A Multicenter, Randomized, Double-Blind, Parallel-Group Study to Assess the Efficacy and Safety of Oral Etrasimod as Induction and Maintenance Therapy for Moderately to Severely Active Crohn's Disease

CD is a chronic, relapsing and remitting, immune-mediated inflammatory
condition that may affect the entire gastrointestinal tract and is associated
with an increased risk for colon cancer. The transmural tissue damage observed
with CD can result in intestinal infections and abscesses, intestinal
perforation, strictures, and fistula formation. Treatment for patients with CD
is generally focused on symptomatic care and mucosal healing with overall goals
of inducing and sustaining clinical remission, improving
quality of life, and preventing more severe disease manifestations and
complications that require hospitalization and surgical intervention. Treatment
of CD includes several major classes of medications: corticosteroids,
immunosuppressants (such as methotrexate [MTX] and the thiopurines azathioprine
[AZA] and mercaptopurine), biologics (anti-tumor necrosis factor alpha [TNFα]
antagonists [infliximab, adalimumab, and certolizumab pegol], interleukin-12
and -23 antagonist [ustekinumab], integrin receptor antagonists [vedolizumab]),
and antibiotics. Janus kinase (JAK) inhibitors are being explored for use in CD
(tofacitinib and filgotinib). Though used in the treatment of IBD more broadly,
the anti-inflammatory drug 5-aminosalicylic acid (5-ASA) demonstrates a low
efficacy preoperatively and at prevention of CD recurrence in the postoperative
setting. CD is considered neither medically nor surgically *curable,* with
clinical, endoscopic, and surgical recurrence reported in 50%, 80%, and 30% of
patients, respectively. The surgical burden in CD remains high. There remains a
great unmet clinical need for new efficacious and safe treatments for CD, as
current therapies often provide only transient or marginal symptomatic relief.
The complex and heterogenous nature of the disease further underscores the need
for a range of therapies for CD. Given that immune system dysregulation is a
pathophysiological feature of many immune-mediated inflammatory disorders,
synthetic small molecule sphingosine 1-phosphate (S1P) receptor modulators have
the potential to act across a wide range of such diseases. S1P receptor
modulators have been shown to reduce inflammation and induce clinical remission
in multiple sclerosis (fingolimod, ponesimod, siponimod, ozanimod), psoriasis
(ponesimod), and ulcerative colitis (ozanimod, etrasimod). Therefore, S1P
receptor modulators may also reduce inflammation in CD and induce clinical
remission. Etrasimod (APD334) is an orally administered, selective, synthetic
S1P receptor 1, 4, 5 modulator that is being developed to treat immune-mediated
inflammatory disorders. A Phase 2 study with etrasimod in adult subjects with
moderately to severely active UC demonstrated consistent and clinically
meaningful improvements in endpoint measures reflecting cardinal symptoms of UC
and objective endoscopic and histologic evidence of colorectal mucosal healing.

This study has been transitioned to CTIS with ID 2024-513569-38-00 check the CTIS register for the current data.

Main objective:
SSA
The safety, tolerability, and efficacy of 2 doses of etrasimod as induction
therapy in subjects with moderately to severely active Crohn's disease (CD)
SS1 - Cohort 1
The dose-response relationship of 2 doses of etrasimod vs placebo as induction
therapy
An oral etrasimod dose, based on efficacy and safety for continued development
SS1 Cohort 2
The dose-response relationship of 2 doses of etrasimod versus placebo as
induction therapy in subjects with moderately to severely active CD
An oral etrasimod dose, based on efficacy and safety, for continued development
along with data generated from SS1 Phase 2b Cohort 1
SS2
The efficacy of the selected etrasimod dose vs placebo as induction therapy in
subjects with moderately to severely active CD
SS3
The efficacy of etrasimod vs placebo as maintenance therapy in subjects
SS4
The long-term safety and tolerability of etrasimod in subjects with moderately
to severely active CD
To evaluate the long-term safety and tolerability of etrasimod in subjects with
moderately to severely active CD

Secundaire doelstelling:
SSA
veiligheid, verdraagbaarheid en werkzaamheid op lange termijn van etrasimod bij
personen met matig tot ernstig actieve coeliakie
PK-effecten van etrasimod als inductie- en onderhoudstherapie bij personen met
matig tot ernstig actieve coeliakie
SS1
Veiligheid, verdraagbaarheid en werkzaamheid van etrasimod bij personen met
matig tot ernstig actieve coeliakie
SS2
veiligheid en verdraagbaarheid van geselecteerde etrasimod Ph3-dosis versus
placebo als inductietherapie bij proefpersonen met matig tot ernstig actieve
coeliakie
SS3
werkzaamheid van etrasimod op aanhoudende klinische remissie en endoscopische
respons, endoscopische remissie en corticosteroïdenvrije klinische remissie
bij personen met matig tot ernstig actieve coeliakie karakteriseren de
veiligheid en verdraagbaarheid van etrasimod als onderhoudstherapie bij
personen met matig tot ernstig actieve coeliakie
SS4
Langetermijnwerkzaamheid van etrasimod bij personen met matig tot ernstig
actieve coeliakie

This is a seamless Phase 2/3, multicenter, randomized, double-blind study that
comprises 5 substudies designed to evaluate the efficacy, safety, and
tolerability of etrasimod as therapy in subjects with moderately to severely
active CD who are refractory or intolerant to at least 1 of the current
therapies for CD (ie, corticosteroids, immunosuppressants, or biologics).
Substudy A - Phase 2 (SSA-P2): A Phase 2, randomized, double-blind, substudy to
assess the safety, tolerability, and efficacy of oral etrasimod
therapy in subjects with moderate to severe CD that supports the selection of
an induction and maintenance dose(s) for Phase 3.
Substudy 1 - Phase 2 (SS1-P2b): A Phase 2b randomized, double-blind,
placebo-controlled, dose-ranging induction substudy to evaluate etrasimod as
induction therapy and select an induction and maintenance dose(s) for continued
evaluation in Phase 3.
Substudy 2 - Induction (SS2-I): A Phase 3 randomized, double-blind,
placebo-controlled substudy to evaluate etrasimod as induction therapy.
Substudy 3 - Maintenance (SS3-M): A Phase 3 randomized, double-blind,
placebo-controlled substudy to evaluate etrasimod as maintenance therapy.
Substudy 4 - Long-Term Extension (SS4-E): A long-term extension (LTE) substudy
for subjects who complete at least 52 weeks of treatment.

Depending on the substudy the subject will be taking etrasimod 3 mg, etrasimod
2 mg or matching placebo.

As of 30 August 2019, etrasimod has been found to be safe and well-tolerated in
approximately 388 adult subjects treated at various doses. The safety and
tolerability of etrasimod has been evaluated in Phase 1 studies with healthy
adult subjects at single doses up to 5 mg and repeated doses up to 4 mg once
daily (qd). In a Phase 2 dose-ranging study in UC patients (APD334-003),
treatment with 2 mg etrasimod qd for 12 weeks led to clinically meaningful and
statistically significant endoscopic and symptomatic improvements versus
placebo. Sustained beneficial effects of etrasimod were observed for up to 46
weeks in the subsequent open-label extension study (APD334-005). Although UC
and CD have different pathophysiology including extent and location of disease,
they are both antigen- and immune-mediated inflammatory bowel diseases and
there is evidence that drugs that are
effective for the treatment of UC may also be efficacious for the management of
CD. Therefore, it is reasonable to hypothesize that etrasimod may offer similar
clinical benefits to CD patients with active disease as UC patients, and this
clinical investigation is necessary to affirm or reject this hypothesis. There
have been no clinically significant safety concerns in clinical studies with
etrasimod. In APD334-003, the most frequently reported treatment emergent
adverse events (TEAEs), reported by > 2 subjects treated with 1 mg or 2 mg
etrasimod were ulcerative colitis (worsening), upper respiratory tract
infection, anemia, and headache. In APD334-005, the open-label extension of
Study APD334-003, the most frequently reported events by > 5 subjects treated
with 2 mg etrasimod were UC (worsening), gamma-glutamyl transferase increase,
anemia, nasopharyngitis, and upper respiratory tract infection. However, rare
adverse events (AEs) such as macular edema, liver enzyme elevations, and
dyspnea have been reported with fingolimod, one of the currently licensed S1P
receptor modulators fingolimod, siponimod and ozanimod. It is believed that the
non-selectivity (ie, activity at all 5 S1P receptors) of this first-generation
S1P receptor modulator contributes to many of these AEs. Etrasimod selectively
modulates S1P receptor subtypes 1, 4, and 5, which is expected to mitigate
off-target effects for an improved safety profile. Based on its mechanism of
action, etrasimod is expected to dose-dependently reduce lymphocyte counts.
This reduction is reversible, with lymphocyte counts returning to baseline
normal levels within 7 days of study drug discontinuation. Furthermore, S1P
receptor modulators are associated with an expected, on-target dose-dependent
effect of reducing heart rate (HR) upon first dosing with HR recovery to
pre-dose baseline thereafter, but there have been no reported cases of
symptomatic bradycardia on first dose and rare first- or second-degree
atrioventricular (AV) block found on ECG has been asymptomatic and transient
(ie, spontaneous resolution) with etrasimod. Based on the preclinical and
clinical data that have been generated from etrasimod studies and the
precautions outlined above, the favorable benefit/risk assessment justifies the
further clinical development of etrasimod in subjects with moderately to
severely active CD in this current Phase 2/3, multicenter, randomized,
double-blind induction, placebo-controlled study.