Mechanistic Studies of Teriflunomide in RRMS

Multiple sclerosis is the most common autoimmune inflammatory and debilitating chronic
demyelinating disease of the central nervous system mainly affecting young adults. There is a
tremendous need to understand the mechanism of action of the treatment and how they might
work in multiple sclerosis patients. Most recently, teriflunomide (AubagioTM) has been
demonstrated to act as an immune modulatory therapy for patients with multiple sclerosis.
Although one biochemical mechanism of action is understood to be related to inhibition of
dihydroorotate dehydrogenase (DHODH) which affects synthesis of pyrimidine nucleotides, there
have also been reports that the functions of regulatory T cells are promoted by these drugs
independent of DHODH. Much accumulating evidence suggests that specialized subsets of B
lymphocytes are important inducers of regulatory T cells, as well as having killer functions
that may preferentially target TH1 and TH17 cells.

This study aims to address the mechanism of action of teriflunomide in a phase IV open label
trial with Teriflunomide in multiple sclerosis

Inclusion Criteria:

1. Patients with clinically-defined relapsing-remitting MS (RRMS) who " are newly
starting on teriflunomide (AubagioTM) at the time of enrollment " have no evidence of
relapse or corticosteroid treatment use within 2 months prior to enrollment

OR

Healthy controls who do not have a significant medical condition such as cancer,
chronic infection, or autoimmune disease, have not taken steroids in the past 2
months, and who are not on an immune suppressant medication.

2. Ability to give informed consent

3. Willing to have blood drawn as scheduled in the protocol

4. Willing and able to complete all procedures and evaluations related to the study

Exclusion Criteria:

1. Medical or psychiatric conditions that may affect the patient's ability to give
informed consent

2. Has received an experimental drug within 30 days of enrollment

3. Concomitant other disease modifying medications (such as Rebif, Betaseron, Avonex,
Copaxone, Gilenya, Tecfidera, Alemtuzumab, methotrexate, azathioprine, mitoxantrone,
cyclophosphamide, cyclosporine, natalizumab, rituxan, ocrelizumab, etc.) without the
minimal washout period stated below:

" rebif, betaseron, avonex, copaxone within 1 month " zinbryta, plegridy, gilenya,
tecfidera within 2 months " natalizumab within 3 months "
immunosuppressive/chemotherapeutic medications (e.g. azathioprine, methotrexate)
within 6 months " cyclophosphamide within 1 year " rituximab, ofatumumab, ocrelizumab,
cladribine within 1 year " alemtuzumab at any time " any mitoxantrone during previous
2 years prior to randomization or evidence of cardiotoxicity following mitoxantrone or
a cumulative life-time dose of more than 60 mg/m2 " lymphoid irradiation, bone marrow
transplantation or other immunosuppressive treatments with effects potentially lasting
over 6 months, at any time

4. Has any contraindication to high-dose immunotherapy, including pregnancy, trying to
become pregnant, or breast feeding during the study.