Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

Abstract

Background:In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS).Objectives:Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT).Methods:Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW.Results:We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders.Conclusions:The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis

“…Fampridine-induced changes in clinical walking tests were not correlated with the self-assessed change in ambulatory performance in the double-blind core study (figure e-1 of long-term PR fampridine treatment. [15][16][17] The proportion of patients experiencing AEs and SAEs was in line with previous reports. 15,16 The frequency of AEs was not different between double-blind treatment with PR fampridine and placebo, indicating that PR fampridine was likely not responsible for the AEs in PwMS treated with the drug.…”

“…8,9 Whereas beneficial effects of short-term treatment with PR fampridine on maximal walking speed [10][11][12][13][14] and additional functional outcomes 7,[13][14][15] (e.g., walking endurance) are wellcharacterized in PwMS, little information exists regarding the long-term safety and efficacy of therapy with PR fampridine. Open-label treatment over periods of 1 and 3 years demonstrated good tolerability and persisting improvement in ambulatory function 16 and fatigue. 7 Positive effects of PR fampridine on dynamic stability and self-perceived walking ability were further demonstrated in a double-blind, placebo-controlled study over a period of 24 weeks.…”

“…In particular, those patients who showed a moderate to poor response in terms of walking improvement under PR fampridine at initial assessment were likely to improve their responsiveness to the drug over time, thus highlighting the necessity to regularly reassess the efficacy of PR fampridine on ambulatory function in PwMS. Persisting drug efficacy, combined with the fact that PR fampridine has also demonstrated beneficial effects in chronic progressive MS, 14,16 where alternative treatment options to improve walking function are virtually absent, confirm PR fampridine as an important option in symptomatic, long-term treatment for gait-impaired PwMS.…”

“…Increased responsiveness to PR fampridine in these initial poor responders, combined with a potential decline of drug efficacy in initial good responders, might explain the approximation of drug effects between responders and nonresponders seen in earlier open-label long-term studies. 16 The observed changes in drug response during long-term treatment suggest that drug efficacy should be reevaluated regularly, in particular in those patients who demonstrate a poor response to PR fampridine after initial assessment. Discussion relating to the mechanisms underlying the observed changes in responsiveness to the study drug over time must remain, for the moment, speculative.…”

Multiple Sclerosis and Clinical Gait Analysis before and after Fampridine: A Systematic Review

“…All forms of MS were included (relapsing remitting, primary progressive, secondary progressive) [12]. There were wide variations in terms of age, ranging from 18 to 70 years [8,[13][14][15][16] or from 18 to 60 years [17,18].…”