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

Br J Clin Pharmacol. 2016 May;81(5):878-90. doi: 10.1111/bcp.12861. Epub 2016 Mar 8.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aminobutyrates / pharmacokinetics
  • Aminobutyrates / pharmacology*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Amyloid beta-Peptides / metabolism
  • Angiotensin Receptor Antagonists / pharmacokinetics
  • Angiotensin Receptor Antagonists / pharmacology*
  • Biphenyl Compounds / pharmacokinetics
  • Biphenyl Compounds / pharmacology*
  • Blood-Brain Barrier / metabolism*
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Healthy Volunteers
  • Heart Failure / drug therapy
  • Humans
  • Male
  • Middle Aged
  • Neprilysin / antagonists & inhibitors*
  • Stroke Volume / drug effects
  • Tetrazoles / pharmacokinetics
  • Tetrazoles / pharmacology*
  • Young Adult

Substances

  • Aminobutyrates
  • Amyloid beta-Peptides
  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Drug Combinations
  • LBQ657
  • Tetrazoles
  • Neprilysin
  • sacubitril-valsartan