A Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Male and Female Subjects With Schizophrenia

This is a single-center, randomized, single-blind, placebo-controlled, ascending single oral
dose study designed to evaluate the safety, tolerability, and PK of SEP-363856 and its
metabolite SEP-363854 in male and female subjects with schizophrenia. This study will
determine the maximum-tolerated dose (MTD) for a single oral dose of SEP-363856, and
characterize the plasma PK profiles of SEP-363856 and its metabolite SEP-363854 in male and
female subjects with schizophrenia.

For each of the dose-escalation cohorts, 12 subjects (9 active subjects and 3 placebo
subjects) will receive a single oral dose. An attempt will be made to have at least
one-third of subjects in each cohort be female.

Each cohort will be comprised of 12 subjects (9 active, 3 placebo). Within each cohort,
subjects will be randomized to receive either SEP-363856 (active) or matched placebo in a
3:1 ratio.

The planned dose levels that will be evaluated are:

- Cohort 1: A single oral 25 mg dose of SEP-363856 or matched placebo.

- Cohort 2: A single oral 50 mg dose of SEP-363856 or matched placebo.

- Cohort 3: A single oral 100 mg dose of SEP-363856 or matched placebo.

- Cohort 4: A single oral 150 mg dose of SEP-363856 or matched placebo.

Inclusion Criteria:

1. Subject must give written informed consent and privacy authorization (Healthcare
Insurance, Portability, and Accountability Act of 1996) prior to participation in the
study. Female subjects of childbearing potential and male subjects must agree to
contraceptive requirements outlined in the informed consent form.

2. Subject must be willing and able to comply with the study procedures and visit
schedules and must be able to follow verbal and written instructions.

3. Male or female subject between 18 to 50 years of age (inclusive) at the time of
consent.

4. Subject's body mass index (BMI) must be at least 19.5 kg/m2 but no more than 37
kg/m2.

5. Female subject must have a negative serum pregnancy test at screening.

6. Female subjects of childbearing potential1 must agree to avoid pregnancy and use
acceptable methods of birth control (see Section 24) from at least 60 days prior to
screening and for at least 90 days after the last study drug administration.

7. Male subjects with female partner(s) of childbearing potential5 must agree to avoid
fathering a child and use acceptable methods of birth control (see Section 24) from
screening until at least 90 days after the last study drug administration.

8. Subject must meet the Diagnostic and Statistical Manual of Mental Disorders Fourth
Edition; Text Revision (DSM-IV-TR) criteria for a primary diagnosis of schizophrenia
with the following subtypes: disorganized (295.10), catatonic type (295.20), paranoid
(295.30), residual (295.60), or undifferentiated (295.90); and in the opinion of the
Investigator has been clinically stable for the past 6 months.

9. Subject must have a Clinical Global Impression-Severity of Illness (CGI-S) score ≤ 4
(normal to moderately ill) at screening.

10. Subject must have a Positive and Negative Syndrome Scale (PANSS) total score ≤ 80 at
screening.

11. Subject must have a score of ≤ 4 (normal to moderate) on the following PANSS items at
screening:

- P7 (hostility)

- G8 (uncooperativeness)

12. Subject must be able and agree to remain off prior antipsychotic medication from
clinic admission through Day 4.

13. Subject must have normal to mild symptoms on all individual items of the MSAS (< 2)
and AIMS (< 3), and the clinical global assessment item of the BARS (< 3).

14. Subject is, in the opinion of the Investigator, generally healthy based on screening
medical history, physical examination, neurological examination, vital signs,
clinical laboratory values (hematology, serum chemistry, urinalysis, lipid panel,
coagulation panel, and thyroid panel), and a 12-lead ECG.

15. Subject must be willing to stay within the clinic for the required period and return
for follow-up visits.

16. Subject must possess an educational level and degree of understanding of English that
enables them to communicate suitably with the Investigator and study coordinator.

17. Subject must agree to comply with all restrictions for the required length of time
(see Section 10.5).

Exclusion Criteria:

1. Subject does not tolerate venipuncture or has poor venous access that would cause
difficulty for collecting blood samples.

2. Subject has participated in an investigational drug study and received
investigational drug within 30 days (or longer if the half-life is known to be ≥ 150
hours) prior to the screening visit, or who is currently participating in another
clinical study. Subject has previously received study drug.

3. Subject has any clinically significant unstable medical condition or any clinically
significant chronic disease that in the opinion of the Investigator, would limit the
subject's ability to complete and/or participate in the study:

- a. Hematological (including deep vein thrombosis) or bleeding disorder, renal,
metabolic, endocrine, pulmonary, gastrointestinal, urological, cardiovascular,
hepatic, neurologic, or allergic disease (except for untreated, asymptomatic,
seasonal allergies at time of dosing).

- b. History of cancer or significant neoplasm.

- c. Disorder or history of a condition, or previous gastrointestinal surgery (eg,
cholecystectomy, vagotomy, bowel resection, or any surgical procedure) that may
interfere with drug absorption, distribution, metabolism, excretion,
gastrointestinal motility, or pH, or a clinically significant abnormality of the
hepatic or renal system, or a history of malabsorption.

- d. Known or suspected excessive alcohol consumption exceeding 14 drinks/week (1
drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor)
within 6 months of the screening visit or a positive breath alcohol test at
screening.

- e. Subject has a clinically significant abnormal 12-lead ECG that may jeopardize
the subject's ability to complete the study or a screening 12-lead ECG
demonstrating any one of the following: heart rate > 100 beats per minute, QRS >
120 ms, QT interval corrected for heart rate using Fridericia's formula (QTcF) >
450 ms (males), QTcF > 470 ms (females), or PR > 220 ms.

4. Female subject who is pregnant or lactating.

5. Subject has a presence or history of a medically diagnosed, clinically significant
psychiatric disorder (including mental retardation, schizoaffective disorder,
schizophreniform disorder, psychotic depression, and bipolar disorder) other than
schizophrenia.

6. Subject experienced an acute exacerbation of psychosis within the last 3 months or
experienced an acute exacerbation of psychosis requiring hospitalization within the
last 6 months.

7. Subject experienced an acute exacerbation of psychosis requiring change in
antipsychotic medication (with reference to drug or dose) within the last 3 months.

8. Subject has a diagnosis or history of substance dependence (except nicotine ≤ 1
pack/day) or substance abuse (except cannabis) according to DSM IV-TR criteria ≤ 3
months prior to screening or a positive urine drug screen (except benzodiazepines) at
screening.

9. Subject is at significant risk of harming himself or others according to the
Investigator's judgment.

10. Subject has had past episodes of significant extrapyramidal symptoms (EPS) under
current medication that required dose modification or the addition of
anti-Parkinson's treatment within the last 6 months.

11. Subject is currently or has within 1 year before entering the study been treated with
a depot antipsychotic medication.

12. Subject is under forced treatment.

13. Subject is taking aripiprazole at screening. Subject takes or has taken other
disallowed recent or concomitant medications (see Section 10.5). Subjects must taper
off schizophrenia medications by Day -1.

14. Subject has a history of allergic reaction to any medication or has a known or
suspected sensitivity to any substance that is contained in the formulation.

15. Subject has any clinically significant abnormal laboratory values (hematology, serum
chemistry, urinalysis, lipid panel, coagulation panel, and thyroid panel) (Note:
clinically significant abnormal findings to be discussed with the Medical Monitor
prior to including subject).

16. Subject has a history of hospitalization within 45 days prior to the screening visit.

17. Subject has a positive test for Hepatitis B surface antigen or Hepatitis C antibody
at screening.

18. Subject has a positive test for Human Immunodeficiency Virus Type 1 or 2 (HIV-1 or
HIV-2) at screening, or subject is known to have tested positive for Human
Immunodeficiency Virus (HIV).

19. Subject has abnormal hepatic function tests (aspartate aminotransferase [AST],
alanine aminotransferase [ALT], bilirubin) or renal function (estimated creatinine
clearance [CrCl] < 95 mL/min for males and < 85 mL/min for females based on serum
creatinine using Modification of Diet in Renal Disease [MDRD]-glomerular filtration
rate [GFR] method) at screening.

20. Subject has experienced significant blood loss (≥ 473 mL) or donated blood within 60
days prior to first dose of study drug; has donated plasma within 72 hours prior to
the first dose of study drug or intends to donate plasma or blood or undergo elective
surgery during study participation or within 60 days after the last study visit.

21. Subject consumes more than 300 mg of caffeine per day (5 cups of coffee or equivalent
in caffeinated beverages).

22. Subject has used prescription or nonprescription drugs, vitamins, or dietary or
herbal supplements within 14 days prior to dosing or anticipates the need for any
medication during their participation in this study [exception: female subjects who
are taking oral, patch, or intrauterine device (IUD) hormonal contraceptives, or
progestin implant or injection]. Enzyme modulating herbal supplements (eg,
Metabolife™) must be discontinued 30 days prior to the first dose of study drug.

23. Subject is a staff member or the relative of a staff member.

24. Subject is in the opinion of the Investigator, unsuitable in any other way to
participate in this study.