A MULTI-CENTER, OPEN-LABEL STUDY OF CP-690,550 IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

Tofacitinib is a potent, selective inhibitor of the JAK family of kinases with
a high degree of selectivity against other kinases in the human genome. In
kinase assays, tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent
TyK2. In cellular settings where JAK kinases signal in pairs, tofacitinib
preferentially inhibits signaling by heterodimers containing JAK3 and/or JAK1
with functional selectivity over JAK2 homodimer signaling. Inhibition of JAK1
and JAK3 by tofacitinibblocks signaling through the common gamma chain
containing receptors for several cytokines, including IL-2, -4,-7,-9, -15 and
-21. These cytokines are integral to lymphocyte activation, proliferation, and
function, and inhibition of their signaling may thus result in modulation of
multiple aspects of the immune response. In addition, inhibition of JAK1 will
result in attenuation of signaling by additional pro inflammatory cytokines,
such as IL 6 and IFN*. At higher exposures, inhibition of erythropoietin,
prolactin and other hormones could occur via inhibition of JAK2 homodimer
signaling.
The broad effects of JAK1/3 inhibition on multiple cytokine pathways provides
the rationale for developing tofacitinibas treatment for several diseases in
which lymphocyte activation/proliferation plays a pathogenic role. Tofacitinib
is being studied as an oral treatment for UC, Crohn*s disease, as a disease
modifying anti-rheumatic drug (DMARD) for the treatment of RA, as treatment for
plaque psoriasis and for the prevention of renal allograft rejection.

Primary Objective
• To assess the safety and tolerability of long-term tofacitinib therapy in
subjects with UC.

Secondary Objectives
• To evaluate the efficacy of long term tofacitinib therapy in subjects with UC.
• To evaluate the effect of long term tofacitinib therapy on quality-of-life in
subjects with UC.

This is a Phase 3, multi center, open label study in subjects who have
completed or demonstrated treatment failure in the maintenance study A3921096,
or who were non responders after completing 8 weeks of treatment in the
induction studies A3921094 or A3921095. Approximately 725 subjects are
expected to become eligible for the study. This study will continue up to
first market approval (FMA) in a global major market which may occur prior to
Month 36.

Subjects who completed Study A3921096 or had early withdrawal due to treatment
failure as defined in the A3921096 protocol are eligible to enroll in this
study, A3921139. In addition, subjects who complete 8 weeks of treatment in
Study A3921094 or A3921095 and are classified as non responders are eligible to
enroll in this study. The eligibility of a subject for this study will be
assessed based on study data collected at Week 8/9 of Study A3921094 or
A3921095 (for non responders) or the Week 52/53 visit (for completers) or early
termination visit (early withdrawals due to treatment failure) of Study
A3921096. The study data collected at the Week 8/9 visit for Study A3921094 or
A3921095 (for non responders) or the Week 52/53 visit or early termination
visit of Study A3921096 will be recorded as the baseline data for Study
A3921139.

Eligible subjects will be assigned to either tofacitinib 5 mg BID or 10 mg BID
depending on whether the subject is in remission at baseline of Study
A3921139. Remission is defined by a total Mayo score smaller than or equal to
2 with no individual subscore >1, and rectal bleeding subscore of 0. Eligible
subjects who are in remission at Week 52 of Study A3921096 will be assigned to
receive tofacitinib 5 mg BID. For treatment assignment, the central read
assessment of the Mayo endoscopic subscores will be used to determine if a
subject is in remission. Subjects who complete Study A3921096 but do not meet
the remission definition or who are early withdrawals due to treatment failure
in Study A3921096 are eligible to receive tofacitinib 10 mg BID. Treatment
failure is defined by an increase in Mayo score of at least 3 points from
baseline value of the maintenance study (A3921096), accompanied by an increase
in rectal bleeding subscore by at least 1 point, and an increase of endoscopic
subscore of at least 1 point (yielding an absolute endoscopic subscore of *2)
after a minimum of 8 weeks of treatment in the maintenance study. Subjects who
complete 8 weeks of treatment in the induction studies A3921094 or A3921095 and
are classified as non responders are also eligible to receive tofacitinib 10 mg
BID.

Tofacitinib dose can be adjusted from 5 mg BID to 10 mg BID for efficacy and
from 10 mg BID to 5 mg BID for safety or tolerability (see Section 5.8 for dose
adjustment guidelines). Dose adjustments should be limited to no more than 1
occurrence per subject during the study and should be implemented at a
regularly scheduled study visit.

Subjects from the induction studies A3921094 or A3921095 (ie, non responders)
who fail to demonstrate clinical response at Month 2 of this study will be
withdrawn from the study. Clinical response is defined by a decrease from the
induction study baseline (A3921094 or A3921095) Mayo score of at least 3 points
and at least 30%, with an accompanying decrease in the rectal bleeding subscore
of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. The
endoscopic subscore based on central reading will be used to assess clinical
response.
All subjects, who withdraw early or who complete this open label study, will
have a 4 week safety follow up evaluation after the last dose of study
medication.

Subjects will be required to remain on stable doses of their concomitant
medications for UC during the study period. Subjects who enter this study on
corticosteroids (eg, subjects who withdraw from Study A3921096 due to treatment
failure or non responders at the end of Study A3921094 or A3921095) will need
to continue the steroid tapering regimen described in Study A3921096 (see
Section 5.5). If a subject requires rescue therapy or undergoes surgery, the
subject should be withdrawn from the study and appropriate agents should be
given at the discretion of the investigator.

Subjects will be assigned to one of two dose groups depending on their
remission status at baseline of Study A3921139:
• Tofacitinib 5 mg BID (subjects in remission).
• Tofacitinib 10 mg BID (all other subjects).

Based on the totality of the non-clinical and clinical data generated thus far,
potentially important safety risks that have been observed with the oral use of
tofacitinib in humans include infections, neutropenia, anemia, increases in
serum creatinine, increases in lipids (increase in total, high density
lipoprotein [HDL], and low density lipoprotein [LDL] cholesterol), and
increases in transaminases. Additional safety risks that may be associated with
the use of tofacitinib include an increased risk for lymphoproliferative
disorders/lymphoma (observed risk in renal transplant population treated with
additional immunosuppressive co medications; potential risk in other
populations) or other cancers and effects on pregnancy and fetus.

Complete information on tofacitinib safety information for the oral use of
tofacitinib can be found in the current version of the tofacitinib
Investigator*s Brochure.