Gilenya's Impact on Cognitive Function and Thalamic Volumes

Cognitive impairment is a well-recognized manifestation of multiple sclerosis (MS) with
prevalence estimates ranging from 43 to 70%. It is also known to occur as early as the first
demyelinating event and is a major factor contributing to quality of life in MS. Treatment
strategies for cognitive impairment in MS are limited. Several agents have been tested as
therapeutics for MS-related cognitive dysfunction and have showed no major benefit. Cognitive
rehabilitation has shown some promise, but the data are limited and many studies have
suffered from methodological shortcomings. Given the lack of well-established treatment
options and the substantial impact of cognitive impairment, protection of cognitive function
from the earliest stages of the disease is of great importance.

Cognitive outcomes received relatively little attention in the pivotal studies of MS disease
modifying therapies (DMT), but some data suggest that DMT may have a positive impact on
cognition. Gilenya is of special interest because it was found to have a significant
protective effect on whole brain atrophy when compared against placebo and intramuscular
interferon β-1a in two phase III studies, showing a 31-35% reduction in percentage brain
volume change. Gilenya's effect on whole brain atrophy leads to the natural hypothesis that
it may have a beneficial effect on cognitive function in MS. Also of particular interest is
the extent to which protection of the thalamus and cortex contributes to Gilenya's effect on
whole brain atrophy and possible effects on cognition.

The study will enroll 15 subjects from the Cleveland Clinic Mellen Center patient population.
Participants must have been on Gilenya for at least 6 months at the time of study entry. The
study will involve three assessments: at baseline, six months, and one year. At each time
point, participants will undergo 7T MRI of the brain with and without contrast. Participants
will also undergo a battery of neurometric testing at each time point. The tests will include
the Brief Visuospatial Memory Test - Revised (visuospatial skills), the iPadTM Processing
Speed Test (processing speed), the Selective Reminding Test (verbal learning and memory), and
the Delis-Kaplan Executive Function System Sorting Test (problem-solving skills; can only be
administered at baseline and one year due to version limitations).

Inclusion Criteria (MS Patients):

1. RRMS phenotype

2. Treated with Gilenya for ≥6 months at the time of the baseline visit.

3. Age 18-50 inclusive.

4. EDSS 0-4.0

5. Disease duration of 5-15 years.

6. At least 12 years of education (high school diploma or general equivalency diploma).

7. Physically capable of completing neurometric testing and MRI studies.

Inclusion Criteria (Healthy Controls):

1. Age 18-50 inclusive.

2. At least 12 years of education (high school diploma or general equivalency diploma)

3. Physically capable of completing neurometric testing and MRI studies.

Exclusion Criteria (MS Patients):

1. Contraindication to MRI (e.g. metal implants)

2. Current use of immunomodulatory or immunosuppressant medications other than Gilenya.

3. Disease of the central nervous system other than MS (e.g. Alzheimer disease, stroke,
epilepsy).

4. Use of anti-psychotic or psychostimulant medications. Patients started on modafinil or
armodafinil more than six months prior to enrollment will not be excluded.

5. Ongoing major depressive disorder that, in the opinion of the investigator, may affect
cognitive functioning.

6. MS relapse within 90 days of study entry.

7. Treatment with corticosteroids within 90 days of study entry.

8. Current illicit substance use.

9. History of alcohol or drug abuse.

Exclusion Criteria (Healthy Controls):

1. Contraindication to MRI (e.g. metal implants, claustrophobia).

2. Disease of the central nervous system (e.g. MS, Alzheimer disease, stroke, epilepsy).

3. Use of anti-psychotic or psychostimulant medications. Patients started on modafinil or
armodafinil more than six months ago will not be excluded.

4. Ongoing major depressive disorder that, in the opinion of the investigator, may affect
cognitive functioning.

5. Current illicit substance use.

6. History of alcohol or drug abuse.