Eisai Presents Non-Clinical Data on Elenbecestat at AAIC 2019 Demonstrating Synaptic Safety at Aβ-Lowering Doses

Tokyo, July 25, 2019 /PRNewswire/ -- Eisai Co., Ltd. (headquartered in Tokyo, Japan; President: Haruo Naito; hereinafter referred to as “Eisai”) presented its latest preclinical study data at the Alzheimer’s Association International Conference (AAIC), which evaluated neural dendritic spine density*¹Examination to confirm the oral BACE (β-site amyloid precursor protein cleaving enzyme) inhibitor Elenbecesta*²Impact on Brain Synaptic Function in Patients with Alzheimer’s Disease (Poster Presentation No. P2-064). The Alzheimer’s Association International Conference (AAIC) was held in Los Angeles, California, USA, from July 14 to 18, 2019.

BACE is a key enzyme in the production of Aβ peptides, cleaving the β-site of amyloid precursor protein (APP). BACE inhibitors can reduce the formation of toxic Aβ peptide aggregates in the brain, and are therefore considered to have disease-modifying potential, possibly slowing disease progression. On the other hand, besides APP, other substrates with physiological roles in synaptic formation and function are believed to be modulated by BACE. In this study, the effects of a four-week administration of a BACE inhibitor on Aβ levels in cerebrospinal fluid and synaptic damage were observed in a novel preclinical mouse model. The compounds used in this assessment included Elenbecestat (internally developed), Verubecestat, and Lanabecestat. Furthermore, through analysis of dendritic spine density (per 10Microndendritic spine density in dendrites) and mitochondrial function (mitochondrial oxygen efficiency) in hippocampal synaptosomes (isolated presynaptic terminals), using this as an index to assess the impact on synapse formation and function. Reduced dendritic spine density and mitochondrial function are considered to impair synaptic function and exacerbate cognitive decline. The doses of each BACE inhibitor were adjusted based on exploratory data evaluating the effects of reducing Aβ levels in mouse cerebrospinal fluid, ensuring comparability with clinical study doses.

The results showed that at doses of 3 and 10 mg/kg, Elenbecestat had no significant effect on dendritic spine density or mitochondrial function, while Aβ levels in the cerebrospinal fluid (CSF) were significantly reduced (P<0.001). For Verubecestat, at administered doses of 10 and 30 mg/kg, a significant decrease in dendritic spine density was observed (P<0.05), along with a significant reduction in CSF Aβ levels (P<0.001). Additionally, Lanabecestat at doses of 30 and 100 mg/kg caused a significant decrease in dendritic spine density (P<0.05) and a significant reduction in CSF Aβ levels (P<0.001). At a dose of 100 mg/kg, mitochondrial function was also significantly impaired (P<0.05).

The above results indicate that Elenbecestat, when administered at doses sufficient to reduce Aβ levels in the cerebrospinal fluid, does not affect synaptic function in the brain.

Leveraging over 35 years of drug development experience in the field of Alzheimer’s disease/dementia, Eisai strives to prevent and treat dementia through comprehensive, multidimensional research. Eisai is committed to accelerating the development of innovative drugs to meet existing medical needs and enhance the well-being of patients and their families.

*1 The human brain contains over 100 billion nerve cells (neurons), and information is transmitted through connections known as synapses. These synapses are formed between the axon terminals of the information-sending neurons (presynaptic neurons) and the dendrites of the information-receiving neurons (postsynaptic neurons). The spine-like protrusions on the dendritic branches of neurons are referred to as dendritic spines.
*2 Elenbecestat was jointly developed by Eisai and Biogen (headquartered in Cambridge, Massachusetts, USA; hereinafter referred to as “Biogen”).