Restoring Axonal Function with 4-Aminopyridine: Clinical Efficacy in Multiple Sclerosis and Beyond
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The oral potassium channel blocker 4-aminopyridine has been used in various neurological conditions for decades. Numerous case reports and studies have supported its clinical efficacy in ameliorating the clinical presentation of certain neurological disorders. However, its short half-life, erratic drug levels, and safety-related dose restrictions limited its use as a self-compounded drug in clinical practice. This changed with the introduction of a prolonged-release formulation, which was successfully tested in patients with multiple sclerosis. It was fully approved by the US FDA in January 2010 but initially received only conditional approval from the European Medicines Agency (EMA) in July 2011. After additional clinical studies, this conditional approval was changed to unrestricted approval in August 2017. This article reviews and discusses these recent studies and places aminopyridines and their clinical utility into the context of a broader spectrum of neurological disorders, where clinical efficacy has been suggested. In 2010, prolonged-release 4-aminopyridine became the first drug specifically licensed to improve walking in patients with multiple sclerosis. About one-third of patients across disease courses benefit from this treatment. In addition, various reports indicate clinical efficacy beyond multiple sclerosis, which may broaden its use in clinical practice.
The authors thank Dr. Peter Göttle for help in creating the figures and Dr. Bernd C. Kieseier for critical review and discussion.
Compliance with Ethical Standards
The authors received no funding for writing this manuscript.
Conflict of interest
VL has received fees for speaking from Biogen, Genzyme, and Novartis and research support from Novartis. XM has received fees for consulting, serving on steering committees, and speaking at symposia from Almirall, Bayer, Biogen, Genzyme, Merck, Roche, Receptos, Sanofi, and Teva. HPH has received, with approval from the Rector of Heinrich-Heine-University, fees for consulting, serving on steering and data monitoring committees, and speaking at scientific symposia from BayerHealthcare, Biogen, Geneuro, Genzyme, Merck, Novartis, Octapharma, Receptos Celgene, Roche, Sanofi, and Teva. None of these were related to the present work.
- 2.Giovannini F, Sher E, Webster R, et al. Calcium channel subtypes contributing to acetylcholine release from normal, 4-aminopyridine-treated and myasthenic syndrome auto-antibodies-affected neuromuscular junctions. Br J Pharmacol. 2002;136(8):1135–45. https://doi.org/10.1038/sj.bjp.0704818.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Burton JM, Bell CM, Walker SE, et al. 4-aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis. Neurology. 2008;71(22):1833–4. https://doi.org/10.1212/01.wnl.0000339380.23073.58.CrossRefPubMedGoogle Scholar
- 29.Goodman AD, Bethoux F, Brown TR, et al. 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. Mult Scler. 2015;21(10):1322–31. https://doi.org/10.1177/1352458514563591.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Hobart J, Ziemssen T, Feys P, Linnebank M, Goodman A, Farrell R, Englishby V, McNeill M, Chang I, Mehta L, Elkins J. Sustained clinically meaningful improvements in walking ability with prolonged-release fampridine: results from the placebo-controlled ENHANCE study. Presented at ECTRIMS 2016, 2016.Google Scholar
- 48.Claassen J, Spiegel R, Kalla R, et al. A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus—effects on slowphase eye velocity, postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry. 2013;84(12):1392–9. https://doi.org/10.1136/jnnp-2012-304736.CrossRefPubMedGoogle Scholar
- 62.Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–292. https://doi.org/10.1161/01.cir.0000441139.02102.80.CrossRefPubMedGoogle Scholar
- 72.Goodman AD, Brown TR, Cohen JA, et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology. 2008;71(15):1134–41. https://doi.org/10.1212/01.wnl.0000326213.89576.0e.CrossRefPubMedGoogle Scholar
- 73.Acorda Therapeutics IAdertpi. 2010. http://ampyra.com/home.
- 74.Australian Government DoHaA, Therapeutic Goods Administration. Australian Public Assessment Report for fampridine, 2012. http://www.tga.gov.au/auspar/auspar-fampridine-110615.htm.
- 75.Health Canada. Drugs and healthcare products. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_fampyra_132859-eng.php.
- 81.Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, Carlesimo GA, Zibellini G, Caltagirone C. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled,, crossover trial of oral 4-aminopyridine. Mult Scler. 2001;7:354–8.CrossRefPubMedGoogle Scholar