A randomized, double-blind, placebo-controlled, multicenter, phase 2a study to evaluate the safety, tolerability, and early proof of concept of TAK-018 for the prevention of postoperative Crohn*s disease recurrence.

Crohn*s disease (CD) is a chronic, relapsing inflammatory disease of the
gastrointestinal tract with no known cure. Its incidence globally is on the
rise, reaching 20 per 100,000 person-years in Western countries. A third of
patients with CD will require a major abdominal resection within
5 years after diagnosis, and up to 60% of patients within a decade. Up to 70%
of patients who undergo resection develop postoperative endoscopic recurrence
within 1 year, and one third need repeat surgery within 10 years. The
pathophysiology of CD relies on a complex interaction of host genetics, the
microbiome and inflammatory responses. Significant human gut commensal
community functional breakdown or dysbiosis is observed in CD. Genome-wide
association study (GWAS) results in CD underscore the theme of aberrant
host-microbiome interactions, pecifically ineffective pathogen clearance from
the mucosa because of genetic defects in bacterial pattern recognition (Nod2)
and in autophagy. Chronic immune stimulation by bacterial antigens is well
established as patients with CD have detectable antibodies to bacterial cell
constituents such
as OmpC and Flagellin, with higher titers of antibodies being associated with a
more severe *complicated* disease phenotype. The question that arises is
whether immune recognition of proteobacteria is causative for inflammation in
CD or is it a secondary phenomenon due to mucosal barrier disruption? Recent
evidence shows that antibacterial antibodies can be detected in serum of
patients with CD several years before clinical symptoms and diagnosis,
supporting the hypothesis of an initial bacterial insult that triggers
inflammation. In addition, metagenomic approaches coupled with classic culture
microbiology from mucosal biopsies from the terminal ileum of patients with
Crohn*s ileitis support the case for proteobacteria as pathobionts in CD. The
specific association of Escherichia coli with invasive properties, termed
adherent-invasive Escherichia coli (AIEC), with CD was first reported by
Darfeuille-Michaud et al. Since then, AIEC have been isolated from multiple
independent studies involving adult and pediatric patients with CD. Using the
multi-component definition of Darfeuille-Michaud et al, the reported prevalence
of AIEC in the literature varies from approximately 36% to over 90% in patients
with CD when evaluating mucosa-associated and intracellular E coli. AIEC are
distinct from other strains of E coli because they show non-classic virulence
factors of adherence and invasion. In particular, AIEC are able to survive and
replicate in intestinal epithelial cells and macrophages, thereby stimulating
the production of inflammatory cytokines such as tumor necrosis factor-alpha
(TNF-*). The interaction between AIEC and the intestinal epithelial cells is
primarily mediated by the FimH adhesin located at the tip of type 1 pili
present on the bacterial surface. Although type 1 pili genes are present in the
genomes of all E coli, AIEC strains specifically express FimH adhesin and
variants that allow them to more efficiently bind to mannose. These mechanisms
set the stage for a selective over-colonization of the epithelium by AIEC and
subsequent biofilm formation. The type 1 pili interact with glycoproteins such
as carcinoembryonic antigen-related cell-adhesion molecule 6 (CEACAM6) on
intestinal epithelial cells, TLR4 on immune cells, and GP2 on intestinal M
cells in a mannose-dependent manner. CEACAM6 and TLR4 receptors are upregulated
by inflammatory cytokines in patients with CD with ileal disease. The binding
of FimH to TLR4 induces the production of TNF-*, IL-6 and IL-8 in the gut,
independently of LPS. Additionally, FimH binding
to GP2 on the surface of M cells in the Peyer*s patches allow AIEC to enter
into the lamina propria. The subsequent phagocytosis of the AIEC by the
macrophages further contributes to the chronic production of TNF-*. A vicious
cycle of proinflammatory cytokine release is produced by the
TNF*-driven overexpression of CEACAM6 and increase in M-cell development. Thus,
FimH appears as a critical factor both in the production of pro-inflammatory
cytokines from the gut epithelium and in the invasion of the lamina propria.

Primary Objective:

to assess the safety and tolerability of TAK-018 in postoperative subjects with
CD after
laparoscopic ileocecal resection with primary anastomosis.

Secondary Objectives:

to evaluate the impact of TAK-018 on intestinal inflammation based on endoscopic
recurrence and serial fecal calprotectin measures.
to characterize the pharmacokinetics (PK) of TAK-018 in postoperative subjects
with CD
after laparoscopic ileocecal resection with primary anastomosis.

This is a randomized, placebo-controlled, double-blind study of TAK-018
(previously known as EB8018) in a total of 45 to 75 postoperative subjects with
Crohn*s disease (CD) after laparoscopic ileocecal resection with primary
anastomosis. All eligible subjects will be randomized 1:1:1 to either TAK-018
low dose (0.30 g taken twice daily [BID]), TAK-018 high dose (1.5 g taken BID),
or placebo (BID) for a 12-week treatment period. Subjects will receive the
first dose of study drug on Day 1 (D1, within 72 hours after surgery) and take
it twice daily immediately after a meal (ie, breakfast and dinner) with water,
approximately 8 to12 hours apart. Subjects will have on-treatment clinic visits
at Week 3 (W3), Week 6 (W6), and Week 12 (W12), and follow-up clinic visits
(off-treatment) at Week 18 (W18) and Week 26 (W26), and a Week 30 (W30) phone
call for safety follow-up. Blood samples will be collected presurgery and after
first and multiple doses at all clinic visits during the treatment period to
characterize disease progression, response to study drug, safety parameters,
and the pharmacokinetics (PK) of TAK-018. Subjects will also collect stool
samples before surgery during the screening period and at W3, W6, W12, W18, and
W26. Fecal calprotectin will be measured before surgery during the screening
period and in every stool collection. Endoscopic assessments will be performed
at the end of the 12-week treatment period (W12) and repeated at W26.
Intestinal resection tissue will be collected at surgery and biopsies will be
performed at W12 and W26. Subjects who relapse clinically or endoscopically
(Rutgeerts score *i2) during the study will discontinue study drug, receive
institutional standard of care in use at their investigational site, attend an
early termination visit 30 days after last dose of study drug, and be
discontinued from the study. The end of study will occur at W30, via telephone
call, for safety follow-up.

As most patients with Crohn's Disease (CD) eventually require an intestinal
resection, postoperative recurrence poses a significant burden to the CD
population. Disease recurrence on the histological level is observed within
days after ileocolonic anastomosis. Most CD therapies, such as probiotics,
aminosalicylates, thiopurines, steroids, antibiotics, and biologics, have
yielded either negative or equivocal results in terms of preventing relapse.

Because of its unique mechanism of action (MOA), TAK-018 blocks the pathobiont
entry underlying chronic inflammation and bowel wall damage observed in
patients with CD. This MOA is distinct from the conventional approach of
neutralizing inflammatory mediators such as TNF-alpha and IL-23, thereby
allowing patients with CD to maintain remission without lifelong immune
suppression. The purpose of this phase 2a, randomized, multicenter,
double-blind study is to evaluate the safety, tolerability, and early proof of
concept of TAK-018 for the prevention of postoperative CD
recurrence.

Please see the schedule of events in the protocol for a detailed overview of
visits, tests and examinations paragraph 9.3. The risks associated with this
study are described in the ICF, paragraph 6.