2. Academic Validation
  3. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease

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

Affiliations

  • 1 Neuroscience, Novartis Institute for BioMedical Research, Basel, Switzerland ulf.neumann@novartis.com cristina.lopez_lopez@novartis.com.
  • 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 ulf.neumann@novartis.com cristina.lopez_lopez@novartis.com.
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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