Cladribine and Fingolimod Each Reduce Relapse in Adults with Relapsing-Remitting Multiple Sclerosis
DynaMed Weekly Update - Volume 5, Issue 5
Relapsing-remitting multiple sclerosis (MS) is commonly treated with parenteral drugs that can lead to adverse events and poor adherence. Three recent phase 3 randomized trials evaluated the efficacy and safety of 2 oral drugs, cladribine (Mylinax) and fingolimod (a novel immunosuppressant), for patients with MS.
The CLARITY trial compared cladribine vs. placebo in 1,326 patients with at least 1 relapse in the previous year. Treatment was given in 4-5 day cycles monthly over a total of 52 weeks, targeting a total cumulative dose of either 3.5 mg/kg or 5.25 mg/kg. Treatment was either 2 or 4 cycles of cladribine in the first 13 weeks, followed by 2 additional cycles at weeks 48 and 52. At 96-week follow-up, both cladribine doses decreased the risk of relapse compared to 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) ( level 1 [likely reliable] evidence). Cladribine was also associated with reduced annualized rates of relapse, lower 3-month sustained progression of disability, and fewer MRI brain lesions. The most common adverse events associated with cladribine treatment were lymphocytopenia and herpes zoster (N Engl J Med 2010 Feb 4;362(5):416).
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. 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 to 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) (level 2 [mid-level] evidence). 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 (N Engl J Med 2010 Feb 4;362(5):387).
The TRANSFORMS trial compared fingolimod (0.5 mg/day or 1.25 mg/day) vs. intramuscular interferon-beta-1a (30 mcg IV weekly) in 1,292 patients treated for 12 weeks. 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) (level 1 [likely reliable] evidence). Fingolimod also reduced the annualized rate of remission and the number of new or enlarged lesions on MRI. There were 2 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 (N Engl J Med 2010 Feb 4;362(5):402).
Neither cladribine nor fingolimod has been approved by the FDA for MS in the United States. Cladribine is approved for treatment of hairy cell leukemia.
For more information, see the Multiple sclerosis topic in DynaMed.