The purpose of this study is to determine if a sequential combination therapy of natalizumab and alemtuzumab induces peripheral tolerance and reduces the annualized relapse rate (ARR) in patients with relapsing-remitting multiple sclerosis (RRMS).

To determine if treatment with alemtuzumab after natalizumab reduces the ARR in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy. The target population for this study are RRMS patients nearing the end of their natalizumab treatment regimen.Participants will be recruited from four different sites. Patients who meet all inclusion/exclusion criteria will be eligible for enrollment in the study.

Alemtuzumab (Lemtrada®) will be administered at a dose of 12 mg/d by intravenous (i.v.) infusion every day for five consecutive days within 14 days of the last dose of natalizumab. After 12 months, patients will be treated with a second course of alemtuzumab 12 mg/d by intravenous (i.v.) infusion every day for three consecutive days, and participants will be followed open-label for another 12 months per standard of care. Outside the scope of this study, the intention is to follow all study participants in participating centers long-term, and to record disease activity and treatment response.

Natalizumab treatment sequesters leukocytes out of the central nervous system (CNS) into the peripheral blood. Immediate sequential alemtuzumab therapy will deplete these cells more completely than alemtuzumab monotherapy, and prevent reactivation of disease activity previously treated with natalizumab. Thus, investigators hypothesize that sequential natalizumab - alemtuzumab therapy will prevent disease activation after cessation of natalizumab, and will provide sustained disease remission in many patients.

Clinical follow up by the treating physician will occur at months 0, 3, 6, 9, 12, 18 and 24 or immediately following clinical exacerbations months. During clinical visits, comprehensive medical history data will be obtained by the treating physician. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to reevaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made.

Standardized MRI studies of the brain will be performed at 0, 6, 12 and 24 months. Clinical imaging studies of the brain will be performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the brain with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Inclusion Criteria:

1. Age between 18 and 60 years, inclusive.
2. Diagnosis of relapsing forms of MS using revised McDonald Criteria1.
3. Expanded Disability Status Scale (EDSS) 0 - 5.5 (note: functional system changes in cerebral (or mental) functions and in bowel and bladder functions not used in determining EDSS for protocol eligibility).
4. Has had a minimum of 12 monthly doses of continuous natalizumab therapy (300 mg/d).
5. Understands English, and gives informed consent.

Exclusion Criteria:

1. Natalizumab failure based on clinician's discretion.

2. Any prior exposure to alemtuzumab.

3. Progressive MS.

4. A diagnosis of Progressive multifocal leukoencephalopathy (PML).

5. Known hypersensitivity to alemtuzumab.

6. Initiation of new immunosuppressant treatment after the subject becomes protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial with immuno-active pharmacotherapies.

7. Uncontrolled diabetes mellitus defined as HbA1c > 8% and/or requiring intensive management.

8. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome.

9. Clinically significant autoimmune disease other than MS that may affect the CNS, including neuromyelitis optica (NMO), systemic lupus erythematosus (SLE), or Behcet disease.

10. Active hepatitis B or C infection or evidence of cirrhosis.

11. HIV positivity.

12. Uncontrolled viral, fungal, or bacterial infection.

13. Positive pregnancy test or inability or unwillingness to use effective means of birth control. Effective birth control is defined as:

    1. Refraining from all acts of vaginal intercourse (abstinence),
    2. Consistent use of birth control pills,
    3. Tubal sterilization or male partner who has undergone vasectomy
    4. Placement of intrauterine device
    5. Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam.

14. Presence of metallic objects implanted in the body that would preclude the ability of the subject to safely have MRI exams.

15. Psychiatric illness, mental deficiency, or cognitive dysfunction making compliance with treatment or informed consent impossible.

Up to 12 months