Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis

Abstract

Background:

Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability, loss of independence, and reduced quality of life. Dalfampridine (4-aminopyridine), a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed.

Objective:

To summarize knowledge about the mechanism of action of dalfampridine in the context of clinical evidence of walking improvement in MS patients.

Methods:

Although this was not a systematic review, which is the primary limitation of this study, searches of PubMed were performed using relevant search terms to identify studies that examined the mechanism of action related to MS and its effects in patients with MS in clinical trials.

Results:

Voltage-gated potassium channels represent a family of related proteins that span cell membranes, open and close in response to changes in the transmembrane potential, and help regulate ionic potassium currents. Action potential conduction deficits in demyelinated axons result in part from the exposure after demyelination of the paranodal and internodal potassium channels that are distributed in the axonal membrane. This exposure leads to abnormal currents across the axonal membrane that can slow action potential conduction, result in conduction failure, or affect the axon's capacity for repetitive discharge. While dalfampridine is a broad-spectrum blocker of voltage-dependent potassium channels at millimolar concentrations, studies have shown improvement in action potential conduction in demyelinated axons at concentrations as low as 1 μM, and therapeutic plasma concentrations (associated with improved walking) are in the range of 0.25 µM. However, no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range, and the effects of the drug at this low concentration appear to be quite selective. Improved conduction translates into clinical benefit as measured by objectively and subjectively assessed walking relative to placebo. Such improvements were observed in approximately one third of patients treated with an extended-release formulation of dalfampridine in clinical trials. These patients who responded to dalfampridine had an average increase in walking speed of approximately 25%, and greater improvements than nonresponders on a self-reported subjective measure of walking.

Conclusions:

The extended-release formulation of dalfampridine has been shown in clinical trials to improve walking speed in approximately one third of MS patients with ambulatory impairment. The putative mechanism of action of dalfampridine is restoration of action potential conduction via blockade of an as yet uncharacterized subset of potassium channels in demyelinated axons.

Key words::

• 4-Aminopyridine
• Ambulation
• Dalfampridine
• Fampridine
• Multiple sclerosis
• Potassium channels

Transparency

Declaration of funding

This study was funded by Acorda Therapeutics, Inc., Hawthorne, NY, USA.

Declaration of financial/other relationships

J.D. has disclosed that he previously served as a consultant for Acorda Therapeutics, Inc.; A.B. discloses that he is an employee and stockholder of Acorda Therapeutics, Inc.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements

Editorial services were provided by Linnéa Elliott of The Curry Rockefeller Group, Tarrytown, NY, USA, and funded by Acorda Therapeutics, Inc.

Notes

*Ampyra is a registered trade name of Acorda Therapeutics, Inc., Hawthorne, NY, USA.