Dalfampridine and Walking Time for Selected Patients with Multiple Sclerosis

Multiple sclerosis (MS) is a chronic and disabling disease of the central nervous system that affects nearly 400,000 Americans; approximately 200 people receive a diagnosis of MS each week. Worldwide, the number of people with the disease is approximately 2.5 million. One of the most frequently reported symptoms of MS is impaired mobility: 64% of patients report having difficulty walking at least twice a week. Of those reporting difficulty walking, 70% considered that symptom the most challenging aspect of their disease. Of those who reported difficulty walking and were employed, 79% said walking difficulties had a negative impact on their ability to work. Dalfampridine represents a potentially novel class of therapy for patients with MS. The agent, a broadspectrum potassium blocker, directly targets the nervous system, modifying the functions of axons demyelinated by the disease. A previous phase 3 trial found that treatment with extended-release tablets of dalfampridine at a dose of 10 mg twice a day improved walking ability in some patients with MS, demonstrating a meaningful therapeutic benefit. Researchers recently conducted a phase 3 trial designed to confirm the results of the earlier study as well as to establish whether improved walking ability was maintained between doses. The researchers also sought to further define safety and pharmacodynamics. They reported trial results in Annals of Neurology [2010;68(4):494-502]. The trial focused on walking ability, measured with the timed 25-foot walk (T25FW). The trial included patients from 39 centers in the United States and Canada. Inclusion criteria included age 18 to 70 years, clinically defined MS, and a T25FW time between 8 and 45 seconds. Exclusion criteria were prior exposure to dalfampridine, MS exacerbation within 60 days, a history of seizures, evidence of epileptiform activity on an electroencephalogram, or any condition that would interfere with study conduct. The study was a randomized, double-blind, placebo-controlled trial. At visit 0, patients were screened to determine eligibility. Eligible patients returned a week later (visit 1) and entered a 2-week, singleblind, placebo run-in period. The patients were instructed to take 1 blinded tablet every 12 hours during the treatment phase. At visit 2, patients were randomized to receive either extended-release dalfampridine (at a dose of 10 mg twice a day) or placebo. Patients then returned every 2 weeks for evaluation (visits 3-6); at visit 6 patients were instructed to return in 1 week (visit 7) after timing their last dose of study medication to allow evaluation at visit 7 to be made between 10 and 12 hours following the last dose. Two weeks later (visit 8), follow-up assessments were made. Response was defined as consistent improvement on the T25FW; the primary outcome measure was the percentage of timed walk responders (TWRs) in each treatment group. The analysis population included 237 patients: 118 in the placebo group and 119 in the dalfampridine group. In the dalfampridine group, 42.9% (n=51) of the patients met the responder criterion, compared with 9.3% (n=11) of the patients in the placebo group (P<.0001). During the efficacy analysis period (visits 3-6), the average change from baseline in walking speed in the TWRs treated with dalfampridine was 24.7% (95% confidence interval [CI], 21.0%-28.4%) compared with change from baseline in walking speed in TWRs in the placebo group of 7.7% (95% CI, 4.4-11.0%). The increase in walking speed in TWRs in the dalfampridine group was maintained across double-blind treatment and was reversed with treatment discontinuation. The researchers concluded by noting that a “significantly higher proportion of dalfampridine-treated patients showed consistently improved walking speed, maintained over the interdosing period of 12 hours. This confirmed the results of the first phase 3 trial showing that treatment with dalfampridine produced clinically meaningful improvement in walking ability in a subgroup of MS patients. These 2 studies suggest that dalfampridine represents a potentially useful and novel class of therapy for MS, as a modulator of neural function that may be complementary to existing immunomodulatory therapies.”