A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

1. Men, women and adolescents 16 to 80 years of age, inclusive, at the time of
assent/consent. Enrollment of subjects < 18 years should be conducted only if
acceptable according to local laws and regulations
2. Ability to provide written informed consent or assent and to be compliant
with the schedule of protocol assessments
3. Diagnosed with UC * 3 months prior to screening confirmed by endoscopic and
histologic evidence
4. Active UC confirmed by endoscopy with * 10 cm rectal involvement.
Subjects with proctitis only at baseline who meet the other eligibility
criteria for inclusion, including the endoscopic and rectal bleeding criteria
for moderate to severe disease,will be capped at 15% of the total subjects
enrolled
5. Moderately to severely active UC defined as MMS of 4 to 9, including an ES
of * 2 and RB score * 1
6. Received a surveillance colonoscopy within 12 months before baseline to rule
out dysplasia in subjects with pancolitis > 8 years duration or subjects with
left-sided colitis > 12 years duration. Subjects without a surveillance
colonoscopy within the prior 12 months will have a colonoscopy at screening
(ie, in place of screening proctosigmoidoscopy). Any adenomatous polyps must be
removed prior to their first dose of study treatment
7. Demonstrated an inadequate response to, loss of response to, or intolerance
to at least 1 of the following therapies as defined below:
Conventional therapy
a. Corticosteroids
b. Thiopurines
Biologic therapy or JAK inhibitor therapy
a. Antitumor necrosis factor alpha (TNF*) antibodies (eg, infliximab,
adalimumab, golimumab, or biosimilars)
b. Anti-integrin antibodies (eg, vedolizumab)
c. Anti-Interleukin 12/23 antibodies (eg, ustekinumab)
d. JAK inhibitors (eg, tofacitinib)
8. Subjects are permitted to be receiving a therapeutic dose of the following
drugs:
* Oral 5 ASA compounds provided the dose has been stable for * 2 weeks
immediately prior to randomization
* Oral corticosteroid therapy (prednisone at a stable dose * 20 mg/day,
budesonide at a stable dose * 9 mg/day, or equivalent steroid) provided the
dose has been stable for the 4 weeks immediately prior to the screening
endoscopy assessment
* Immunosuppressive agents such as oral azathioprine or 6 mercaptopurine must
be discontinued * 2 weeks prior to randomization
* Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the dose has
been stable for the 2 weeks immediately prior to randomization
If oral 5-ASA or corticosteroids have been recently discontinued, they must
have been stopped for at least 2 weeks prior to the endoscopy used for the
baseline MMS.
9. Adequate hematological function defined by white blood cell count * 3.5 ×
109/L with absolute neutrophil count (ANC) * 1.5 × 109/L, lymphocyte count *
0.8 × 109/L, platelet count * 100 × 109/L, and hemoglobin * 8 g/dL
10. Adequate hepatic function defined by a total bilirubin level * 1.5 × the
upper limit of normal (ULN) range and aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) levels *2.0 × ULN. Subjects with an isolated
total bilirubin and normal AST and ALT diagnosed with Gilbert's syndrome may
participate
For other criteria see the protocol.

1. Severe extensive colitis as evidenced by:
Physician judgement that the subject is likely to require hospitalization for
medical care or surgical intervention of any kind for UC (eg, colectomy) within
12 weeks following randomization
Current evidence of fulminant colitis, toxic megacolon or recent history
(within last 6 months) of toxic megacolon, or bowel perforation
Previous total or partial colectomy
2. Diagnosis of Crohn's disease (CD) or indeterminate colitis or the presence
or history of a fistula consistent with CD
3. Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis
4. Hospitalization for exacerbation of UC requiring IV steroids within 12 weeks
of screening
5. Positive assay or stool culture for pathogens or positive test for
Clostridioides difficile toxin at screening
6. Pregnancy, lactation, or a positive serum * hCG measured during screening
7. Clinically relevant neurological, endocrine, metabolic, psychiatric,
cognitive impairment, alcohol/drug abuse/dependence, or other major systemic
disease making implementation of the protocol or interpretation of the study
difficult or would put the subject at risk
8. Have any of the following conditions or receiving treatments that may affect
cardiovascular function:
Myocardial infarction, unstable angina, stroke/transient ischemic attack,
decompensated heart failure requiring hospitalization or Class III/IV heart
failure * 6 months prior to & during the Screening Period
History or presence of second-degree or third-degree atrioventricular block,
sick sinus syndrome, or periods of asystole for > 3 seconds without a
functional pacemaker
History or presence of recurrent symptomatic bradycardia or recurrent
cardiogenic syncope
Screening and W0/D1 prerandomization vital signs with a heart rate < 50 bpm OR
systolic blood pressure < 90 mm Hg OR diastolic BP < 55 mm Hg & Screening or
W0/D1 prerandomization ECG with PR interval > 200 ms or Fridericia's corrected
QT interval QTcF * 450 ms in men or * 470 ms in women
Start, stop, change or planned in dosage of any anti-arrhythmic drugs (Class I
to IV) *1 week before screening or 1w before or after randomization
9. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) <
70% of predicted values and FEV1/FVC ratio < 0.70 at screening
10. Uncontrolled diabetes as determined by hemoglobin A1c (HbA1c) > 9% at
screening, or subjects with diabetes with significant comorbid conditions such
as retinopathy
For other criteria see the protocol.