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

  • EMBO Mol Med. 2018 Nov;10(11):e9316. doi: 10.15252/emmm.201809316.
Ulf Neumann  1 ,  Mike Ufer  2 ,  Laura H Jacobson  3 ,  Marie-Laure Rouzade-Dominguez  2 ,  Gunilla Huledal  4 ,  Carine Kolly  5 ,  Rainer M Lüönd  6 ,  Rainer Machauer  6 ,  Siem J Veenstra  6 ,  Konstanze Hurth  6 ,  Heinrich Rueeger  6 ,  Marina Tintelnot-Blomley  6 ,  Matthias Staufenbiel  3 ,  Derya R Shimshek  3 ,  Ludovic Perrot  3 ,  Wilfried Frieauff  5 ,  Valerie Dubost  5 ,  Hilmar Schiller  4 ,  Barbara Vogg  4 ,  Karen Beltz  4 ,  Alexandre Avrameas  7 ,  Sandrine Kretz  7 ,  Nicole Pezous  2 ,  Jean-Michel Rondeau  8 ,  Nicolau Beckmann  9 ,  Andreas Hartmann  5 ,  Stefan Vormfelde  2 ,  Olivier J David  10 ,  Bruno Galli  10 ,  Rita Ramos  10 ,  Ana Graf  10 ,  Cristina Lopez Lopez  11
Affiliations
  • 1. Neuroscience, Novartis Institute for BioMedical Research, Basel, Switzerland [email protected] [email protected].
  • 2. Translational Medicine, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 3. Neuroscience, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 4. PK Sciences, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 5. Preclinical Safety, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 6. Global Discovery Chemistry, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 7. Biomarker Discovery, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 8. Chemical Biology and Therapeutics, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 9. Musculoskeletal Diseases, Novartis Institute for BioMedical Research, Basel, Switzerland.
  • 10. Global Drug Development, Novartis, Basel, Switzerland.
  • 11. Global Drug Development, Novartis, Basel, Switzerland [email protected] [email protected].
PMID: 30224383 DOI: 10.15252/emmm.201809316
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
Alzheimer's disease; BACE‐1 inhibitor; drug discovery; prevention; β‐amyloid.
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