The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects

AIMS LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid-beta (A beta). Its inhibition may increase A beta levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of A beta. The aim of this study was to assess the blood-brain-barrier penetration of LBQ657 and the potential effects of LCZ696 on cerebrospinal fluid (CSF) concentrations of A beta isoforms in healthy human volunteers. METHODS In a double-blind, randomized, parallel group, placebo-controlled study, healthy subjects received once daily LCZ696 (400 mg, n=21) or placebo (n=22) for 14 days. RESULTS LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable A beta species 1-42 or 1-40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P=0.919] and 1.05 [95% CI 0.82, 1.34; P=0.702], respectively). A 42% increase in CSF AUEC(0,36h) of soluble A beta 1-38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P=0.023]). CSF levels of LBQ657 and CSF A beta 1-42, 1-40, and 1-38 concentrations were not related (r(2) values 0.022, 0.010, and 0.008, respectively). CONCLUSIONS LCZ696 did not cause changes in CSF levels of aggregable A beta isoforms (1-42 and 1-40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin. The clinical relevance of the increase in soluble CSF A beta 1-38 is currently unknown.