The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey.
Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p=0.026), Aβ1-40 (35.2%; p=0.04) and Aβtotal (29.8%; p=0.04) acutely; this returned to normal as expected with repeated dosing for 15days. CSF concentrations of newly generated Aβ (AUC(0-24h)) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p=0.039) and day 15 (34.7%; p=0.0003) and in shorter forms Aβ1-40 (23.4%; p=0.009), Aβ1-38 (64.1%; p=0.0001) and Aβtotal (50.45%; p=0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300mg/kg) or vehicle control for 39weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings.
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. Electronic address: heidi.schoenfeld@novartis.com.
Heidi A
HA
Schoenfeld
C2N Diagnostics, St. Louis, MO, USA.
Tim
T
West
C2N Diagnostics, St. Louis, MO, USA.
Philip B
PB
Verghese
C2N Diagnostics, St. Louis, MO, USA.
Mary
M
Holubasch
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Neeta
N
Shenoy
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
David
D
Kagan
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Chiara
C
Buono
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Wei
W
Zhou
Novartis Institutes for BioMedical Research, East Hanover, NJ, USA.
Marc
M
DeCristofaro
Charles River Laboratories ULC, Montreal, Quebec, Canada.
Julie
J
Douville
Charles River Laboratories, Inc., Reno, NV, USA.
Geoffrey G
GG
Goodrich
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Keith
K
Mansfield
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Chandra
C
Saravanan
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Frederic
F
Cumin
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Randy L
RL
Webb
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Randall J
RJ
Bateman
D000284:Administration, Oral; D000613:Aminobutyrates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D001713:Biphenyl Compounds; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007553:Isotope Labeling; D008252:Macaca fascicularis; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism; D018570:Risk Assessment; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015854:Up-Regulation; D000068756:Valsartan
D000613:Aminobutyrates; D016229:Amyloid beta-Peptides; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
Alzheimer's disease; Amyloid beta; Angiotensin receptor neprilysin inhibitor; LCZ696; SILK-Aβ; Sacubitril/valsartan