Proof of Concept (POC) in Patients With Ischaemic Stroke

Myelin-associated glycoprotein (MAG) is one of the key proteins known to inhibit neuronal
regeneration when released from oligodendrocytes in conditions of neuronal injury, such as
stroke. GSK249320 is a humanised monoclonal antibody (mAb) that binds with high specificity
to MAG and antagonises or neutralises MAG-mediated inhibition and has been shown to improve
functional recovery after stroke in pre-clinical models, possibly by promoting
neuroregeneration and plasticity. The present study (MAG104615) is designed to establish
Proof of Concept (PoC) for GSK249320 in ischemic stroke patients. MAG104615 will be a
placebo-controlled, double-blind, multicenter, randomized, repeat dose, Bayesian design
study. PoC will be achieved by demonstrating a clinically meaningful improvement in lower
limb motor recovery, specifically by evaluating changes in gait velocity from baseline to Day
90/Month 3. Subjects will also be followed out to Day 180/Month 6 to further evaluate longer
term motor recovery and safety. Additional secondary efficacy measures of motor recovery will
be evaluated to further demonstrate and characterize the extent and duration of overall motor
recovery after treatment with GSK249320. Changes in disability and neurological impairment
will be characterized after treatment with GSK249320 and explored for how they relate to
motor recovery. This PoC study will also further characterize the safety, PK, and
immunogenicity of GSK249320 will explore pharmacodynamic (PD) markers, and will explore use
of actigraphy to measure motor recovery. Subjects will be stratified by gait velocity at
baseline for randomization (1:1 allocation) into one of two treatment groups: 15mg/kg
GSK249320, or placebo. Each subject will receive 2 repeat IV doses of GSK249320 or placebo.

Inclusion Criteria:

- Have a confirmed diagnosis of stroke according to the World Health Organization
definition which is, 'a rapid onset event of vascular origin reflecting a focal
disturbance of cerebral function, excluding isolated impairments of higher function,
and persisting longer than 24 hours [World Health Organization, 1989].

- Stroke onset must be within the last 24-72 hours of the first infusion of
Investigational Product. Time of stroke onset is defined at the time at which the
patient/relative is first aware of the stroke deficit. For patients who awake with
deficits, or who are found unconscious, the time of onset is defined as the time at
which they were last known to be symptom free.

- Have a stroke that is radiologically confirmed to be ischemic and supratentorial. The
diameter of the ischemic lesion is >15mm in any single direction or the volume is
>4cc. See the Study Procedures Manual (SPM) for guidance on how to calculate the
lesion size.

- Have a total NIHSS score of 3-21.

- Have a lower limb deficit from the incident stroke which is defined as a score of 1-4
on the NIHSS Motor Leg question (question #6).

- Aged 18-90, inclusive.

- Expectation the subject will receive standard physical, occupational and speech
rehabilitation therapy as indicated for the post stroke deficits.

- Male subjects and female subjects of non-child-bearing and child-bearing potential are
allowed to participate in this study. See Section 11, Appendix 1 for definitions.
Females of child-bearing potential must have a negative pregnancy test prior to
enrollment and must agree to use one of the contraceptive methods specified in Section
11, Appendix 1.

Exclusion Criteria:

- Ability to walk >0.8m/s as measured by the Gait Velocity assessment.

- History of a previous symptomatic stroke within 3 months prior to study entry.

- Presence of significant disability prior to the current stroke. Significant disability
is defined as having a pre-stroke Rankin score of >2.

- Subjects who are not alert or are unresponsive as defined by a score of 2 or 3 on the
NIHSS Level of Consciousness question (Question 1a).

- Presence of significant aphasia likely to confound or interfere with completion of the
study assessments.

- Presence of a significant pre-existing gait deficit prior to study entry that is
likely to confound clinical evaluations

- Presence of pre-existing neurologic or psychiatric disease which is active and not
adequately controlled such that it interfered with major activities of daily living
immediately prior to the current stroke and is likely to interfere with study
participation/visits or confound clinical evaluations.

- The subject poses a significant suicide risk, in the opinion of the investigator.

- Current or chronic history of liver disease, known hepatic or biliary abnormalities
(except Gilbert's syndrome or asymptomatic gallstones), or known history of hepatitis
B or hepatitis C infection. A positive hepatitis B or hepatitis C result on the GSK
labs drawn at baseline/Study Day 1 do not exclude a subject from continuing in the
study unless there are associated clinical signs/symptoms of liver disease; however,
the subject should be treated as clinically indicated and the GSK Medical Monitor
should be contacted for further discussion.

- Presence of either a central or peripheral demyelinating disease, such as multiple
sclerosis or IgM monoclonal gammopathy of unknown significance (MGUS).

- Expected death due to the incident stroke, or evidence of a chronic co-morbid
condition or unstable acute systemic illness which, in the opinion of the
investigator, could shorten the subject's survival such that it would limit his/her
ability to complete the study.

- Presence of the following ECG values on baseline ECG: QTc > 500 msec (using either
Bazett's formula (QTcB) or Fridericia's formula (QTcF)); or uncorrected QT >600msec
(machine or manual over-read). If the ECG indicates a prolonged QTc interval value
outside these limits, two further ECGs should be performed during the same sitting and
the average QTc value of these triplicate ECGs calculated. If the average value
exceeds the stated limits, the subject is not eligible.

- Participation in any investigational rehabilitation paradigm targeting stroke recovery
during the duration of this study.

- Have a contraindication to MRI as per local hospital practice/guidelines.

- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).

- Prior treatment with GSK249320.

- History of sensitivity to Investigational Product excipients (acetate buffer,
polysorbate 80 and sodium chloride) that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates the subject's participation.

- Pregnant females as determined by positive urine hCG test prior to enrollment.

- Lactating females.

- Subjects considered unwilling or unable to comply with the procedures and study visit
schedule outlined in the protocol.