In 1983, a project aimed at creating a treatment for Alzheimer's disease (AD) was initiated at Tsukuba Research Laboratories. Since then, over the past 40 years, we have consistently pursued research and development (R&D) of drugs for dementia including AD, and accumulated knowledge that is unique to Eisai through the creation of donepezil (product name: Aricept®), the most used drug for AD in the world. Our unique knowledge led to the creation of lecanemab (product name: LEQEMBI®), which was granted traditional approval in the U.S. in 2023 as the world's first AD treatment confirmed to slow cognitive and functional decline.
We have designated dementia as one of our key strategic areas, and under Deep Human Biology Learning (DHBL) drug discovery and development, we are focusing on R&D of therapeutic drugs for dementia in the drug discovery areas (Domains) of "Protein Integrity & Homeostasis" and "InflammAging & Senescence" etc., based on Human Biology. We aim to create innovative new drugs with new targets and mechanisms of action from these Domains to contribute to the treatment of dementia, including AD. We also strive to incorporate the latest findings based on Human Biology, and are collaborating with academia, including Keio University, University College London (UCL), and Washington University School of Medicine in St. Louis on joint research.


1984 Project for Alzheimer's Disease Drugs Based on the Acetylcholine Hypothesis Started at Tsukuba Research Laboratories

Studies in the 1970s using biochemical techniques had shown decreased activity of choline acetyltransferase and decreased cholinergic neurons in the Nucleus of Meynert in the basal forebrain in AD brains. In 1984, at Tsukuba Research Laboratories, we initiated a project to develop a therapeutic drug for AD based on the acetylcholine hypothesis and created donepezil.

1989 Clinical Study of Donepezil

Clinical study of donepezil was initiated in Japan in 1989. Based on Phase III clinical studies in AD, the drug was approved by the U.S. FDA in 1997 for the treatment of AD and was launched under the brand name Aricept. In Japan, the drug was approved and launched in 1999 for the treatment of mild to moderate AD. Subsequently, in 2007, the drug was approved for an additional efficacy and dosage for severe AD, and in 2014, the drug was approved for the indication of dementia with Lewy bodies. In addition, orally disintegrating tablets (Aricept D tablets), jelly formulations, and dry syrups were developed and approved as new formulations that are easier to take for patients who have difficulty taking their medication.
Aricept is approved in more than 100 countries worldwide, including Japan, the United States, Europe, and Asia.

1992 Amyloid-beta (Aβ) Hypothesis Published, R&D of AD Disease-Modifying Drugs Initiated

With the progress of research on the pathogenesis and disease mechanism of AD, the Aβ hypothesis (that the accumulation of Aβ in the brain is the cause of AD) was published in 1992. As clinical studies of donepezil progressed, momentum for R&D of drugs that slow disease onset and disease progression increased at Eisai, and a project to create a drug that prevents neuronal cell death, in line with the Aβ hypothesis, was initiated at Tsukuba Research Laboratories in the same year. In addition, other projects such as one directed toward compounds that inhibit Aβ aggregation were being conducted in parallel. This was the beginnings of our R&D of AD disease-modifying therapies (AD-DMT). Our efforts to create AD-DMT for each drug discovery concept are as below.

γ-Secretase Modulators

In 1995, presenilin was identified as the causative gene for familial AD, and in 2000, it was reported that presenilin is the catalytic subunit of γ-secretase, an important enzyme that cuts off the C-terminal side of Aβ and defines the length of Aβ.
In addition to Aβ, there were a variety of known substrates for γ-secretase including NOTCH, which plays an important role in cell differentiation and fate determination, therefore γ-secretase inhibitors were expected to cause side effects due to inhibition of cleavage of these substrates. In 2003, a project with the aim of inhibiting the production of highly cohesive Aβ42 was initiated at Tsukuba Research Laboratories, resulting in the creation of a γ-secretase modulator E2012 that reduces the production of Aβ42 and Aβ40 but increases the production of less cohesive and shorter types of Aβ (Aβ37, Aβ38), thus not changing the total amount of Aβ, and not affecting NOTCH cleavage. A Phase I clinical study of E2012 was initiated in 2006, followed by a clinical study of the improved version named E2212 in 2010, but development was terminated in 2011.

β-Secretase Inhibitor

In 1999, β-secretase (β-site APP cleaving enzyme: BACE), an enzyme that cuts the N-terminal side of Aβ from APP, was identified.
In 2000, following progress in understanding the molecular mechanism of Aβ production, a project to inhibit Aβ production by inhibiting β-secretase was initiated in collaboration between the Tsukuba Research Laboratories and Eisai's London Research Laboratories. After several failures, E2609 (generic name: elenbecestat) was created at the Tsukuba Research Laboratories in 2007, and a Phase I clinical study was initiated in December 2010. In October 2016, Phase III clinical studies MISSION AD1 and MISSION AD2 for patients with early AD were initiated. However, in September 2019, a safety review conducted by the Independent Data Safety Monitoring Board (DSMB) determined that the benefits of continuing the study would not ultimately outweigh the risks, and the decision was made to discontinue the studies.


Professor Lars Lannfelt of Uppsala University conducted a genetic analysis of familial AD in the northern Swedish city of Umeå and found that the glutamic acid at position Aβ22 was mutated (E693G) to glycine, which he named the "Arctic mutation". Aβ with this mutation is unique in that it forms soluble Aβ aggregates (protofibrils) with increased aggregation, but few insoluble aggregates. Based on the idea that soluble Aβ protofibrils are the cause of AD pathogenesis, Professor Lannfelt and his colleagues founded BioArctic AB in 2003 with protofibril removal as a therapeutic concept for AD, a concept which relies on Human Biology - the knowledge of familial AD. In 2005, Eisai initiated a collaboration with BioArctic AB for the discovery of immunotherapeutic agents for AD, and in 2007, we entered into a licensing agreement for humanized monoclonal antibody lecanemab, which was developed in collaboration with BioArctic AB.

2010 Clinical Study of Lecanemab

In 2010, the Phase I clinical study of lecanemab was initiated, and in 2012, a large-scale (856 enrolled subjects), placebo-controlled, double-blind, parallel-group, randomized Phase II clinical study (Study 201) in early AD patients with confirmed amyloid accumulation in the brain was initiated in Japan, the United States and Europe. In Study 201, ADCOMS (Alzheimer's Disease Composite Score) for evaluating clinical symptoms, showed a statistically significant slowing in clinical decline in the 10 mg/kg biweekly group compared to the placebo group at 18 months after the start of treatment. In the same treatment group, Aβ accumulation in the brain measured by amyloid PET at 18 months showed statistically significant reduction amyloid accumulation, and in converting the amyloid PET image readings from positive to negative, compared to the placebo group. Study 201 was extremely important in establishing the right population, right endpoint, and right dosing for the subsequent Phase III Clarity AD study.
Based on the results of Study 201, the Phase III Clarity AD study was initiated in 2019 with a 10mg/kg biweekly dose of lecanemab, a dosing period of 18 months, and a primary endpoint of CDR-SB (Clinical Dementia Rating Sum of Boxes). This was a placebo-controlled, double-blind, parallel-group, randomized global Phase III clinical study of 1,795 early AD patients with confirmed amyloid accumulation in the brain.
In September 2022, the Clarity AD study met its primary endpoint and demonstrated a statistically significant reduction of clinical decline. The results of this study were presented in detail at CTAD (15th Conference on Clinical Trials for Alzheimer's Disease) held in November of the same year, and were also published in the New England Journal of Medicine, one of the most prestigious peer-reviewed medical journals in the world.

2021 E2814 Selected as the First Anti-Tau Agent in DIAN-TU's Phase II/III Clinical Study (Tau NexGen Study) for Dominantly Inherited Alzheimer's Disease (DIAD)

E2814 is an anti MTBR (microtubule binding region) tau antibody created as a result of a collaborative research with University College London (UCL) in the UK.
In AD, the distribution of pathologic tau accumulation (neurofibrillary tangles) in the brain is correlated with clinical symptoms. The spread of neurofibrillary tangles is thought to occur by propagation of tau aggregates moving between neurons. Tau aggregates that migrate by propagation are composed of MTBR-containing tau, and E2814 is expected to prevent the spread of tau pathology by inhibiting its propagation.
In March 2021, E2814 was selected as the first anti-tau agent in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Phase II/III clinical study (Tau NexGen study) for dominantly inherited Alzheimer's disease (DIAD) by the Dominantly Inherited Alzheimer's Disease Network Trials Unit (DIAN-TU) led by Washington University School of Medicine in St. Louis. Subsequently, in response to growing evidence from clinical studies showing that Aβ-targeted therapy can reduce biomarkers of AD, lecanemab was selected as the background anti-Aβ therapy in this study.
The subjects in this study are people with a genetic mutation known to cause AD, and many tend to develop symptoms at approximately the same age as their parents who developed the disease. The purpose of this study is to evaluate the safety, tolerability, biomarkers and effects on cognitive function of E2814 in symptomatic and asymptomatic individuals with the genetic mutation responsible for familial AD. In January 2022, the first subject was enrolled and the study is currently ongoing.

2023 Lecanemab was Granted Approval in the U.S. and Japan

In January 2023, U.S. Food and Drug Administration (FDA) granted lecanemab accelerated approval for the treatment of AD based on the results of the Phase II clinical trial Study 201.
In the following July, based on the results of the Phase III clinical study Clarity AD, lecanemab was granted traditional approval from the FDA as the first approved treatment shown to reduce the rate of disease progression and to slow cognitive and functional decline. In September of the same year, lecanemab was granted approval in Japan.