Short-term treatment with LCZ696 in patients with stable chronic heart failure: effect on biomarkers

Abstract

Purpose: LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) developed for the treatment of hypertension and heart failure (HF). Here, we evaluate the responses of plasma biomarkers, including aldosterone, active renin concentration (ARC), renin activity (PRA), and endothelin-1 to LCZ696. Methods: Patients with stable chronic HF (NYHA II-III, LVEF <40%) entered the open-label, 2-dose Phase II uptitration study. After a 24-h run-in period, patient received LCZ696 100mg bid for 7 days, followed by 200mg bid for 14 days. Plasma biomarkers were determined at baseline, and on Day 7 and Day 21, at the end of each dose treatment period. Results: 30 subjects entered the study, and 27 completed the study. The geometric mean ratio to baseline are (95% CI) for aldosterone (pg/mL): 0.93 (0.76, 1.14) on Day 7 and 0.79 (0.65, 0.95)* on Day 21; PRA (ng/mL/h): 3.94 (2.27, 6.87)* on Day 7 and 2.27 (1.20, 4.32)* on Day 21; ARC (pg/mL): 4.30 (2.78, 6.64)* on Day 7 and 3.50 (2.13, 5.76)* on Day 21; endothelin-1 (pg/ml): 0.90 (0.80, 1.01) on Day 7 and 0.80 (0.71, 0.91)* on Day 21 (*p< 0.05). No serious adverse events occurred during the study. Conclusion: Short-term treatment of HF patients with LCZ696 100mg and 200mg bid significantly increased PRA and ARC, and in addition LCZ696 200 mg bid significantly decreased plasma aldosterone and endothelin-1. These results indicate a significant impact on multiple components of the renin angiotensin aldosterone system in NYHA functional class II-III patients, and support the ongoing development programs of LCZ696 in HF and hypertension.