The Year in Neurology: Studies Not to Miss From 2011

Andrew N. Wilner, MD


November 23, 2011

In This Article

Multiple Sclerosis

Teriflunomide, an oral disease-modifying therapy for relapsing forms of multiple sclerosis, reversibly inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis used for DNA replication. As a result, T- and B-cell activation, proliferation, and function are reduced in response to autoantigens. However, slowly-dividing cells may still replicate and function if they use exogenous supplies of pyrimidine nucleotides.[10] The phase 3 TEMSO trial reduced the annualized relapse rate by 31.2% with a daily 7-mg dose and by 31.5% with a daily 14-mg dose compared with placebo (P < .0001). Reduction of progression of disability was 23.7% with the 7-mg dose (NS) and 29.8% with the 14-mg dose (P = .03). Notable side effects with a dose effect were diarrhea, nausea, hair thinning, and elevated alanine aminotransferase levels. There were no serious opportunistic infections or deaths.

BG-12 (dimethyl fumarate) has recently completed 2 phase 3 trials. Initial results of the DEFINE trial were presented at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) in October 2011 in Amsterdam, The Netherlands. In a randomized, double-blind, placebo-controlled, dose-comparison study of 1234 patients, those taking BG-12 (240 mg twice daily) had a decrease in annualized relapse rate of 53% compared with those taking placebo, and those taking BG-12 (240 mg 3 times daily) had a decrease of 48%. Time to disability progression was reduced 38% in the twice-daily group and 34% in the thrice-daily group compared with placebo. The most common adverse events were flushing, diarrhea, nausea, and abdominal pain. There was no increase in infections or malignancies. Results of the CONFIRM trial, similar in design and dosing to DEFINE but with an additional arm of glatiramer acetate, were released on October 26, 2011. The annualized relapse rate decreased by 44% with the twice-daily dose (P < .0001) and by 51% with the thrice-daily dose (P < .0001) vs placebo at 2 years. Decrease in disability progression was not significant vs placebo. Peer-reviewed publication of the details of these 2 studies is eagerly awaited.

Since its approval last year for relapsing multiple sclerosis, more than 20,000 patients have taken fingolimod, a sphingosine 1-phosphate (S1PR) modulator and the first oral drug for multiple sclerosis. Five-year follow-up data from an extension of a phase 2 multicenter study showed a low overall annualized relapse rate of 0.2 and no new safety concerns.[11] The 1-year postmarketing safety experience of dalfampridine, a symptomatic treatment to increase walking speed in patients with multiple sclerosis, revealed that the most frequently reported adverse events were the same as those seen during clinical development.[12] These included dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain. In addition, 82 seizures occurred in 46,200 exposed patients (5.7/1000 patient years), which was similar to the incidence in clinical trials. For patients taking natalizumab, antibody and DNA testing for the JC virus will allow risk stratification of patients regarding the occurrence of progressive multifocal leukoencephalopathy.[12]


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