A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY
TO EVALUATE THE EFFICACY AND SAFETY OF ETROLIZUMAB AS AN INDUCTION AND MAINTENANCE TREATMENT FOR PATIENTS WITH MODERATELY TO SEVERELY ACTIVE
CROHN*S DISEASE

So far, there is no cure for CD. The treatment goals for CD are to induce and
maintain
symptom improvement, induce mucosal healing, avoid surgery, and improve quality
of
life. Etrolizumab, a subcutaneously administered mAb, is a novel anti-integrin
which unlike
vedolizumab, targets both the *4*7 and *E*7 receptors that regulate
trafficking, and
retention of T-cell subsets in the intestinal mucosa, respectively. Thus,
etrolizumab
offers the potential of an additive therapeutic effect in CD via a dual
mechanism of action
(MOA), without generalized immunosuppression.

Induction Phase (IP)
* To independently evaluate the efficacy of etrolizumab dose regimens compared
with placebo in inducing clinical remission and endoscopic improvement at the
end of the Induction Phase (Week 14)
Maintenance Phase (MP)
* To independently evaluate the efficacy of etrolizumab compared with placebo
in achieving clinical remission and endoscopic improvement at 1 year of
maintenance treatment (Week 66), for patients who achieved a Crohn's Disease
Activity Index (CDAI) 70 response (defined as a decrease of at least 70 points
from baseline CDAI) at Week 14 Safety Objectives
* To evaluate the overall safety and tolerability of etrolizumab compared with
placebo during Induction and Maintenance Phases of therapy
*in achieving clinical remission at Week 6
*in achieving an SES-CD *4, with no segment having a subcategory score that is
>1, at Week 14
* in achieving a reduction of CD signs and symptoms Evaluate in MP the efficacy
of etrolizumab compared with placebo:
*in maintaining clinical remission at Week 66 for patients who achieved
clinical remission at Week 14
*in achieving corticosteroid-free clinical remission at Week 66
*in maintaining endoscopic improvement at Week 66 for patients who achieved
endoscopic improvement at Week 14
*in achieving a SES CD *4, with no segment having a subcategory score that is
>1, at Week 66
*in achieving durable clinical remission during 1 year of maintenance therapy
*in change of CD signs and symptoms from baseline to Week 66
*corticosteroid-free clinical remission at Week 66 in patients who were
receiving corticosteroids at baseline

The study design will comprise 1) a Screening Phase (up to 28 days) to
determine patients*
eligibility for the study, 2) an Induction Phase (14 weeks), followed by 3) a
Maintenance Phase
(60 weeks) in patients demonstrating a CDAI-70 response at the end of the
Induction Phase,
and 4) a Safety Follow-Up Phase (12 weeks) after administration of the last
dose of study drug
in the Maintenance Phase for those patients who are not participating in Part 1
of open-label
extension Study GA29145 to receive etrolizumab treatment. At the completion of
the Safety
Follow-Up Phase, patients will be asked to enter an extended PML-monitoring
phase
(open-label extension Study GA29145, Part 2) for 92 weeks. An independent Data
Monitoring
Committee (iDMC) will monitor safety and study conduct on an ongoing basis.
Patients will have an option to consent and participate in a PK/PD substudy.
The objective of
the substudy is to determine the relationship between etrolizumab exposure and
receptor
occupancy in peripheral blood in patients with CD. To achieve this objective,
it is planned to
enroll approximately 150 patients in the substudy. Blood sampling for the PK/PD
substudy will
continue in the Maintenance Phase. Patients in all cohorts will provide blood
samples for
population PK analysis and PD characterization.

Depending on the dose assignment in the Induction Phase,
patients receive either study drug in a 1-mL PFS containing 0.7 mL of
etrolizumab (105-mg
dose) or a 2.25-mL PFS containing 1.4 mL of etrolizumab (210-mg dose) according
to the
treatment schedule. To preserve the blind to study drug assignment in the
Induction Phase, at
Weeks 0, 4, 8, and 12 all patients receive two injections: one 0.7-mL dose and
a second
1.4-mL dose, and either one (if in one of the study drug arms) or both (if in
placebo arm) will
contain placebo.
At Week 2, all patients will receive one 1.4-mL dose injection, which will
contain placebo for patients in the low-dose etrolizumab and placebo arms and
study drug for
the high-dose etrolizumab arm. In the Maintenance Phase, patients receive a
single 0.7-mL
dose (105-mg dose) that will either contain etrolizumab or placebo, according
to the treatment
schedule.

Given the significant clinical and non-clinical data generated to date for
etrolizumab,
there is a strong rationale and a positive benefit-risk assessment for studying
etrolizumab in a Phase III clinical trial in CD, supported by:
- An anti-*4*7 mAb, vedolizumab, approved for the treatment of patients with
moderate to severe CD.
- Completed studies with etrolizumab in UC demonstrating clinically meaningful
benefit, as well as a full characterization of the PK/PD profile in UC, and
importantly,
an acceptable safety profile in previous etrolizumab studies.
- Data that implicate *4*7 receptors in the pathobiology of CD with the
possibility that
inhibition of the *E*7/E-cadherin interaction by etrolizumab could bring
enhanced
efficacy.
- An acceptable safety profile in the ongoing clinical development program,
and a
carefully designed Phase III CD program with robust safety monitoring.