A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Etrasimod in Adult Subjects with Eosinophilic Esophagitis

EoE is a chronic and progressive, allergen-driven, immune-mediated disease of
the esophagus, with risk factors including atopy and other allergic diseases,
including asthma, allergic rhinitis, and atopic dermatitis. Histologically, EoE
is characterized by the accumulation of eosinophils in the lining of the
esophagus, a tissue that under normal conditions lacks these cells. The
presence of these eosinophils has been shown to have a direct effect on immune
function and tissue damage. The eosinophilic predominant inflammation
characteristic of EoE results in a variety of symptoms including but not
limited to difficulty swallowing (dysphagia and/or odynophagia) and
regurgitation, central chest pain, upper abdominal pain, food impaction, food
refusal, and malnutrition. Current treatment options for EoE are dietary,
pharmacologic, or endoscopic in nature. These treatments are subject to a
variety of disadvantages including difficulty in adhering to dietary therapy,
potential safety concerns associated with long-term use of systemic
corticosteroids, lack of efficacy of topical steroids in some
steroid-refractory patients, and invasiveness and risks of endoscopic
treatment, including esophageal dilation. Therefore, there is a need to
develop and find new long-term, safe and effective treatments for people with
EoE.
Etrasimod (APD334) is an orally administered, selective modulator of S1P
receptors 1, 4, 5 that is being developed to treat immune-mediated inflammatory
disorders (IMIDs). Etrasimod is a substance designed to block the movement of
lymphocytes to areas of inflammation. By blocking this movement etrasimod may
reduce inflammation of the esophagus, leading to an improvement in the symptoms
of EoE.

Primary:
* To evaluate the effects of etrasimod on esophageal eosinophilia in adult
subjects with active eosinophilic esophagitis (EoE)
* To evaluate the dose-response relationship of 2 doses of etrasimod versus
placebo in adult subjects with active EoE
* To select an etrasimod dose based on efficacy and safety for continued
development
Secondary:
* To evaluate the effect of etrasimod on dysphagia symptoms in adult subjects
with active EoE

This Phase 2, randomized, double-blind, multi-center study will evaluate the
efficacy, safety, and pharmacokinetics (PK) of etrasimod compared with placebo
in adults with active EoE.
The study will consist of a Screening Period of up to 28 days, 24 weeks of
double-blind treatment (Double-Blind Treatment Period), 28 weeks of active
extended treatment (Extension Treatment Period), and 4 weeks of follow-up
(Safety Follow-Up Period) for a total study duration of up to 60 weeks.
Eligible subjects will be randomized in a double-blind fashion (3:3:2 ratio) to
etrasimod 1 mg, etrasimod 2 mg, or matching placebo once daily. Randomization
will be stratified by baseline history of esophageal dilation (yes/no) and
concurrent proton pump inhibitor (PPI) therapy (yes/no).

During the Double-Blind Treatment Period, eligible subjects will be randomized
in a double-blind fashion (3:3:2 ratio) to etrasimod 1 mg, etrasimod 2 mg, or
matching placebo once daily. Subjects who were in the etrasimod 1 mg or
etrasimod 2 mg groups in the Double-Blind Treatment Period will continue the
same etrasimod dose in the Extension Treatment Period. Subjects who were in the
placebo group during the Double-Blind Treatment Period will be re-randomized
(1:1 ratio) to etrasimod 1 mg or etrasimod 2 mg at entry into the Extension
Treatment Period.

Subject's participation will last a total of approximately 57 weeks (1 year and
1 month) and consists of 4 periods: a screening period to determine eligibility
to participate, a 24-week treatment period, a 28-week extension treatment
period, and a 4-week follow-up period. Aside from the intervention described
above, participation in this study involves blood draws at multiple visits,
biopsy and endoscopies. Participants will also be subjected to: questions
regarding medical history, use of concomitant medications/procedures and
adverse events; measurement of vital signs; physical examination; eye tests;
pulmonary functions tests; ECGs, Esophagogastroduodenoscopy (EGD); eDiary
reporting and patient reported outcomes questionnaires.

The most common side effects seen in healthy volunteers were headache,
dizziness, mouth ulcers, skin rash caused by direct contact of the skin with a
substance, constipation, diarrhea, and a reduction in white blood cell counts
(the blood cells that help to fight infection). There were episodes of slower
heart rate after the first dose and changes in heart rhythm, but participants
did not feel any symptoms. This effect of etrasimod on the heart is a known
effect and it generally improved over time. The most common side effects seen
in patients with UC were upper respiratory tract infection, nasopharyngitis
(the common cold), anemia (low numbers of red blood cells), and headache.
Slower heart rate without feeling symptoms after the first dose, changes in
heart rhythm, and a reduction in white blood cell counts were also observed.
When patients with UC received etrasimod for longer (up to 52 weeks), some of
the patients experienced increased anemia and increased gamma-glutamyl
transferase (GGT).

The safety profile of etrasimod coupled with a potent effect on the lymphocyte
count demonstrate that etrasimod may be an effective oral treatment option for
IMIDs such as EoE. Based on the favorable clinical safety and efficacy data
that has been generated from etrasimod studies in healthy adults and subjects
with UC, the precautions outlined above, and the current lack of safe and
effective long-term oral medications for the treatment of EoE, the benefit/risk
assessment justifies the further clinical development of etrasimod in subjects
with EoE and the current Phase 2 study multi-center, randomized, double-blind,
placebo-controlled study.