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 multiple
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 MTD for once-daily multiple oral administration of SEP-363856, and
characterize the plasma and urine PK profiles of SEP-363856 and its metabolite SEP-363854 in
male and female subjects with schizophrenia. The effect of SEP-363856 on the PANSS, CGI-S,
and CDSS scales will also be assessed.

For each of the dose-escalation cohorts, 12 subjects (9 active subjects and 3 placebo
subjects) will be dosed for 7 consecutive days with serial collection of PK blood samples
after the first and last doses, and daily collection of trough PK blood samples. An attempt
will be made to have at least one-third of subjects in each cohort be female.

Inclusion Criteria:

- 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.

- 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.

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

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

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

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

- Male subjects with female partner(s) of childbearing potential1 must agree to avoid
fathering a child and use acceptable methods of birth control from screening until at
least 90 days after the last study drug administration.

- 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.

- Subject must have a CGI-S score ≤ 4 (normal to moderately ill) at screening.

- Subject must have a PANSS total score ≤ 80 at screening.

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

- P7 (hostility)

- G8 (uncooperativeness)

- Subject must be able and agree to remain off prior antipsychotic medication from
clinic admission through Day 10.

- 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).

- 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, thyroid panel, serum prolactin, and glycosylated hemoglobin
(HbA1C)], and a 12-lead ECG.

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

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

- Subject must agree to comply with all restrictions for the required length of time

Exclusion Criteria:

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

- 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.

- 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.

- Female subject who is pregnant or lactating.

- 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.

- 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.

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

- 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.

- Subject is at significant risk of harming himself or others according to the
Investigator's judgment or as indicated by an answer of "yes" to "Suicidal Ideation"
Items 4 or 5 on the C-SSRS at the screening visit within the last 2 years on the
lifetime version of C-SSRS.

- 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.

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

- Subject is under forced treatment.

- Subject is taking aripiprazole at screening. Subject takes or has taken other
disallowed recent or concomitant medications. Subjects must taper off antipsychotic
medications by Day -1.

- 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.

- Subject has any clinically significant abnormal laboratory values (hematology, serum
chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, and serum
prolactin) (Note: abnormal findings that may be clinically significant or of
questionable significance will be discussed with the Medical Monitor prior to
including subject).

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

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

- 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).

- 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.

- 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.

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

- Subject has used disallowed prescription (see Sections 10.5.1 and 10.5.2) or
disallowed nonprescription drugs, vitamins, or dietary or herbal supplements
including enzyme-inhibiting supplements within 14 days prior to dosing or anticipates
the need for any disallowed 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-inducing herbal
supplements (eg, Metabolife™) must be discontinued 30 days prior to the first dose of
study drug.

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

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