The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.

Abstract

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Aβ reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.

• Authors: Ulf Neumann, Mike Ufer, Laura H Jacobson, Marie-Laure Rouzade-Dominguez, Gunilla Huledal, Carine Kolly, Rainer M Lüönd, Rainer Machauer, Siem J Veenstra, Konstanze Hurth, Heinrich Rueeger, Marina Tintelnot-Blomley, Matthias Staufenbiel, Derya R Shimshek, Ludovic Perrot, Wilfried Frieauff, Valerie Dubost, Hilmar Schiller, Barbara Vogg, Karen Beltz, Alexandre Avrameas, Sandrine Kretz, Nicole Pezous, Jean-Michel Rondeau, Nicolau Beckmann, Andreas Hartmann, Stefan Vormfelde, Olivier J David, Bruno Galli, Rita Ramos, Ana Graf, Cristina Lopez Lopez
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 10 Issue 11 (11 2018) ISSN: 1757-4684 [Electronic] England
• PMID: 30224383 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Novartis AG. Published under the terms of the CC BY 4.0 license.

Chemical References

• Amyloid beta-Protein Precursor
• Oxazines
• Umibecestat
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human
• Bace1 protein, mouse
• Cathepsin D

Topics

• Alzheimer Disease (blood, cerebrospinal fluid, drug therapy, prevention & control)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
• Amyloid beta-Protein Precursor (cerebrospinal fluid, metabolism)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors, metabolism)
• Astrocytes (metabolism)
• Brain (pathology)
• Cathepsin D (antagonists & inhibitors, metabolism)
• Cerebral Hemorrhage (pathology)
• Female
• Hominidae (genetics)
• Humans
• Inflammation (pathology)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (metabolism)
• Oxazines (blood, chemistry, pharmacology, therapeutic use)
• Translational Research, Biomedical