title: The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects.
abstract: OBJECTIVE
  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.
authors.affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Langenickel
authors.affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tsubouchi
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA.
authors.forename: Surya
authors.initials: S
authors.lastname: Ayalasomayajula
authors.affiliation: Biostatistical Sciences, Integrated Development Functions and Regions, Novartis Healthcare Pvt Ltd, Hyderabad, India.
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Valentin
authors.affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Hinder
authors.affiliation: PAREXEL International, Glendale, California, USA.
authors.forename: Stanford
authors.initials: S
authors.lastname: Jhee
authors.affiliation: California Clinical Trials Medical Group in Affiliation with PAREXEL International, Glendale, California, USA.
authors.forename: Hakop
authors.initials: H
authors.lastname: Gevorkyan
authors.affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Rajman
mesh_terms: D000293:Adolescent; D000328:Adult; D000613:Aminobutyrates / Q000493:pharmacokinetics / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D064368:Healthy Volunteers; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013318:Stroke Volume / Q000187:drug effects; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D016229:Amyloid beta-Peptides; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; C000609743:LBQ657; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: CSF; LCZ696; amyloid-β; heart failure; neprilysin