Eisai Co.,Ltd.(Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced its latest data of nonclinical research which examined the effect to the synaptic function in the brain by spinal densities^*1?in regard to oral BACE (beta-site amyloid precursor protein cleaving enzyme) inhibitor elenbecestat^*2?were presented at the Alzheimer’s Association International Conference (AAIC) held in Los Angeles, California, United States, from July 14 to 18, 2019 (Poster Presentation No.: P2-064).

BACE is a key enzyme in the production of Aβ peptides, which inhibits β site of amyloid precursor protein (APP). BACE inhibitor may decrease the formation of toxic Aβ peptide aggregates in the brain, thereby thought to exert disease modifying effects and may have potential to slow the disease progression. On the other hand, in addition to APP, the other substrates with physiological role in synapse formation and function are known as a substance (substrate) changed by BACE. At this time, the effect to Aβ level in CSF and synaptic damage were examined after 4 weeks of administration of BACE inhibitors using novel preclinical model mouse. For the examination compounds, elenbecestat (in-house discovery), verubecestat, and lanabecestat were used. In addition, the effect to the synapse formation and function were evaluated by setting the numerous spinal densities on dendrite of brain cortex (number of spines per 10 μm of dendrites) and mitochondrial function (mitochondrial oxygen efficiency) of hippocampal synaptosomes (isolated presynaptic terminal) as an index. It is believed that decreases in spinal densities and mitochondrial function damage the synaptic function and deteriorate the cognitive function.

The dose of each BASE inhibitor was adjusted so as to be equivalent to the dose for clinical study in accordance with exploratory data of lowering effect of Aβ in mouse CSF.

As a result, elenbecestat did not show significant effects on spinal density and mitochondrial function at dose of 3, 10mg/kg with significant decline of Aβ level in CSF (p<0.001).

As for the verubecestat, significant decline of spinal density was shown at the dose of 10, 30mg/kg (p<0.05) with significant decline of Aβ level in CSF (p<0.001).

Also, as for lanabecestat, significant decline of spinal density was shown at the dose of 30, 100mg/kg (p<0.05) with the significant decline of Aβ level in CSF (p<0.001), as well as the significant decline of mitochondrial function was shown at the dose of 100mg/kg (p<0.05).

These results suggest that elenbecestat does not affect the synaptic function in the brain with an effective dose to decline the Aβ level in CSF.

Eisai aims to realize the prevention and cure of dementia through a multi-dimensional and holistic approach with a foundation of over 35 years of experience of drug discovery activities in the area of Alzheimer’s disease and dementia. Eisai strives to create innovative medicines as soon as possible to further contribute to addressing the unmet medical needs of, as well as increasing the benefits provided to, patients and their families.

^*1?There are more than 100 billion nerve cells (neurons) in the brain, the information is transmitted by forming each bond, called a synapse. This synapse is formed between the axon terminal (presynaptic neuron) sending information and the neuron dendrite (postsynaptic neuron) receiving information. Many supraspinal structures on the neuron dendrite which forms synapse is called spine.

^*2?Elenbecestat, is being jointly developed by Eisai and Biogen Inc. (Headquarters: Cambridge, Massachusetts, United States, “Biogen”).

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Public Relations Department,
Eisai Co., Ltd.
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[Notes to editors]
1.?About Elenbecestat (generic name, development code: E2609)
Discovered by Eisai, elenbecestat is an investigational next-generation oral candidate for the treatment of Alzheimer’s disease (AD) that inhibits BACE (beta amyloid cleaving enzyme). By inhibiting BACE, a key enzyme in the production of Aβ peptides, elenbecestat reduces Aβ production, and by reducing amyloid plaque formations in the brain, exerts disease modifying effects of potentially slowing the progression of AD. Currently, two global Phase III clinical studies (MISSION AD1/2) of elenbecestat in early AD including mild cognitive impairment (MCI) due to AD or the mild AD are underway. In addition, the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development of elenbecestat, a process allowing priority reviews by the FDA for drugs deemed as having potential to treat serious conditions and tackle key unmet medical needs.

2.?About joint development agreement between Eisai and Biogen for Alzheimer’s disease
Eisai and Biogen are collaborating on the joint development and commercialization of Alzheimer’s disease treatments. Eisai serves as the lead in the co-development of elenbecestat, a BACE inhibitor, and BAN2401, an anti-amyloid beta (Aβ) protofibril antibody, and the companies plan to pursue marketing authorizations for the two compounds worldwide. If approved, the companies will also co-promote the products in major markets, such as the United States, the European Union and Japan. As to BAN2401 and elenbecestat, both companies will equally split overall costs, including research and development expenses. Eisai will book all sales for elenbecestat and BAN2401 following marketing approval and launch, and profits will be equally shared between the companies.

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced today that it has been included in the FTSE4Good Index Series for the 18th consecutive year since its initial inclusion in 2002.? The FTSE4Good Index Series is a global index series for socially responsible investment.

The FTSE4Good Index Series is designed to help investors integrate the global standard factors of environmental, social and governance (ESG) into their investment decisions. Eisai received particularly high scores in “Customer Responsibility”, “Labor Standards”, “Corporate Governance”, “Anti-Corruption”, and “Climate Change”, among others. As of July 2019, a total of 1,034 companies from around the world have been selected for the FTSE4Good Developed Index, including 175 companies from Japan.

Along with being listed in the FTSE4Good Index Series, Eisai is also listed in the MSCI Japan Empowering Women Index (WIN), the FTSE Blossom Japan Index, the MSCI Japan ESG Select Leaders Index, and S&P/JPX Carbon Efficient Index, which are the four ESG investment indices for Japanese stocks adopted by the Government Pension Investment Fund (GPIF).

Eisai’s corporate philosophy is to give first thought to patients and their families, and increase the benefits that health care provides as well as address diverse healthcare needs worldwide. By strengthening its ESG initiatives and increasing non-financial value, Eisai is striving to sustainably enhance corporate value based on this corporate philosophy.

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Eisai Co., Ltd.
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July 3, 2019 – Eisai China Inc. announced that it would again donate 350,000 yuan to China Population Welfare Foundation for the project “Public Welfare Stars Invite You to Help the Elderly with Cognitive Impairment Go Home”, which was jointly organized by China Population Welfare Foundation and Tencent News.

It was reported that this charitable activity will be carried out with “stars appealing and netizens forwarding the appeals”. Each forwarding by a participant will bring one “helping hand”, which is equivalent to one yuan donated to the charitable fund, and one yellow bracelet will be donated for every 326 yuan, or 326 times of forwarding. The charitable money will be donated by benevolent enterprises (scan the two-dimensional code below for details of the activity). This activity aims to call public attention to patients with cognitive impairment.

The related funds donated by Eisai China Inc., one of the benevolent enterprises, will be used to purchase 1,000 Positioning Yellow Bracelets. Patients with cognitive impairment and their families can get the yellow bracelets for free in memory clinics of relevant hospitals. The Positioning Yellow Bracelet has the functions of real-time positioning, movement track checking, safety fence, emergency call and so on. Families of the elderly can track and positioning the location of the elderly through mobile APP, which help change passive search into active care.

Cognitive impairment is a progressive declining brain disease, which is often mistaken for normal aging. In addition to the misunderstandings, there is still serious discrimination against the elderly with cognitive impairment in our society. What’s more, such patients have a strong sense of shame, resulting in a low rate of medical treatment. The disease is still incurable up to now, which brings heavy burdens in finance, care-giving and psychology to families of such patients. China sees large population with cognitive impairment and high incidence of the disease with tens of millions of such patients becoming a huge challenge in the aging society.

Since entering China market in the 1990s, we have always been adhering to our company philosophy of?hhc?(human health care), giving our first thoughts to patients and their families, and to increasing the benefits health care provides. We always commit to promoting the progress and development of neuroscience, one of the key treatment fields we focus on.

In 2019, we will continue to cooperate with the China Population Welfare Foundation to promote a total of nearly 200 online and offline activities regarding Yellow Bracelets, which is expected to benefit more than 10,000 people, as well as large-scale science popularizations and free clinics. Meanwhile, we will collect caregiver stories jointly with China Association for Alzheimer’s Disease and carry out online disease education and more activities in cooperation with JD.com. We are willing to work with all sectors of the society to improve the life quality of patients, promote the development of disease-related industries, enhance social understanding and prevention of the disease and actively help improve public policies to address the challenges brought by an ageing society.?

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced today that a joint research group including scientists from Eisai and Professor Yoshito Kishi’s group of Harvard University has achieved a total synthesis and obtained results of nonclinical studies of the novel compound, E7130, derived from total synthesis of halichondrin. These results have been published in?Scientific Reports, a scientific journal of?Nature.¹?Currently a Phase I study to investigate E7130 in solid tumor is underway in Japan.

Halichondrins, which was isolated from the marine sponge?Halichondria okadai?in 1986, was known for their outstanding antitumor activity in mice, however the supply from natural sources were limited. Furthermore, the very complicated chemical structure has prevented drug discovery and development based on intact halichondrins. The joint research group strictly controlled 31 asymmetric carbons and achieved a total synthesis of E7130, on a >10 g scale with >99.8% purity under GMP (good manufacturing practice) conditions.
The joint research team also demonstrated that E7130 is not only a novel microtubule dynamics inhibitor but can also increase intratumoral CD31-positive endothelial cells (vascular remodeling activity) and reduce alpha-SMA (smooth muscle actin)-positive cancer-associated fibroblasts (anti-CAF effect), which are important constituents of the tumor microenvironment and may be involved in the malignant transformation of cancers in nonclinical in vivo studies.

According to these unique effects, E7130 augments the effect of antitumor treatments in nonclinical studies. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery and development even for complex natural products.

“In 1992, it was unthinkable to synthesize a gram-quantity of a halichondrin,” said Yoshito Kishi, Morris Loeb Professor of Chemistry, Emeritus, in the Department of Chemistry and Chemical Biology at Harvard University, said “but three years ago we proposed it to Eisai. Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago. We are very delighted to see our basic chemistry discoveries have now made it possible to synthesize this compound at large scale.”

Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. We will maximize the potential of halichondrins by adding E7130 project to two investigational projects of Eisai’s eribulin platform; MORAb-202 (antibody-drug conjugate with eribulin as the payload) and liposomal formulation of eribulin, as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

* Harvard has exclusively licensed the intellectual property associated with this research project to Eisai for the commercial development of therapeutics.

Media Inquiries:
Public Relations Department,
Eisai Co., Ltd.
+81-(0)3-3817-5120

[Notes to editors]
About E7130
E7130 is a next-generation agent improving tumor microenvironment, which has been developed by a joint research with Eisai and Harvard University. E7130 is derived from total synthesis of halichondrin, a natural product isolated from the marine sponge?Halichondria okadai. E7130 is believed to improve tumor microenvironment by unique action for potential effect on immune activation by releasing hypoxia and suppressing interaction between cancer cells and stroma. A Phase I study to investigate E7130 in solid tumor is currently underway in Japan.

^1.?Kawano S et al., “A landmark in drug discovery based on complex natural product synthesis”?Scientific Reports?2019.

Eisai Co.,Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) today announced that latest information on lemborexant, an investigational sleep-wake regulation agent being studied for the treatment of multiple sleep-wake disorders, including insomnia and Irregular Sleep-Wake Rhythm Disorder (ISWRD) will be presented at the 33rd Annual Meeting of the Associated Professional Sleep Societies (SLEEP 2019), from June 8 to 12 in San Antonio, Texas, the United States.

Eight posters including the integrated analysis of lemborexant’s effects on daily function and disease severity as well as sleep onset and sleep maintenance for the combined 1,955 patient population of two pivotal clinical Phase III studies, SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303) in insomnia disorders, and an evaluation of results on respiratory function after administration of lemborexant in elderly and mild obstructive sleep apnea, and the latest pre-clinical data on ISWRD will be presented.

Lemborexant acts on the orexin neurotransmitter system and is believed to regulate sleep and wake by controlling arousal without affecting awakening by external stimuli, and is being developed for the treatment of multiple sleep-wake disorders including insomnia disorder. In December 2018 and March 2019, new drug applications seeking approval of lemborexant for use in the treatment of insomnia disorder were submitted in the United States and Japan, respectively. For the ongoing clinical studies, please visit clinicaltrials.gov.

Through the development of lemborexant, Eisai is aiming to bring to patients suffering from sleep-wake disorders a new treatment option to improve their ability to fall and stay asleep and wake without impairing the next morning, and is striving to further contribute to satisfying unmet medical needs and improve the benefits to patients and their families.

■ Presentations for Lemborexant:

Poster session: P18, Presentation date: Monday June 10, 5:15pm – 7:15pm (local time)

Separate from the poster presentations, Eisai will host a symposium, an interactive dialogue on insomnia diagnostic and therapeutic decision making, which will be held on Sunday, June 9, from 6:15pm – 8:30pm (local time).

Media Inquiries:
Public Relations Department,
Eisai Co., Ltd.
+81-(0)3-3817-5120

[Notes to editors]

1. About Lemborexant

Lemborexant is a novel investigational small molecule compound, discovered and developed by Eisai, that inhibits orexin signaling by binding competitively to both orexin receptor subtypes (orexin receptors 1 and 2). In individuals with normal daily sleep-wake rhythms, orexin signaling is believed to promote periods of wakefulness. In individuals with sleep-wake disorders, it is possible that orexin signaling that regulates wakefulness is not functioning normally, suggesting that inhibiting inappropriate orexin signaling may enable initiation and maintenance of sleep. Eisai is investigating lemborexant as a potential treatment option for multiple sleep-wake disorders, such as insomnia.

Additionally, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder (ISWRD) and mild to moderate Alzheimer’s dementia is underway.

2. About Sleep Disorders

Several population studies show that sleep disorders affect many more people worldwide than previously thought.¹?Insomnia disorder is the most common sleep disorder, with persistent insomnia symptoms experienced by approximately 30 percent of the adult population.^1,2?Insomnia disorder is characterized by difficulty falling asleep, staying asleep, or both, despite an adequate opportunity to sleep, that can lead to daytime consequences such as fatigue, difficulty concentrating and irritability.^3,4

Sleeping well is essential for good health, including brain health. Poor sleep is associated with a wide range of health consequences, including an increased risk of hypertension, accidental injury, diabetes, obesity, depression, heart attack, stroke, dementia, as well as adverse effects on mood and behavior.^3,5

Experimental studies in animals and humans provide evidence of associations between sleep and disease risk factors, diseases, and mortality.⁶?Studies suggest an optimal sleep duration between seven and eight hours.⁷

Women are 1.4 times more likely than men to suffer from insomnia.⁸?Older adults also have higher prevalence of insomnia; aging is often accompanied by changes in sleep patterns, including disrupted sleep, frequent walking, and early waking, that can lead to less sleep time.⁹

¹?Ferrie JE, et al. Sleep epidemiology – a rapidly growing field.?Int J Epidemiol. 2011;40(6):1431–1437.
²?Roth T. Insomnia: definition, prevalence, etiology and consequences.?J Clin Sleep Med. 2007;3(5 Suppl):S7–S10.
³?Institute of Medicine. Sleep disorders and sleep deprivation: An unmet public health problem. Washington, DC: National Academies Press. 2006.
⁴?Ohayon MM, et al. Epidemiology of insomnia: what we know and what we still need to learn.?Sleep Med Rev. 2002;6(2):97-111.
⁵?Pase MP, Himali JJ, Grima NA, et al. Sleep architecture and the risk of incident dementia in the community.?Neurology. 2017;89(12):1244-1250.
⁶?Cappuccio FP et al. Sleep and cardio-metabolic disease.?Curr Cardiol Rep. 2017;19:110.
⁷?Cappuccio FP et al. Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies.?Sleep. 2010;33(5):585-592.
⁸?Roth T, et al. Prevalence and perceived health associated with insomnia based on DSM-IV-TR; International Statistical Classification of Diseases and Related Health Problems, tenth revision; and Research Diagnostic Criteria/International Classification of Sleep Disorders, second edition criteria: results from the America Insomnia Survey.?Biol Psychiatry. 2011;69:592– 600.
⁹?Crowley, K. Sleep and sleep disorders in older adults.?Neuropsychol Rev. 2011;21(1):41-53.