A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2027 in Healthy Subjects

Inclusion Criteria Parts A, B,C and D

1. Nonsmoking, male or female, age ≥50 years and ≤85 years old at the time of informed
consent 2. Body mass index (BMI) ≥18 and ≤32 kilogram per square meter (kg/m2) at Screening
Part B 3. Born in Japan to Japanese parents and grandparents of Japanese descent 4.
Lifestyle, including diet, has not changed significantly since leaving Japan Exclusion
Criteria

1. Clinically significant illness that requires medical treatment within 8 weeks or a
clinically significant infection that requires medical treatment within 4 weeks of
dosing

2. Females who are breastfeeding or pregnant at Screening or Baseline (documented by a
negative beta-human chorionic gonadotropin [beta (ß)-hCG] (or human chorionic
gonadotropin [hCG]) test with a minimum sensitivity of 25 International Unit per Liter
(IU/L) or equivalent units of ß-hCG [or hCG]). A negative urine pregnancy test is
required before the administration of the 1st dose per cohort.

3. Females of childbearing potential who:

- Had unprotected sexual intercourse within 30 days before study entry and do not
agree to use a highly effective method of contraception (eg, total abstinence, an
intrauterine device, a double barrier method [such as condom plus diaphragm with
spermicide] or have a vasectomized partner with confirmed azoospermia but
hormonal contraceptives are not permitted) throughout the entire study period and
for 28 days after study drug discontinuation

- Are currently abstinent, and do not agree to use a double barrier method (as
described above) or refrain from sexual activity during the study period or for
28 days after study drug discontinuation NOTE: All females will be considered to
be of childbearing potential unless they are postmenopausal (amenorrheic for at
least 12 consecutive months, in the appropriate age group, and without other
known or suspected cause) or have been sterilized surgically (ie, bilateral tubal
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
least 1 month before dosing).

4. Males who have not had a successful vasectomy (confirmed azoospermia) or they and
their female partners do not meet the criteria above (ie, not of childbearing
potential or practicing highly effective contraception throughout the study period or
for 28 days after study drug discontinuation). No sperm donation is allowed during the
study period or for 28 days after study drug discontinuation

5. Medical conditions which are not adequately and stably controlled on stable doses of
medications or which, in the clinical opinion of the Principal Investigator (PI), may
interfere with study procedures or participant safety within 4 weeks before dosing
(eg, psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney,
respiratory system, endocrine system, hematological system, neurological system, or
cardiovascular system, or participants who have a congenital abnormality in
metabolism). Participants with the following stable medical conditions, adequately
controlled with stable doses of concomitant medications, need not be excluded if in
the opinion of the PI, their conditions do not compromise participant safety or study
procedures:

- hypertension without cerebrovascular or cardiovascular complications, controlled
on not more than 1 antihypertensive drug

- hyperlipidemia without cerebrovascular or cardiovascular complications,
controlled with diet or monotherapy medication

- mild, localized diseases of the skin, respiratory tract which do not require
systemic medication treatment and without systemic complications

- mild, localized diseases of the eyes which are not symptomatic and do not require
systemic medication treatment and without systemic complications

- osteoarthritis which does not require opioids for treatment of pain

6. History of cerebrovascular disease (including transient ischemic attack or stroke)

7. Any history of abdominal surgery that may affect pharmacokinetic (PK) profiles of
E2027 (eg, hepatectomy, nephrectomy, digestive organ resection) at Screening or
Baseline

8. Any other clinically abnormal symptom or organ impairment found by medical history,
physical examinations, vital signs, electrocardiogram (ECG) finding, or laboratory
test results that requires medical treatment at Screening or Baseline

9. A prolonged QT/QTc interval (QTc >450 millisecond [ms]) demonstrated on ECG at
Screening or Baseline (based on average of triplicate ECGs). A history of risk factors
for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT
Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval

10. Left bundle branch block at Screening or Baseline

11. Persistent systolic blood pressure (BP) >160 millimeter of mercury (mm Hg) or
diastolic BP >100 mm Hg at Screening or Baseline (based on BP measured on at least 3
occasions over 2 weeks)

12. Persistent heart rate (HR) less than 50 beats/minute (min) or more than 90 beats/min
at Screening or Baseline (based on HR measured on at least 3 occasions over 2 weeks)

13. History of myocardial infarction, ischemic heart disease or cardiac failure

14. History of clinically significant arrhythmia or uncontrolled arrhythmia

15. Known history of clinically significant drug allergy at Screening or Baseline

16. Known history of food allergies or presently experiencing significant seasonal or
perennial allergy at Screening or Baseline

17. Known to be human immunodeficiency virus (HIV) positive at Screening

18. Active viral hepatitis (A, B, or C) as demonstrated by positive serology at Screening

19. History of drug or alcohol dependency or abuse within the 2 years before Screening, or
those who have a positive urine drug or alcohol test at Screening or Baseline
(participants whose positive urine drug test is considered by the investigator and
sponsor medical monitor to be due to permitted concomitant medications need not be
excluded)

20. Participants who smoke or have used tobacco or nicotine-containing products within 4
weeks before to dosing

21. A Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation score of 4 or 5 at
Screening or Baseline or for the period within 6 months before to Screening or
Baseline or any lifetime suicidal behavior

22. Currently enrolled in another clinical study or used any investigational drug or
device within 30 days (or 5 half-lives, whichever is longer) preceding informed
consent

23. Engagement in strenuous exercise within 2 weeks before check-in (eg, marathon runners,
weight lifters)

24. Any contraindications to cerebrospinal fluid (CSF) sampling by lumbar puncture (LP)

25. Participants with platelet count <60,000, international normalized ratio (INR) >1.2,
or partial thromboplastin time (PTT) > upper limit of normal (ULN) at Screening

26. Intake of caffeinated beverages or caffeinated food within 72 hours before dosing

27. Intake of nutritional supplements, juice, and herbal preparations or other foods or
beverages that may affect the various drug metabolizing enzymes and transporters (eg,
alcohol, grapefruit, grapefruit juice, grapefruit-containing beverages, apple or
orange juice, vegetables from the mustard green family [eg, kale, broccoli,
watercress, collard greens, kohlrabi, brussel sprouts, mustard], and charbroiled
meats) within 1 week before dosing

28. Intake of herbal preparations containing St. John's Wort within 4 weeks before dosing.

29. Intake of over-the-counter (OTC) medications within 14 days (or 5 half-lives,
whichever is longer) before dosing unless the principal investigator and sponsor
medical monitor consider that they do not compromise participant safety or study
assessments

30. Participants who are taking prohibited medications as listed in Concomitant
Drug/Therapy section within 14 days before dosing