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

Abstract

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-β (Aβ). Its inhibition may increase Aβ levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of Aβ. 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 Aβ 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 Aβ 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(0,36 h) of soluble Aβ 1-38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P = 0.023]). CSF levels of LBQ657 and CSF Aβ 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 Aβ 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 Aβ 1-38 is currently unknown.

Keywords: CSF; LCZ696; amyloid-β; heart failure; neprilysin.

Figure 1

Concentration of amyloid‐β isoforms by timepoint at baseline and on day 14 for LCZ696 (green lines) and placebo (blue lines) groups, (A) amyloid‐β 1–42 in cerebral spinal fluid, (B) amyloid‐β 1–40 in cerebral spinal fluid, (C) amyloid‐β 1–38 in cerebral spinal fluid and (D) amyloid‐β 1–40 in plasma

Figure 2

Individual subject ping‐pong plots of amyloid‐β isoform AUEC(0,36 h) at baseline and at day 14 for LCZ696 (left‐hand graph of each panel) and placebo (right‐hand graph of each panel) groups, (A) amyloid‐β 1–42 in cerebral spinal fluid, (B) amyloid‐β 1–40 in cerebral spinal fluid, (C) amyloid‐β 1–38 in cerebral spinal fluid and (D) amyloid‐β 1–40 in plasma

Figure 3

Individual subject LBQ657 concentrations vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily, (A) plasma and (B) cerebral spinal fluid. Left‐hand graph of each panel is a linear plot with an expanded time scale, right‐hand graph of each panel is a semi‐logarithmic plot

Figure 4

Panels (A)–(C) show individual scatter plots of cerebral spinal fluid concentrations of amyloid‐β isoforms vs. LBQ657 concentrations on day 14 following oral administration of LCZ696 at 400 mg once daily (open circles) or placebo (plus signs), (A) amyloid‐β 1–42, (B) amyloid‐β 1–40 and (C) amyloid‐β 1–38. The solid line represents the regression (r ²). Panel (D) shows mean amyloid‐β 1–42 concentrations in cerebral spinal fluid (solid line, left y‐axis) and LBQ657 concentrations in cerebral spinal fluid (dashed lines, right y‐axis) vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily