A Pilot Study Assessing the Impact of Gilenya Therapy on Bone Density Change in Relapsing Forms of Multiple Sclerosis

To assess the effect of Gilenya on the rate of decline in bone mass density and expression of
selected bone turnover biomarkers in ambulatory subject with a relapsing form of Multiple
Sclerosis compared to control subjects matched for age, race, gender, duration of disease,
and disability on an alternative FDA approved disease modifying therapy or no therapy at 24
months compared to baseline.

Inclusion Criteria:

- • Male and female subjects, 21 years of age or older.

- Subjects must be able to give consent by signing and dating an informed consent
form (written in English) prior to any study assessments being performed.

- Ambulatory with an Expanded Disability Status Scale(EDSS) between 2.5 - 6.5
inclusive.

- Must meet McDonald criteria for a relapsing form (relapsing remitting and
secondary progressive) of Multiple Sclerosis.

- Gilenya therapy group subjects must have been treated with Gilenya a minimum of 3
months uninterrupted prior to screening visit, and approved by the principal
investigator to continue on this agent.

- Control therapy group subjects must have been consistently on an FDA approved
disease modifying therapy other than Gilenya or off such therapy a minimum of 6
months prior to screening visit.

- Subjects must be neurologically stable and have not received any form of steroid
therapy for 4 weeks prior to screening visit.

- Subjects must abide by safety surveillance monitoring studies appropriate to
their disease modifying therapy and considered standard of care. Such monitoring
will be considered outside the scope of this study.

- Subjects must be willing and able to comply with the protocol requirements for
the duration of the study.

Exclusion Criteria:

- • Subjects must not have been treated with Fingolimod, Gilenya or other experimental
Sphingosine 1-phosphate receptor agonist therapy in a clinical trial prior to
enrollment in this study.

- Subjects on an FDA approved disease modifying therapy other than Gilenya, or on
no therapy, must not have received Gilenya therapy within 12 months of screening
visit.

- Current or previous use of bisphosphonate therapy, estrogen replacement,
calcitonin, Depo-Provera, dehydroepiandrosterone, or methotrexate within 12
months of screening visit.

- Medical contraindication to daily calcium intake of at least 1000 mg daily, and
vitamin D3 supplementation of 800 IU daily.

- Vitamin D insufficiency (25-hydroxy vitamin D level <=30 ng/ml) at the time of
baseline visit.

- Meeting National Osteoporosis Foundation criteria for osteoporosis requiring
treatment with study prohibited therapies:

- History of osteoporosis with baseline Dexa bone scan T score <-1.5 but >-2.0 with
one or more risk factors for fracture (age >50 years, current smoking, low Body
Mass Index (i.e. < 18.5), previous fragility fracture, parental history of
osteoporosis or of fragility fracture of hip, femur, or vertebrae , alcohol
consumption greater than 3 units per day, daily glucocorticoid usage).

- Dexa bone scan T score < -2.0 with or without additional risk factors.

- Subjects with Body Mass Index >=40 kg/m2 due to artifacts in Body mass density
measurement with Dexa unit used.

- Subjects with anatomical deformities or vertebral fractures that would
potentially distort Body mass density measurements.

- Current diagnosis of parathyroid disorder, untreated hyperthyroidism or
hypothyroidism, renal insufficiency (Glomerular filtration rate- (GFR) <= 55),
history of renal calculi or stones, uncontrolled mood disorder, drug or alcohol
abuse.

- Current use of "first generation" anticonvulsant medication (barbiturate,
phenytoin, carbamazepine, valproate), or of "second generation" anticonvulsant
levetiracetam (implicated recently in accelerated bone density loss). Stable use
of "second generation" anticonvulsant medication (gabapentin, pregabalin,
lamotrigine, topiramate, lacosamide, zonisamide, oxcarbazepine) for symptoms
management will be acceptable. Stable use of dopamine reuptake inhibitor class,
Serotonin Norepinephrine Reuptake Inhibitors, Selective serotonin re-uptake
inhibitor antidepressant therapies will be allowed.

- Continuous or "pulsed" treatment with a corticosteroid for any medical condition.
Brief therapy with intravenous methylprednisolone 1 gram for 3-5 days with no
oral taper, for a confirmed neurological relapse will be allowed.

- Subjects must not have any unstable medical or psychiatric condition per the
judgment of the principal investigator which would risk safety or completion of
the study.