteronism (PA). Design and Methods: After a two-week placebo run-in, 14 patients with PA received oral LCI699 (0.5 mg bid) for two weeks, LCI699 (1 mg bid) for two weeks, and placebo for one week. We assessed the effects of a 70 to 90% inhibition of aldosterone synthase on 24 h ambulatory SBP/DBP, office SBP/DBP and plasma potassium (K) levels and safety. From the screening visit onwards, all patients received oral KCl (3 to 6 g/day) to ensure that plasma K remained >/= 3.0 mmol/L and 10/14 patients received a calcium channel blocker alone or in combination with prazosin to ensure that home BP remained ≤ 170/105 mmHg. Results: At baseline, patients (13/14 men, age: 50.3 ± 6.7 yrs) had high office SBP/DBP (151 ± 17/91 ± 12 mmHg) and 24 h ambulatory SBP/DBP (145 ± 9/89 ± 7 mmHg) and low plasma K (3.0 mmol/L [min:2.5;max:3.5]). They also had high plasma aldosterone (630 pmol/L [359;997]), low plasma renin (4.5 mU/L [1.0;9.5]) concentrations, and high aldosterone/renin ratio (123 pmol/pg [84;553]). LCI699 over four weeks reduced the 24 h ambulatory SBP/DBP by −3.8 (95%CI: −7.5; −0.1)/−1.9 (95%CI: −4.1;+0.3) mmHg (P = 0.046/P = 0.08). Office SBP/DBP decreased by −7.0 (95%CI: −14.2;+0.2)/−1.9 (95%CI: −6.7;+3.0) mmHg on Day 15 and by −9.5 (95%CI: −16.7; −2.4)/−4.9 (95%CI: −11.0;+1.3) mmHg on Day 29 (P = 0.044/P = 0.284). Office BP returned to baseline one week after LCI699 interruption. On Day 8, 0.5 mg LCI699 significantly increased plasma K by 0.76 mmol/L ([95%CI:0.58;0.94]; P < 0.0001) and corrected hypokalemia (4.03 ± 0.33 mmol/L). This allowed oral KCl to be interrupted in 13 patients on Day 15. The plasma K on 1 mg LCI699 remained stable until Day 29 (3.89 ± 0.35 mmol/L; P < 0.0001 vs. Day 1). Hypokalemia reoccurred one week after LCI699 interruption (3.38 ± 0.35 mmol/l, P < 0.00001 vs. Day 29). Conclusion: The four-week administration of LCI699, up to 1 mg bid, effectively and safely corrected the hypokalemia and decreased BP in patients with PA.