The Effect of LCZ696 on Amyloid-β Concentrations in Cerebrospinal Fluid in Healthy Subjects

ABSTRACT (Word limit=150; word count=149) LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with systolic dysfunction. Neprilysin is one of multiple enzymes that degrade amyloid-β (Aβ); its inhibition may increase Aβ levels. Randomized healthy male subjects received once-daily LCZ696 (400mg; N=21) or placebo (N=22) for 14 days. LCZ696 had no significant effect on cerebrospinal fluid (CSF) levels of the aggregable Aβ species Aβ 1–42 or Aβ 1–40 compared with placebo, whereas a 42% increase in CSF AUEC0–36h of soluble Aβ 1–38 was observed. CSF levels of LBQ657 (the LCZ696 metabolite that inhibits neprilysin) and CSF Aβ 1–42, 1–40, and 1–38 were not related (R-square values: 0.022, 0.010, and 0.008, respectively). In conclusion, LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1–42 and 1–40). The clinical relevance of the increase in soluble CSF Aβ 1–38 is unknown