A multi-center, phase 1, open-label evaluation of the effect of PF-00547659 (anti MadCam monoclonal antibody) on cerebrospinal fluid (CSF) lymphocytes in volunteers with Crohn*s Disease or Ulcerative Colitis who are anti-TNF inadequate responders.

The purpose of this study is to confirm the hypothesis that treatment with PF
00547659 will not alter the number or type of lymphocytes in the CSF or reverse
the CD4+:CD8+ ratio, thus indicating that it is unlikely to impair CNS immune
surveillance. No studies of CSF T lymphocyte populations have been published
to date in patients with Crohn*s disease or Ulcerative Colitis. Therefore,
baseline values will be examined to determine whether they are consistent with
those in the normal population, or demonstrate evidence of impaired immune
surveillance due to prior or concomitant treatment with Immunosuppressants
and/or anti TNFs which have been reported to be associated with opportunistic
infections as well as demyelination syndromes.

Normal individuals have approximately 2000 3000 WBCs/mL in the CSF of which
approximately 90% are lymphocytes. Of these lymphocytes, 66% 75% of them are
CD4+ cells. In order to have enough cells for FACS analysis, 10 mL CSF will be
centrifuged to concentrate the cells. This should allow for approximately
25,000 cells for analysis. The supernatant may be used for determination of
soluble MAdCAM, VCAM 1 and ICAM 1.

In order to assess the effects of PF 00547659 on peripheral blood and CNS
lymphocyte trafficking, a panel of T and B cell markers will be tested by FACS
analysis as well as by LSC in samples of CSF and blood.
Lymphocyte trafficking in the gut will be assessed in an exploratory fashion in
the optional Endoscopic Biopsy Substudy (see Section 7.6). This will confirm
the mechanism by which PF 00547659 reduces intestinal inflammation. Thus, this
study will simultaneously investigate T cell trafficking into all 3
compartments, CSF, gut and blood in subjects with active Crohn*s disease or
Ulcerative Colitistreated with PF 00547659.

The primary objective is to determine whether PF 00547659 alters central
nervous system immune surveillance in subjects with active, moderate to severe
Crohn*s disease or active, moderate to severe Ulcerative Colitis by altering
the absolute lymphocyte count in the CSF

This is a multi center, phase 1, open label sequential cohort study in
volunteers with active, moderate to severe CD/UC who are inadequate responders
or intolerant to immunosuppressants (azathioprine [AZA], 6 mercaptopurine [6
MP] and/or methotrexate [MTX]) and anti TNFs. All volunteers must meet all
inclusion/exclusion criteria before undergoing a LP (see Section 4 of protocol
am 2).

Cohort 1
The purpose of Cohort 1 is to determine the baseline CSF characteristics in
subjects with active, moderate to severe CD who have failed or are intolerant
to immunosuppressants and anti TNFs. Two LPs in 5 subjects will establish the
intra and inter subject variability for CSF lymphocytes. If the variability
is greater than expected, an additional 5 subjects may be enrolled.
Cohort 1 will consist of approximately 5 10 evaluable CD volunteers meeting all
entry criteria for active CD who will undergo 2 lumbar punctures (LPs) (see
Section 7.5). If the first LP is acceptable subjects will have a second LP 2 4
weeks later (* 3 days). Subjects who have a traumatic first LP (RBC count is
>1/*L) must proceed to dosing. Subject who have a serious complication such as
headache requiring a blood patch, may have a second LP, or proceed to dosing
without a second LP if they choose. A sufficient number of subjects will be
enrolled to replace all subjects without 2 evaluable LPs. If after 48 hours
following the second LP all AE*s have resolved, the subject will then receive
the first of 3 monthly doses of PF 00547659 (see Section 6). At Week 12,
subjects who have a clinical response to the treatment, (see Section 3.1.5) are
eligible to enter the open label extension study (A7281007). Non responders
will enter the follow up period of this study.

Cohort 2
Cohort 2 will consist of at least 15 20 evaluable CD or UC volunteers who meet
the same criteria as for cohort 1. They will have a LP, receive 3 doses of
study drug and then have a second LP if results of the first LP are acceptable,
eg, non traumatic (see Section 7.5.1.1). A sufficient number of subjects will
be enrolled to ensure at least 15 paired, evaluable, LPs are obtained. Whether
or not the LPs are evaluable or both are performed, subjects may receive
treatment. At week 12, subjects who have a clinical response to the treatment,
(see Section 3.1.5) are eligible to enter the open label extension study
(A7281007 for CD subjects or A7281010 for UC subjects). Non responders will
enter the follow up period.

Optional Endoscopic Biopsy Substudy
In order to evaluate lymphocyte trafficking in the gut, a substudy will
evaluate pre and post treatment lymphocyte subsets and MAdCAM in colonoscopic
biopsy samples. This substudy has two arms. Colonic tissue biopsies will be
obtained from normal and inflamed mucosa (Arm 1) or from a single site 10 cm
distal to the entry point of the scope (anus or stoma) (Arm 2).

Subjects will be monitored closely for neurologic symptoms, evidence of
infection, evidence of allergy, and evidence of myocardial changes. In addition
all subjects receiving the LP's will undergo a 48-hours observation at the
treating hospital. Please see the OVERALL RISK_BENEFIT ASSESSMENT which is part
of the IMPD (D2 in submission package) for further information.