Level 1: Likely reliable evidence

Relapsing-remitting multiple sclerosis (MS) is commonly treated with parenteral drugs that can lead to adverse events and poor adherence. Three phase 3 randomized trials evaluated the efficacy and safety of two oral drugs, cladribine (Mylinax) and fingolimod, for patients with MS.

The CLARITY trial compared cladribine vs. placebo in 1,326 patients with at least one relapse in the previous year (N Engl J Med. 2010;362:416-426). Treatment was given in four- to five-day cycles monthly over a total of 52 weeks, targeting a cumulative dose of either 3.5 mg/kg or 5.25 mg/kg. Treatment was either two or four cycles of cladribine in the first 13 weeks, followed by two additional cycles at weeks 48 and 52. At 96-week follow-up, both cladribine doses decreased the risk of relapse compared with placebo (20.3% for the lower dose, 21.9% for the higher dose, 39.1% for placebo, p <0.001 for each dose vs. placebo, NNT 6). Cladribine was also associated with reduced annualized rates of relapse, lower three-month sustained progression of disability, and fewer MRI brain lesions. The most common adverse events associated with cladribine treatment were lymphocytopenia and herpes zoster.

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The FREEDOMS trial compared fingolimod treatment for 24 months (0.5 mg/day or 1.25 mg/day) vs. placebo in 1,272 patients with history of MS relapse and low-to-moderate disability (N Engl J Med. 2010;362:387-401). In an analysis of 1,033 patients, each dose of fingolimod was associated with reduced annualized relapse rate, reduced disability progression, and improved MRI-related outcomes. Both fingolimod doses reduced the risk of relapse compared with placebo (25.3% for the lower dose, 29.6% for the higher dose, 54.4% for placebo, p <0.001 for each dose vs. placebo, NNT 4). Adverse events with fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver enzyme levels, and mild hypertension.

The TRANSFORMS trial compared fingolimod (0.5 mg/day or 1.25 mg/day) vs. intramuscular interferon-beta-1a (30 μg IV weekly) in 1,292 patients treated for 12 weeks (N Engl J Med. 2010;362:402-415). Each fingolimod dose reduced risk of relapse (19.5% for the lower dose, 17.5% for the higher dose, 29.9% for interferon, p <0.001 for each dose vs. interferon, NNT 8-10). Fingolimod also reduced the annualized rate of remission and the number of new or enlarged lesions on MRI. There were two fatal infections in patients receiving the 1.25-mg dose. Other adverse events with fingolimod included those noted in the FREEDOMS trial, plus nonfatal herpesvirus infections and skin cancer.

Neither cladribine nor fingolimod has been approved by the FDA for MS. Cladribine is approved for treatment of hairy cell leukemia.