A Phase II, Open-label, Multicentre Study to Evaluate the Long-term Safety and Efficacy of MT-1303 in Subjects with Moderate to Severe Active Crohn*s Disease who have Completed the MT-1303-E13 Study

Sphingosine-1-phosphate (S1P), a multi-functional phospholipid mediator, is
generated from sphingosine by sphingosine kinases and binds five types of G
protein-coupled S1P receptors (S1P1, S1P2, S1P3, S1P4 and S1P5 receptors). It
has been well documented that S1P and the S1P1 receptor play an essential role
in lymphocyte egress from secondary lymphoid organs because it has been
demonstrated that lymphocytes are unable to exit from secondary lymphoid organs
to the periphery in mice lacking lymphocytic S1P1.

Fingolimod (FTY720), the first-in-class S1P receptor modulator, has been
marketed widely and has demonstrated good efficacy in relapsing-remitting
multiple sclerosis (RRMS) patientsThe active metabolite, fingolimod-phosphate,
strongly internalises S1P1 receptors and acts as a functional antagonist at
lymphocytic S1P1 receptors. Consequently, fingolimod inhibits S1P1-dependent
lymphocyte egress from secondary lymphoid organs to the periphery, decreases
circulating lymphocytes including autoreactive T cells, and exhibits
immunomodulating effects . Fingolimod however is reported to cause a transient
and mild reduction in heart rate , which is possibly associated with agonistic
activity at S1P1 and S1P3 receptors on atrial myocytes]. According the Summary
of Product Characteristics (SmPC) for fingolimod, time to reach peak plasma
concentration (tmax) of fingolimod is approximately 12-16 hours (h) and hence
there is no obvious correlation between tmax and the timing of bradycardia .
The reason for this discrepancy is not yet fully understood, however, it is
considered due to different kinetics of receptor occupancy and receptor
internalisation; the most plausible explanation is that internalisation of
S1P1/3 receptors on atrial myocytes would occur more rapidly (i.e., within 6 h
after the initial dose) than those on lymphocytes. The internalised receptors
on atrial myocytes would no longer respond to a further exposure of fingolimod
and therefore more severe bradycardia is unlikely to occur after 6-h post-dose

MT-1303, discovered by MTPC, was designed to be a selective S1P receptor
compound, in the hope that it would have fewer adverse effects than fingolimod.
MT-1303 is effectively converted to its active metabolite, (S)-MT-1303-P in
vivo. In humans, (S)-MT-1303-P shows greater selectivity for the S1P1 receptors
and shows no clear affinity to human S1P2/3 receptors. The long half-life
(approximately 380-400 h in humans) of MT-1303 and MT-1303-P indicates that
both will slowly accumulate to steady state over a period of about 10 weeks
[19]. (Accumulation ratios were 16-29 and 7-10 for MT-1303 and MT-1303-P,
respectively.) This pharmacokinetic (PK) profile therefore may be advantageous
in initiating MT-1303 treatment, as initial low doses of MT-1303 will have
little effect on heart rate and desensitisation can be expected to occur
gradually over several weeks of accumulation, rendering dose titration
unnecessary.

Oral administration of MT-1303 inhibited the development of colitis induced by
adoptive transfer of CD4+CD45RBhigh T cells in severe combined immunodeficiency
(SCID) mice, an animal model of inflammatory bowel disease (IBD) [19].
Moreover, MT-1303 is effective in animal models of multiple sclerosis,
psoriasis and systemic lupus erythematosus (SLE). These results indicate that
MT-1303 may have a therapeutic potential for IBD, RRMS, psoriasis and SLE,
while its effect on heart rate is anticipated to be less than that of
fingolimod.

The mechanism of action of MT-1303, its potential modulation of physiological
and pathological pathways and its safety profile warrant further investigation
of MT-1303 in inflammatory and autoimmune diseases in humans.

Primary Objective:
* To evaluate the long-term safety and tolerability of MT-1303 in subjects with
moderate to severe active CD
Secondary Objectives:
* To evaluate the long-term effects of MT-1303 on clinical outcomes in subjects
with moderate to severe active CD
* To explore the pharmacodynamic (PD) effects of MT-1303 in subjects with
moderate to severe active CD

This is a phase II, multicentre, open-label extension study to evaluate safety,
tolerability and efficacy of MT-1303 administered orally once daily (o.d.) for
up to 36 weeks in subjects with moderate to severe active CD who satisfactorily
complete the 14-week Treatment Period of the MT-1303-E13 study.
Subject eligibility will be confirmed at Visit 7 (Week 14) in MT-1303-E13 and
eligible subjects who wish to continue in the open-label extension will be
entered at Visit 1 (Week 0) in MT-1303-E14. There will be no interruption in
treatment between completion of Visit 7 (EOT; End of Treatment) in MT-1303-E13
and initiation of treatment in MT-1303-E14. All subjects will receive MT-1303
0.4 mg regardless of treatment received in MT-1303-E13 (i.e., MT-1303 or
placebo). Except for the first day of treatment, study medication should be
taken in the morning at approximately the same time each day; the first dose
will be administered at the clinical unit and will be followed by a 24-hour (h)
period of Holter ECG monitoring with at least the first 6 h completed within
the clinic.
Routine safety assessments (12-lead electrocardiogram [ECG], vital signs,
clinical safety laboratory and physical examination, including skin assessment)
and adverse events (AEs) will be documented at regular intervals during the
Treatment Period. In addition the Crohn*s Disease Activity Index (CDAI) scoring
system will be used to assess, clinical response and of clinical remission
following treatment.
Permitted medication for the treatment of CD during the study will include oral
5-ASA, limited dose of oral corticosteroid, antibiotics (i.e., metronidazole or
ciprofloxacin) and non-parenteral nutrition therapy.
Following completion of open-label treatment, all subjects will enter a 12-week
safety Follow-up Period.

Treatment Period:
Eligible subjects will be receive a 36-week treatment with
- once daily an oral capsule of 0,4 mg MT-1303

Although at the time of entering the MT-1303-E14 study there will be no
documented benefits for subjects, there is an expectation that subjects treated
with MT-1303 will experience a selective reduction in lymphocytes which may be
translated into clinical benefit. Following completion and reporting of
MT-1303-E13 study, it may be possible to outline any specific benefits of
long-term treatment with MT-1303.

The MT-1303-E14 study closely follows the design of the MT-1303-E13 study which
is carefully designed to minimise the identified and potential risks to
subjects. The screening procedure mandated in the MT-1303-E13 study excludes
all subjects for whom the MT-1303-E14 study is considered to pose an
unacceptable risk. Regular safety monitoring during the treatment and safety
Follow-up Periods for all subjects in MT-1303-E14 will ensure that any
unanticipated effects of study participation are identified promptly and
managed appropriately.

At the level of the individual subject, the Protocol states well-defined
criteria for intensive Cardiovascular Safety Monitoring, including extended
monitoring (Section 4.5.1) and the permanent discontinuation of study
medication (Section 4.5.3). In addition, an independent Data and Safety
Monitoring Board (DSMB) will continue to review selected data across the study
at regular, predefined intervals. The DSMB is empowered to make recommendations
regarding continuation, termination or modification of the study, as
appropriate (Section 11.3).

In particular, if it becomes clear that continuing treatment with MT-1303 is
not clinically or ethically justified, the MT-1303-E14 study will be terminated.
Overall, based on data from non-clinical and clinical studies of MT-1303 and
the risk-minimisation strategies discussed above, the risk/benefit profile of
this study is considered acceptable.