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Title: The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey

Abstract

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 (50 mg/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 15 days. CSF concentrations of newly generated Aβ (AUC{sub (0–24} {sub h)}) indicated elevations in the more aggregable form Aβ1-42more » 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 (300 mg/kg) or vehicle control for 39 weeks; 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. - Highlights: • Sacubitril/valsartan reduced Aβ clearance on day 1, but not after 15 daily doses. • Sacubitril/valsartan increased CSF Aβ but did not result in increases in brain Aβ. • No Aβ brain pathology in 39 week monkey study with high dose sacubitril/valsartan.« less

Authors:
; ;  [1]; ; ;  [2]; ;  [3];  [4];  [5]; ;  [2];  [6];  [7];  [8]
  1. C2N Diagnostics, St. Louis, MO (United States)
  2. Novartis Institutes for BioMedical Research, Cambridge, MA (United States)
  3. Novartis Institutes for BioMedical Research, East Hanover, NJ (United States)
  4. Charles River Laboratories ULC, Montreal, Quebec (Canada)
  5. Charles River Laboratories, Inc., Reno, NV (United States)
  6. Novartis Institutes for BioMedical Research, Basel (Switzerland)
  7. Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States)
  8. Department of Neurology, Washington University School of Medicine, St. Louis, MO (United States)
Publication Date:
OSTI Identifier:
22690977
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 323; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABUNDANCE; ANGIOTENSIN; BRAIN; CEREBROSPINAL FLUID; CLEARANCE; CONCENTRATION RATIO; ENDOTHELINS; ENZYMES; FLUORESCENCE; FORMALDEHYDE; HEART; MONKEYS; PARAFFIN; RECEPTORS; STABLE ISOTOPES

Citation Formats

Schoenfeld, Heidi A., E-mail: heidi.schoenfeld@novartis.com, West, Tim, Verghese, Philip B., Holubasch, Mary, Shenoy, Neeta, Kagan, David, Buono, Chiara, Zhou, Wei, DeCristofaro, Marc, Douville, Julie, Goodrich, Geoffrey G., Mansfield, Keith, Saravanan, Chandra, Cumin, Frederic, Webb, Randy L., and Bateman, Randall J. The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.03.014.
Schoenfeld, Heidi A., E-mail: heidi.schoenfeld@novartis.com, West, Tim, Verghese, Philip B., Holubasch, Mary, Shenoy, Neeta, Kagan, David, Buono, Chiara, Zhou, Wei, DeCristofaro, Marc, Douville, Julie, Goodrich, Geoffrey G., Mansfield, Keith, Saravanan, Chandra, Cumin, Frederic, Webb, Randy L., & Bateman, Randall J. The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey. United States. doi:10.1016/J.TAAP.2017.03.014.
Schoenfeld, Heidi A., E-mail: heidi.schoenfeld@novartis.com, West, Tim, Verghese, Philip B., Holubasch, Mary, Shenoy, Neeta, Kagan, David, Buono, Chiara, Zhou, Wei, DeCristofaro, Marc, Douville, Julie, Goodrich, Geoffrey G., Mansfield, Keith, Saravanan, Chandra, Cumin, Frederic, Webb, Randy L., and Bateman, Randall J. Mon . "The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey". United States. doi:10.1016/J.TAAP.2017.03.014.
@article{osti_22690977,
title = {The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey},
author = {Schoenfeld, Heidi A., E-mail: heidi.schoenfeld@novartis.com and West, Tim and Verghese, Philip B. and Holubasch, Mary and Shenoy, Neeta and Kagan, David and Buono, Chiara and Zhou, Wei and DeCristofaro, Marc and Douville, Julie and Goodrich, Geoffrey G. and Mansfield, Keith and Saravanan, Chandra and Cumin, Frederic and Webb, Randy L. and Bateman, Randall J.},
abstractNote = {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 (50 mg/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 15 days. CSF concentrations of newly generated Aβ (AUC{sub (0–24} {sub h)}) 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 (300 mg/kg) or vehicle control for 39 weeks; 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. - Highlights: • Sacubitril/valsartan reduced Aβ clearance on day 1, but not after 15 daily doses. • Sacubitril/valsartan increased CSF Aβ but did not result in increases in brain Aβ. • No Aβ brain pathology in 39 week monkey study with high dose sacubitril/valsartan.},
doi = {10.1016/J.TAAP.2017.03.014},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 323,
place = {United States},
year = {2017},
month = {5}
}