Effects of Mexiletine on Cortical and Peripheral Nerve Hyperexcitability in Sporadic ALS

Objective: To determine the effects of mexiletine (MEX) on cortical neuronal and peripheral motor nerve hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Background: Transcranial magnetic stimulation (TMS) and axonal excitability studies have established the presence of cortical and axonal nerve hyperexcitability in ALS, potentially contributing to pathogenesis. MEX is a sodium channel blocker that could reduce hyperexcitability in this disease. Design/Methods: 20 ALS subjects from 10 centers were randomized 1:1:1 to placebo, MEX 300 mg, and MEX 600 mg per day for 4 weeks followed by 4 weeks off treatment. The primary and key secondary endpoints were resting motor threshold (RMT) and motor evoked potential (MEP) amplitude, expressed as percentage of the compound muscle action potential response. Results: 20% of screened subjects were cortically inexcitable. RMT was significantly reduced over 4 weeks with MEX (combined active therapies) compared to placebo by mixed model analysis (mean±SE: placebo=4.7%±2.2, MEX 300 mg=−2.4%±2.3, MEX 600 mg=0.8%±2.2, p=0.039). Dose-dependent reductions of the MEP amplitude was evident at 4 weeks (ratio [95% CI]: placebo=1.308 [0.249 to 0.965], MEX 300 mg=0.589 [0.315 to 1.102], MEX 600 mg=0.490 [0.249 to 0.965], p=0.013). Accommodation half-time was significantly reduced over 4 weeks with MEX (mean±SE: placebo=5.4ms±2.1, MEX 300 mg=−2.6ms±2.1, MEX 600 mg=−1.2ms±2.3, p=0.002). Conclusions: 20% of ALS subjects demonstrated cortical inexcitability by TMS at screening, comparable to other recent studies. The reduction of RMT by MEX was unexpected but could result from motor neurons recovering from depolarization block as well as unaccounted medications influencing TMS. The change in MEP amplitude supports a reduction of cortical hyperexcitability by MEX therapy in ALS. The change in accommodation halftime supports reduced excitability of peripheral motor nerve axons with treatment. The study was underpowered due to significant challenges with recruitment and further study is warranted. Disclosure: Dr. Weiss has received research support from ALS Association and ALS Finding a Cure. Yes - DSMB member for Shire Human Genetic Therapys and for Novartis, Steering Committee member for a Biogen trial, advisory board member for Cerevance, Intrance, and Inventram Yes - My institution received research funding on my behalf from Amylyx Pharmaceuticals, GlaxoSmithKline, Mitsubishi Tanabe Pharma AmericaDr. McIlduff has nothing to disclose. Dr. Vucic has nothing to disclose. Dr. Wainger has nothing to disclose. Dr. Kiernan has nothing to disclose. Yes - scientific advisory for Biogen, IFT PharmaYes - Speaking: CSL Behring Scientific Advisory boards in the past year: MT Pharma, Alexion, Genzyme/Sanofi, Sarepta, ArgenyxDr. Rutkove has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myolex, Biogen, Axcella Health, Merck. Dr. Rutkove has received personal compensation in an editorial capacity for Annals of Neurology. Dr. Rutkove has received compensation for serving on the Board of Directors of Myolex, Inc. Dr. Rutkove holds stock and/or stock options in Myolex, Inc. Yes - Amylyx Advisory BoardDr. Chen has nothing to disclose. Dr. Harms has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi, and Maze Therapeutics. Dr. Harms has received research support from Biogen. Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Ionis, Akcea, Alnylam, Shire, and CSL Behring. Dr. Brannagan has received research support from Ionis, Alnylam, Viromed, Catalyst, Pharnext, Flexpharma, Novartis, Grifols. Dr. Lacomis has nothing to disclose. Dr. Zivkovic has nothing to disclose. Dr. Ma has nothing to disclose. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Argenx.. Dr. Wang holds stock and/or stock options in GWPH, Spark Therapeutics. Dr. Wang has received research support from Fulcrum Therapeutic. Dr. Simmons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven, Biogen, Cytokinetics.. Dr. Simmons has received personal compensation in an editorial capacity for Muscle & Nerve. Dr. Simmons has received research support from Biogen, Biohaven, Cytokinetics, Genzyme, Mallinckrodt, .Dr. Rivner has nothing to disclose. Yes - I received personal compensation from Cytokinetics, Avexis, Revalasio, Biohaven, Neurosense, MTPA, and Otsuka, for consulting regarding design of ALS trials Yes - I received personal compensation for serving as neuromuscular section editor for UpToDate. Yes - Research support received from Cytokinetics, Biogen, Brainstorm, MTPA, Amylyx.Dr. Cudkowicz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with takeda, biogen, cytokinetics, sunovian, immunitypharm, avexis.Dr. Atassi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, GSK, MT Pharma, and Neuropore Therapies.