Development of dalfampridine, a novel pharmacologic approach for treating walking impairment in multiple sclerosis

Abstract

Walking impairment is a clinical hallmark of multiple sclerosis (MS). Dalfampridine-ER, an extended-release formulation of dalfampridine (also known by its chemical name, 4-aminopyridine, and its international nonproprietary name, fampridine), was developed to maintain drug plasma levels within a narrow therapeutic window, and assessed for its ability to improve walking in MS. The putative mechanism of action of dalfampridine-ER is restoration of axonal conduction via blockade of the potassium channels that become exposed during axonal demyelination. Two pivotal phase III clinical trials demonstrated that dalfampridine-ER 10-mg tablets administered twice daily improved walking speed and patient-reported perceptions of walking in some patients. Dalfampridine-ER was generally well tolerated, and, at the approved dose, risk of seizure was neither elevated relative to placebo nor higher than the rate in the MS population. Dalfampridine-ER (AMPYRA®) was approved in the United States for the treatment of walking in patients with MS as demonstrated by an increase in walking speed. The use of the dalfampridine-ER is contraindicated in patients with a history of seizure. It is the first pharmacologic therapy for this indication and has been incorporated into clinical management of MS.

Keywords: 4-aminopyridine; dalfampridine; fampridine; multiple sclerosis; walking.