A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

1. Men or women 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 law 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
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.
Subjects without a surveillance colonoscopy within the prior 12 months will
have a colonoscopy at screening (ie, in place of screening proctosigmoidoscopy).
7. Demonstrated an inadequate response to, loss of response to, or intolerance
to at least 1 of the following therapies:
a. Corticosteroids
b. Thiopurines
Biologic therapy or JAK inhibitor therapy
a. Antitumor necrosis factor alpha (TNF*) antibodies
b. Anti-integrin antibodies
c. Anti-Interleukin 12/23 antibodies (eg, ustekinumab)
d. JAK inhibitors
Concomitant treatments:
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
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
11. Adequate renal function defined by an estimated glomerular filtration rate
* 30 mL/min/1.73 m2 by the CKD-epidemiology collaboration equation at screening
12. Females must meet either a or b of the following criteria and males must
meet criterion c to qualify for the study:
a. A female who is not of childbearing potential must meet 1 of the following:
* Postmenopausal, defined as no menses for 12 months without an alternative
medical cause;
* Permanent sterilization procedure, such as hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy.
b. Non-pregnant female of childbearing potential must agree to using a highly
effective contraception method during treatment and for 30 days following
treatment that can achieve a failure rate of less than 1% per year when used
consistently and correctly. The following are considered highly effective birth
control methods:
* Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation, which may be oral, intravaginal, or
transdermal
* Progestogen-only hormonal contraception associated with inhibition of
ovulation, which may be oral, injected, or implanted
* Intrauterine device (IUD)
* Intrauterine hormone-releasing system
* Bilateral tubal occlusion
* Vasectomized partner, provided that partner is the sole sexual partner of the
WOCBP trial subject and that the vasectomized partner has received medical
assessment of the surgical success.
* Sexual abstinence. The reliability of sexual abstinence needs to be evaluated
in relation to the duration of the clinical study and the preferred and usual
lifestyle of the subject. Periodic abstinence is not acceptable.
c. A male subject with a pregnant or non-pregnant female of childbearing
potential partner must agree to using condoms during treatment and for 30 days
following treatment

1. Severe extensive colitis as evidenced by
Physician judgment that subject is likely to require hospitalization for
medical care or surgical intervention for UC within 12 weeks following
randomization
Current evidence of fulminant colitis, toxic megacolon or recent history (last
6 months) of toxic megacolon, or bowel perforation
Previous total or partial colectomy
2. Diagnosis of 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 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 or during Screening period
History or presence of:
Second-degree or third-degree atrioventricular block, sick sinus syndrome or
periods of asystole >3 seconds without a functional pacemaker
History or presence of recurrent symptomatic bradycardia or recurrent
cardiogenic syncope
Screening or W0/Day 1 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/Day 1 prerandomization ECG with PR interval > 200 ms or
Fridericia's corrected QT interval * 450 ms in men or * 470 ms in women
Start, stop, change or planned change in dosage of any anti-arrhythmic drugs
(Class I to IV) *1 week before screening or within 1 week before or after
randomization
9. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) <
70% of predicted values & 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
11. History of macular edema or retinopathy
12. History of active tuberculosis (TB), history of untreated or inadequately
treated latent TB infection, active or latent TB infection at screening
13. clinically significant active infection * 28 days prior to randomization,
required IV medication * 14 days prior to randomization or that may worsen
14. Have HIV/acquired immune deficiency syndrome or test positive for HIV
antibodies
15. Have acute or chronic hep B infection or test positive for hepatitis B
virus at screening (detectable HBV DNA or positive for hep B surface antigenor
negative for HBsAg and positive for antihepatitis B core antibody in
conjunction with detectable HBV DNA, or detectable HBV DNA)
16. Have current hep C infection or test positive for hep C virus (HCV)
17. History of an opportunistic infection or history of disseminated herpes
simplex or disseminated herpes zoster
18. History of or currently active primary or secondary immunodeficiency
19. History of cancer within the last 5 years, including solid tumors and
haematological malignancies (except basal cell and in situ squamous cell
carcinomas of the skin that have been excised and resolved) or colonic mucosal
dysplasia
20. History of lymphoproliferative disorder, lymphoma, leukemia,
myeloproliferative disorder, or multiple myeloma
21. Hypersensitivity to etrasimod or any of the excipients or placebo compounds
22. Prior treatment with S1P receptor modulators
23. Treatment with a biologic agent *8 weeks or a small molecule agent *5
elimination half-lives and detectable drug level prior to randomization
24. Treatment with an investigational therapy *3 months prior to randomization
25. Treatment with * 3 biologic agents or * 2 biologics plus a JAK inhibitor
approved for treatment of UC
26. Treatment with topical rectal 5-ASA, short-chain fatty acid enemas, or
steroids *2 weeks prior to and during screening
27. Treatment with topical rectal traditional medicine (e.g. Chinese medicine),
herb enemas, or suppositories *2 weeks prior to randomization
28. Treatment with methotrexate *8 weeks prior to and during screening or
cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil *16 weeks prior to
and during screening
29. Receipt of a live vaccine *4 weeks prior to randomization
30. Previous treatment with natalizumab
31. Previous treatment with lymphocyte-depleting therapies
32. Previous treatment with D-penicillamine, thalidomide, dimethyl fumarate, or
pyrimidine synthesis inhibitors
33. Treatment with IV immune globulin or plasmapheresis, *3 months prior to
randomization
34. Chronic use of therapies that moderately/strongly inhibit/induce cytochrome
P450 (CYP) 2C8 and 2C9 metabolism and inhibitors of UGT1A7 *4 weeks prior to
randomization