EMBO Molecular Medicine (Nov 2018)
The BACE‐1 inhibitor CNP520 for prevention trials in Alzheimer's disease
- 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
Affiliations
- Ulf Neumann
- Neuroscience Novartis Institute for BioMedical Research Basel Switzerland
- Mike Ufer
- Translational Medicine Novartis Institute for BioMedical Research Basel Switzerland
- Laura H Jacobson
- Neuroscience Novartis Institute for BioMedical Research Basel Switzerland
- Marie‐Laure Rouzade‐Dominguez
- Translational Medicine Novartis Institute for BioMedical Research Basel Switzerland
- Gunilla Huledal
- PK Sciences Novartis Institute for BioMedical Research Basel Switzerland
- Carine Kolly
- Preclinical Safety Novartis Institute for BioMedical Research Basel Switzerland
- Rainer M Lüönd
- Global Discovery Chemistry Novartis Institute for BioMedical Research Basel Switzerland
- Rainer Machauer
- Global Discovery Chemistry Novartis Institute for BioMedical Research Basel Switzerland
- Siem J Veenstra
- Global Discovery Chemistry Novartis Institute for BioMedical Research Basel Switzerland
- Konstanze Hurth
- Global Discovery Chemistry Novartis Institute for BioMedical Research Basel Switzerland
- Heinrich Rueeger
- Global Discovery Chemistry Novartis Institute for BioMedical Research Basel Switzerland
- Marina Tintelnot‐Blomley
- Global Discovery Chemistry Novartis Institute for BioMedical Research Basel Switzerland
- Matthias Staufenbiel
- Neuroscience Novartis Institute for BioMedical Research Basel Switzerland
- Derya R Shimshek
- Neuroscience Novartis Institute for BioMedical Research Basel Switzerland
- Ludovic Perrot
- Neuroscience Novartis Institute for BioMedical Research Basel Switzerland
- Wilfried Frieauff
- Preclinical Safety Novartis Institute for BioMedical Research Basel Switzerland
- Valerie Dubost
- Preclinical Safety Novartis Institute for BioMedical Research Basel Switzerland
- Hilmar Schiller
- PK Sciences Novartis Institute for BioMedical Research Basel Switzerland
- Barbara Vogg
- PK Sciences Novartis Institute for BioMedical Research Basel Switzerland
- Karen Beltz
- PK Sciences Novartis Institute for BioMedical Research Basel Switzerland
- Alexandre Avrameas
- Biomarker Discovery Novartis Institute for BioMedical Research Basel Switzerland
- Sandrine Kretz
- Biomarker Discovery Novartis Institute for BioMedical Research Basel Switzerland
- Nicole Pezous
- Translational Medicine Novartis Institute for BioMedical Research Basel Switzerland
- Jean‐Michel Rondeau
- Chemical Biology and Therapeutics Novartis Institute for BioMedical Research Basel Switzerland
- Nicolau Beckmann
- Musculoskeletal Diseases Novartis Institute for BioMedical Research Basel Switzerland
- Andreas Hartmann
- Preclinical Safety Novartis Institute for BioMedical Research Basel Switzerland
- Stefan Vormfelde
- Translational Medicine Novartis Institute for BioMedical Research Basel Switzerland
- Olivier J David
- Global Drug Development Novartis Basel Switzerland
- Bruno Galli
- Global Drug Development Novartis Basel Switzerland
- Rita Ramos
- Global Drug Development Novartis Basel Switzerland
- Ana Graf
- Global Drug Development Novartis Basel Switzerland
- Cristina Lopez Lopez
- Global Drug Development Novartis Basel Switzerland
- DOI
- https://doi.org/10.15252/emmm.201809316
- Journal volume & issue
-
Vol. 10,
no. 11
pp. n/a – n/a
Abstract
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.
Keywords