Safety and Effectiveness of Switching Relapsing MS Patients Treated With Natalizumab at Risk for PML to Teriflunomide

Teriflunomide is the primary metabolite of leflunomide, which is marketed worldwide for the
treatment of rheumatoid arthritis. Teriflunomide inhibits dihydroorotate dehydrogenase(
DHODH), the forth enzyme in the de novo synthesis pathway of pyrimidines.Activated
T-lymphocytes utilize both the de novo pyrimidine and salvage pathways of pyrimidines
ribonucleotide synthesis.After mitogen stimulation, teriflunomide inhibits in vitro T cell
proliferation, DNA and RNA synthesis and expression of cell surface and nuclear antigens that
are directly involved in T-cell activation and proliferation.

Natalizumab (NTZ) is a FDA approved treatment for relapsing-forms of multiple sclerosis (MS)
with pivotal studies showing an annualized relapse-rate (ARR) reduction of 68%, a reduction
of new gadolinium (Gd+) lesions by 92% and a reduction of disability of 42% compared to
placebo.NTZ is highly effective in controlling MS but the risk of developing progressive
multifocal leukoencephalopathy (PML) increases with the duration of the use of natalizumab.
It can have a serious and life threatening complication in about 1 in 500 to 1 in 250
patients who have had more that 18 infusions due PML and who have a detected antibody (Ab)
for the JC virus. The risk of PML is much greater in patients who have had prior
immunosuppressive (IS) treatment. The combination of detected anti-JCV Ab , duration of NTZ
treatment of greater than 24 months and prior IS increases the risk of development PML to an
incidence of 11 per 1000 treated patients. So there is a need to have an alternative MS
disease modifying treatment (DMT) to use for patients at risk to develop PML from NTZ
treatment that might be sufficiently effective for MS so as not to have the patients' MS
worsen while lowering or eliminating the risk of PML.

Inclusion Criteria:

- Male and female patients, age 21 to 60 with relapsing forms of MS, treated with
natalizumab for 12 consecutive months or longer with anti-JCV Ab positive during that
time period.

- Able to understand and sign Informed Consent Document.

- Stable disease during treatment with natalizumab. No clinical relapses for at least 12
months.

- Stable MRI on follow-up MRI scans for prior 12 months without evidence of new or
enlarging T-2 hyperintensities or Gd+ lesions.

- No clinical evidence by imaging or CSF for PML.

- No evidence of significant cognitive limitation or psychiatric disorder.

- EDSS of 1.0 to 6.0 inclusive.

Exclusion Criteria:

- Any mental condition of such that patient is unable to understand the nature, scope
and possible consequences of the study.

- Patients that are known HIV positive.

- Patients with a known history of hepatitis.

- Known history of active tuberculosis not adequately treated, or a positive ppd skin
test or positive quantiferon gold.

- Any persistent or severe infection.

- Any malignancy within 5 years, except for Basal or Squamous cell skin lesions, which
have been surgically excised, with no evidence of metastasis.

- Clinically relevant or unstable cardiovascular, neurological (i.e. progressive
weakness, increasing hypesthesia), endocrine, or other major systemic diseases.

- History of drug or alcohol abuse within the past year.

- Any significant depression or psychiatric disease (BDI II greater than 25) within the
past year.

- Any significant lab abnormality as deemed by the investigator including but not
limited to the following:

1. Hypoproteinemia with serum albumin < 3.0g/dl.

2. Serum creatinine >133umol/L (or >1.5 mg/dl)

3. Hematocrit <24% and/or

4. Absolute white blood cell count < 4,000 cells/mm3 (µl) and/or

5. Platelet Count <150,000 cells/mm3 (µl) and /or

6. Absolute neutrophil < 1,500 cells/mm3 (µl)

7. Liver function impairment or persisting elevations of SGPT/ALT, SGOT/AST, or
direct bilirubin greater than 1.5 fold the upper limit of normal.

- Any confounding illness or other diseases of the spine or bone that would impair
evaluation of the patient or treatment effects.

- Any clinical, CSF or MRI evidence for PML.

- Prior treatment with immunosuppressive drugs except for past use of intravenous
steroids to treat MS relapses.

- Pregnant or breast feeding women.

- Women of childbearing potential not protected by effective contraceptive method of
birth control and/or are unwilling or unable to be tested for pregnancy.

- In the conception of a child during the course of the trial.

- Known history of hypersensitivity to teriflunomide or leflunomide.

- Persisting elevations (confirmed by retest) of serum amylase or lipase greater than
2-fold the upper limit of normal.

- Known history of chronic pancreatic disease or pancreatitis.

- Prior use within 4 weeks before randomization or concomitant use of phenytoin,
warfarin, tolbutamide, cholestyramine, or products containing St. John's Wort