MedicalResearch.com Interview with:
Linard Filli, PhD
Gait Research Lab
Department of Neurology
University Hospital Zurich
MedicalResearch.com: What is the background for this study?
Response: Gait dysfunction is common in patients with multiple sclerosis (MS) and is perceived as the most restricting of symptoms. Fampridine (4-aminopyridine, dalfampridine), a blocker of voltage-gated potassium channels, is currently the only approved medication for the symptomatic treatment of walking disorders in patients in both the early and late phases of multiple sclerosis.
MedicalResearch.com: What are the main findings?
Response: The current study showed that long-term treatment with prolonged-release (PR)-fampridine was well tolerated and led to significant persisting improvements of walking function in a cohort of patients with MS treated in a double-blind, randomized and placebo-controlled design. Monitoring single subjects’ drug responsiveness over more than 2 years revealed that many patients showed changes in fampridine-induced effects on walking function over time.
Particularly those patients with poor initial responsiveness to PR fampridine after short-term treatment often showed a remarkable increase in responsiveness after long-term treatment. More than one third of patients who did not respond to PR fampridine initially, changed their responsiveness after long-term treatment and improved more than 10% in either maximal gait speed (Timed 25-Foot Walk) or walking endurance (6-Minute Walk Test).
MedicalResearch.com: What should readers take away from your report?
Response: Long-term treatment with PR-fampridine is able to improve gait performance not only in early, but also in chronic progressive patients with multiple sclerosis, where alternative treatment options to improve walking function are virtually absent. Regular drug holidays allow for a subjective (patient-based) and objective (clinical walking tests) re-evaluation of drug efficacy over time, thus enabling to adapt and optimize the treatment with PR fampridine. Similar results in open-label (drug holidays) and double-blind (placebo-controlled) re-evaluation of drug efficacy argues for the value of regular drug holidays in clinical practice. Against the background of some patients changing their responsiveness to PR fampridine over time, periodic drug holidays seem to be crucial to adapt medication, i.e. stopping treatment in patients losing their responsiveness over time. On the other hand, regular assessments of PR fampridine’s effects might also help to uncover drug efficacy in initially non-responding patients.
Moreover, the results of our study showed that sensitive functional outcomes (T25FW, 6MWT, MSWS-12) disclosed significant and relevant improvements as induced by PR fampridine, whereas the Expanded Disability Status Scale (EDSS), an endpoint frequently used in MS-related clinical trials, did not disclose any drug effects. This data underscores the importance of future clinical trials to use more sensitive and specific endpoint measures to assess the efficacy of interventions on functional (e.g. walking) performance.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The mechanisms underlying the change in responsiveness to PR-fampridine over time remain speculative for the moment and need to be addressed in future studies. Potential reasons explaining longitudinal changes in drug responsiveness might comprise dynamic alterations in de-myelination and neuronal degeneration in a given patient. Hence, it would be interesting to correlate changes in drug responsiveness with structural alterations in the central nervous system integrity as measured by magnetic resonance imaging. Alternative mechanisms of improved responsiveness to PR fampridine over time might include long-term training effects as induced by PR fampridine that are not observed during short-term treatment (e.g. muscle reinforcement by improved mobility). We are currently screening for demographic and clinical factors that might be used as predictors of patients’ responsiveness to PR-fampridine in the future.
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Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis
1. Linard Filli, PhD, Björn Zörner, MD, PhD, Sandra Kapitza, MD, Katja Reuter, MD, Lilla Lörincz, MSc, David Weller, Tabea Sutter, MD, Tim Killeen, MRCS, Philipp Gruber, MD, Jens A. Petersen, MD, Michael Weller, MD and Michael Linnebank, MD
2. Published online before print February 1, 2017, doi: http://dx.doi.org/10.1212/WNL.0000000000003656Neurology 10.1212/WNL.0000000000003656
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