Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-beta (A beta), there is a theoretical risk of A beta accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of AS isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK (TM))-A beta methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human A beta-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50 mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK (TM)-A beta. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of A beta 1-42 (653%; p = 0.026), A beta 1-40 (35.2%; p = 0.04) and A beta total (29.8%; p = 0.04) acutely; this returned to normal as expected with repeated dosing for 15 days. CSF concentrations of newly generated A beta (AUC((0-24 h))) indicated elevations in the more aggregable form A beta 1-42 on day 1 (20.4%; p = 0.039) and day 15 (34.7%; p = 0.0003) and in shorter forms A beta 1-40 (23.4%; p = 0.009), A beta 1-38 (64.1%; p = 0.0001) and A beta total (50.45%; p = 0.00002) on day 15. However, there were no elevations in any A beta isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300 mg/1<g) or vehicle control for 39 weeks; no microscopic brain changes or A beta deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings. (C) 2017 The Authors. Published by Elsevier Inc.