A Phase 3, Open-label Study to Determine the Long-Term Safety and Efficacy of Vedolizumab (MLN0002) in Patients with Ulcerative Colitis and Crohn's Disease

Ulcerative colitis (UC) is a relapsing, remitting inflammatory disease of the
colonic mucosa and submucosa. The prevalence of UC is approximately 200/100,000
of population in the United States (US) and approximately 150/100,000 of
population in Western Europe. A
genetic contribution to the disease is indicated by the increased incidence of
UC (of 30 to 100 times that of the general population) among first-degree
relatives of patients with UC.
The characteristic pathology is one of chronic inflammation characterized by
large numbers of lymphocytes and histiocytes in the diseased mucosa and
submucosa with an acute inflammatory infiltrate composed of neutrophils
variably present.
Crohn*s disease (CD) is a relapsing, remitting inflammatory disease that may
involve any portion of the length of the gastrointestinal tract from mouth to
anus in a transmural fashion from mucosa to serosa. The prevalence of CD is
approximately 150/100,000 of population
in the US and approximately 125/100,000 of population in Western Europe. The
characteristic pathology involves a chronic inflammatory infiltrate consisting
of neutrophils and macrophages. Hallmarks of CD include granulomatous
inflammation and aphthous ulceration.
Clinical manifestations of both diseases include diarrhea (typically bloody in
patients with UC), as well as abdominal pain, fecal urgency, and incontinence.
Systemic features such as fever, weight loss, malaise, and fatigue are
indicators of more extensive disease. Extraintestinal
manifestations such as uveitis, arthritis, ankylosis spondylitis, or primary
sclerosing cholangitis may also be seen in conjunction with inflammatory bowel
disease (IBD). The diagnosis of UC or CD is usually made by histopathologic
examination of endoscopic mucosal biopsy specimens obtained on ileocolonoscopy.
Current treatments have been effective for many patients with UC or CD but have
numerous limitations for patients with moderate to severe disease.
5-Aminosalicylates (5-ASAs) are the mainstay of UC pharmacotherapy for
induction and maintenance of remission for
patients with mild to moderate disease, but are less effective in severe
disease. The National Cooperative Crohn*s Disease Study demonstrated a role for
sulfasalazine (a 5-ASA containing molecule) in moderate to severe Crohn*s
disease , however, the efficacy of 5-
ASAs in CD has been called into question by a recent meta analysis.
Corticosteroids are often required for the one-third of patients who fail to
respond to 5-ASAs. While highly effective for induction of remission,
corticosteroids are not useful in either disease for
maintenance of remission and carry significant undesirable side effects,
including osteoporosis, glucose intolerance, and increased risk of infection.
Immunomodulatory agents, including 6-mercaptopurine and azathioprine, have a
role in maintenance of remission in moderate to severe UC and moderate to
severe CD. Their relatively slow onset of action precludes their use during
flares of disease, and the use of these agents has been reported to potentially
increase the risk of lymphoma in patients with IBD. Intravenous cyclosporine
has a role in the management of severe UC; however, it is impractical in
non-hospitalized patients, requires intense monitoring, and may cause
irreversible nephrotoxicity, all of which limit its use to severe cases.
Methotrexate, while ineffective in UC, has a role in the management of
refractory CD; however, it also
demonstrates a number of dose-limiting toxicities. Antibiotics have marginal
efficacy in maintenance of remission in CD and are not effective in UC.
Biologic agents, including monoclonal antibodies against tumor necrosis factor
alpha (TNF*), such as infliximab (Remicade®) and adalimumab (Humira®), have
been studied and have proven useful for both induction and maintenance of
remission in CD. Infliximab is
also useful for induction and maintenance of remission in UC. However, only
approximately one-third of patients have a sustained remission at one year
following treatment with these agents. In addition, treatment with TNF*
antagonists has been associated with a number of serious adverse events (SAEs)
involving hypersensitivity and infection. Reactivations of latent tuberculosis
(TB) and disseminated histoplasmosis have
been reported, and in some cases have been fatal. Induction of remission with
infliximab occurs in only 31% to 39% of patients with UC and durable clinical
remission (at 1 year) occurs in only 26% of patients with UC. Efficacy data for
both infliximab and adalimumab
in CD are quite similar to the infliximab data in UC with only a minority of
patients having a durable response at 1 year.
Failure of medical therapy leads to colectomy in 9% to 35% of patients with UC
within 5 years. Colectomy is considered to be an important adjunct treatment
for refractory UC;
however, colectomy with ileal pouch anal anastomosis (the standard surgical
therapy) has many limitations and is associated with its own set of
complications, including high stool frequency, female infertility, and a
cumulative incidence of pouchitis of 50% at 10 years. Surgical removal of
highly diseased, strictured, or stenotic segments of bowel in CD is not
curative. Relapse occurs in a majority of patients with CD who undergo
segmental resections, and the need for reoperation is the rule rather than the
exception.
The limitations of current therapies for IBD indicate that there is a
significant need for safer and more effective therapies. MLN0002 is being
developed to fulfill this important unmet medical need.

Study Objectives:
Primary Objective
* To determine the safety profile of long-term MLN0002 treatment

Resource Utilization and Patient-Reported Outcome Objectives
* To determine the effect of long-term MLN0002 treatment on time to major
inflammatory bowel disease (IBD)-related events (hospitalizations, surgeries,
and procedures)
* To examine the effect of long-term MLN0002 treatment on health-related
quality of life (QOL) measurements

Overview of Study Design:
Following enrollment all patients will be administered 300 mg vedolizomab every
4 weeks for the duration of the study, followed by a 16-week posttreatment
observation and safety assessment period. The total duration of MLN0002
treatment will vary by patient based on continued benefit until March 2016, or
until vedolizumab is available in the country in which the patient resides, or
until patient withdrawal, whichever is sooner.

Patients receiving oral corticosteroids will begin an oral corticosteroid
tapering regimen once they achieve clinical response or if, in the opinion of
the investigator, they demonstrate sufficient improvement in clinical signs and
symptoms. After 6 months±
* patients still on oral corticosteroids should not exceed a daily oral
corticosteriod dose of the equivalent of 5 mg/day of prednisone or 3 mg/day of
budesonide. Attempts to taper and discontinue corticosteriods should continue,
in clinically indicated.
* For patients who are otherwise doing well (in the opinion of the
investigator) short-term oral corticosteriod courses (up to the equivalent of
30 mg/day of prednisone or 9 mg/day of budesonide) are permitted for documented
disease exacerbations. In such instances, however, the dose must be tapered to
the equivalent of 5mg/day of prednisone or 3 mg/day of budesonide within 3
months.

Patients who meet the criteria for treatment failure will be withdrawn from the
study. In addition, patients who, in the opinion of the investigator or
patient, are not benefiting from therapy will be withdrawn from the study;
investigators should also consider withdrawing patients who require
corticosteriod increases fot the control of their IBD more often than every 6
months.

Safety assessments and exploratory efficacy assessments (using the partial Mayo
Score [for patients with UC] or the Harvey-Bradshaw Index (HBI) score [for
patients with CD]) will be made throughout the treatment period, and at the
Final Safety Visit/Early Termination visit. Serious
adverse events (SAEs) and adverse events (AEs) will be collected throughout the
study. Data pertaining to health care utilization and patient-reported outcomes
will also be collected regularly throughout the study. In addition, safety data
will be reviewed with reference to an external administrative database as part
of a separate observational study.

see: study design above and the flowchart, protocol page: 5 - 8.

Potential Risks and Benefits (see: Protocol page 23-26)
Summary of Risks and Benefits
The integrated safety analysis for all completed and ongoing clinical studies
(as of 10 March 2008) demonstrates that MLN0002 has an acceptable safety
profile. Phase 2 studies have demonstrated efficacy in UC and CD. These data
support a favorable benefit-to-risk profile
for MLN0002. In addition, based on its targeted mechanism of action, MLN0002
may prove to have a superior benefit-to-risk profile compared with conventional
systemic immunosuppressive therapies for IBD, such as corticosteroids and TNF*
antagonists. On this basis, as well as the risk management procedures
implemented in this study, further investigation of this novel compound for the
treatment of IBD is warranted.