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

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-beta (A beta), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-A beta 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) A beta in rats and dogs, and A beta 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 A beta reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.