Sara Yasrebi

Introduction. Alzheimer’s Disease is the 6^th leading cause of U.S. deaths. and of the top 10, it is the only one without a known cause or cure.¹ This age-related neurodegenerative disease is caused by the action of b-secretase (BACE-1) on APP instead of a-secretase, inducing the formation and deposition of pathogenic b-Amyloid plaques in neurons of the neocortex and hippocampus. These hallmark b-amyloid plaques thus cause progressive memory loss, personality changes and cognitive/motor impairment.² Many clinical trials hoping to inhibit the pathologic action of BACE-1 enzyme have failed because their drugs interact with other enzymes such as BACE-2 and Cathepsin-D, inducing severe side effects. A study by Neumann et. all developed the drug CNP520 and chemically modified it to avoid these adverse interactions.³ Methods. CNP520 contains an amino-oxazine head group that has affinity for Asp-32 and Asp-228 of BACE-1, reducing its binding to BACE-2 and Cathepsin-D and preventing ocular toxicity.³ Trifluoromethyl groups were also added to encourage passage into the blood-brain barrier and it’s slightly-basic pH of 7.2 prevented CNP520 from traveling to peripheral areas and causing liver toxicity.³ Aniline groups were removed to prevent metabolically-induced gene destruction and its mutagenic effects.³ CNP520 was then tested on mice with b-amyloid plaque deposition.³ Brain biopsies showed a reduction in b-amyloid plaque area and immunohistochemistry targeted for microglia and astrocytes revealed a decrease in neuroinflammation with no ocular/hepatotoxicity within normal dose ranges.³ Five human studies, including a 3-month Phase IIa study, were also done on cognitively-normal and post-menopausal female subjects of age ranges 18-55 and ≥ 60 years.⁴ Results. A 750mg dose of CNP520 showed a maximum 79.1 ± 8.9% reduction of Ab40 plaque from baseline and a dose-dependent increase of non-amyloidogenic a-amyloid protein³. Additionally, enzyme inhibition assays confirmed that CNP520 was a potent and selective inhibitor of BACE-1 over other proteases such as BACE-2 and CatD. Replacement of aniline-type structures with fluoropyridyl moieties successfully avoided the risk of genotoxic aniline metabolites. An apical-to-basolateral transport rate of 6.6 x 10-6 cm/s indicated successful BBB permeation. Discussion/Conclusion. CNP520 proved to be successful at slowing the progression of Alzheimer’s Disease by dramatically reducing the formation of b-amyloid plaque. Additionally, its unique chemical structure allowed it to selectively inhibit BACE-1 and reduce ocular/hepatotoxicity, genotoxic effects, and drug efflux from the CSF. CNP520’s success has allowed it to progress into further clinical trials and shows promising effect as a revolutionary drug against Alzheimer’s Disease.⁴

1. Alzheimer’s Disease and Dementia. (2019). Facts and Figures. [online] Available at: https://www.alz.org/alzheimers-dementia/facts-figures.
2. Shen Y, Wang H, Sun Q, et al. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals with Mild Cognitive Impairment. Biol Psychiatry. 2017;83(5):447–455. doi:10.1016/j.biopsych.2017.02.007
3. Neumann U, Ufer M, Jacobson LH, et al. The BACE‐1 inhibitor CNP520 for prevention trials in Alzheimers disease. EMBO Molecular Medicine. 2018;10(11). doi:10.15252/emmm.201809316.
4. Lopez Lopez C, Caputo A, Liu F, Riviere ME, Rouzade‐Dominguez M‐L, Thomas RG,Langbaum JB, Lenz R, Reiman EM, Graf Aet al (2017) The Alzheimer’s prevention initiative generation program: evaluating CNP520 efficacy in the prevention of Alzheimer’s disease. J Prev Alzheimers Dis 4: 242–246