Treatment of walking impairment in multiple sclerosis with dalfampridine

Abstract

Potassium channel blockade has long been considered a potential therapeutic strategy for treatment of multiple sclerosis (MS) based on the pathophysiology of demyelinated axons. Dalfampridine, which is also known as fampridine or 4-aminopyridine (4-AP), is the potassium channel blocker that has been studied most extensively in MS and other demyelinating neurologic disorders. An extended-release formulation of dalfampridine was recently approved by the US Food and Drug Administration to improve walking in patients with MS. In randomized, double-blind, placebo-controlled trials, with dalfampridine extended release tablets 10 mg taken twice daily, about 12 h apart, walking speed was improved in approximately one-third of treated patients; in these patients, average walking speed on therapy was about 25% above baseline. This improvement was clinically meaningful as assessed by concurrent measurement of patient-reported severity of walking-related disability. Dalfampridine extended release tablets were generally well tolerated, with a range of adverse effects that appear to be related to increases in central nervous system excitation. There is a dose-dependent increase in the occurrence of seizures at doses higher than the recommended 10 mg twice daily.

Keywords: 4-aminopyridine; dalfampridine; fampridine; multiple sclerosis; potassium channel blockade; walking speed.

Figure 1.

Percentage change in walking speed as measured by the timed 25-foot walk at each visit after randomization (MS-F203). *p < 0.001 versus placebo and fampridine-treated timed-walk nonresponders; ^†p < 0.001 versus placebo only. (Reproduced with permission from Goodman et al. [2009].) CI, confidence interval.

Figure 2.

(a) Percentage of timed-walk responders in placebo- and dalfampridine-treated patients. (b) Percentage change from baseline walking speed at each visit following randomization, by responder analysis group. The dalfampridine-treated timed-walk responder showed sustained improvement during treatment that was completely reversed at the 2-week follow-up visit. The dalfampridine-treated timed-walk nonresponder showed a smaller increase, similar to that seen in the placebo-treated group. (Adapted with permission from Goodman et al. [2010].) BID, twice daily; CI, confidence interval.