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Parenteral agents including interferon and glatiramer are the most common treatments for relapsing-remitting multiple sclerosis (MS), but adherence can be a concern. Oral alternatives to daily subcutaneous injection have been studied including the FDA-approved drugs fingolimod (Gilenya) and teriflunomide (Aubagio). Other oral agents that have shown benefit for reducing relapse rates but are not yet FDA-approved for this use include cladribine (Leustatin) (N Engl J Med 2010 Feb 4;362(5):416) and laquinimod (N Engl J Med 2012 Mar 15;366(11):1000). Another oral drug, dimethyl fumarate (BG-12), an antiinflammatory and cytoprotective agent, was submitted for FDA approval for use in relapsing-remitting MS in February 2012. Two recent randomized trials evaluated its efficacy.
In the CONFIRM trial, 1,430 adults with relapsing-remitting MS were randomized to dimethyl fumarate 240 mg orally (2 times daily vs. 3 times daily) vs. glatiramer 20 mg subcutaneously daily vs. oral placebo for 96 weeks. Relapse was defined as new or recurrent neurologic symptoms (not associated with fever or infection) lasting for ≥ 24 hours and new objective neurologic findings. About 20% of patients withdrew during follow-up and 1% discontinued the study drug but completed the trial. The intention-to-treat analysis included 99% of randomized patients who received at least 1 dose of the study drug.
Both doses of dimethyl fumarate were associated with significantly reduced annualized relapse rates compared to placebo. The estimated 2-year risk of relapse was 29% for 2 times daily dosing (p < 0.05 vs. placebo, NNT 9), 24% for 3 times daily dosing (p < 0.05 vs. placebo, NNT 6), and 41% for placebo (level 2 [mid-level] evidence). Glatiramer was also associated with a significantly reduced risk of relapse (p < 0.05 vs. placebo). There were no significant differences in progression of disability at 2 years.The most common adverse events with dimethyl fumarate were flushing and gastrointestinal symptoms (N Engl J Med 2012 Sep 20;367(12):1087).
In the DEFINE trial, 1,237 adults were randomized to the same doses of oral dimethyl fumarate as above vs. placebo for 96 weeks. About 23% withdrew from the trial but were included in the intention-to-treat analysis. As in the CONFIRM trial, both doses of dimethyl fumarate were associated with significant reduction in annualized relapse rates compared to placebo. The estimated 2-year risk of relapse was 27% for 2 times daily dosing (p < 0.05 vs. placebo, NNT 6), 26% for 3 times daily dosing (p < 0.05 vs. placebo, NNT 5), and 46% for placebo (level 2 [mid-level] evidence). Unlike the CONFIRM trial, dimethyl fumarate was also associated with reduced risk of disability progression at 2 years, with estimated rates of 16% for 2 times daily dosing (p < 0.05, NNT 9), 18% for 3 times daily dosing (p < 0.05, NNT 12), and 27% for placebo (N Engl J Med 2012 Sep 20;367(12):1098).
For more information, see the Multiple sclerosis topic in DynaMed.