Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Abstract

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.

Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.

Design, setting, and participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.

Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.

Main outcomes and measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.

Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).

Conclusions and relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

Trial registration: ClinicalTrials.gov Identifier: NCT02450552.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Wainger is a New York Stem Cell Foundation-Robertson Investigator; reported receiving grants from the National Institutes of Health (NIH; 1DP2-NS10664), the ALS Association, GlaxoSmithKline, Harvard Stem Cell Institute, Target ALS, ALS Finding a Cure, MassLifeSciences, Revalesio, AITherapeutics, and Sanofi during the conduct of the study; personal fees from Amgen, Quralis, Apic Biosciences, Q-State Biosciences outside the submitted work; and had patent US9517223B2 issued for use of potassium channel openers in neurodegenerative diseases. Dr Macklin reported receiving institutional support from grants from Acorda Therapeutics Grant, Amylyx Pharmaceuticals Grant, the Mitsubishi Tanabe Pharmaceutical America, Biohaven Pharmaceuticals Grant, Clene Nanomedicine Grant, Prilenia Therapeutics Grant, and Ra Pharmaceuticals; personal fees from serving as a Biogen Steering Committee member, a Stoparkinson Healthcare LLC Steering Committee member, an Acorda Therapeutics data safety monitoring board member, a Novartis Pharmaceuticals data safety monitoring board member, a Takeda Pharmaceuticals data safety monitoring board member, a Cerevance advisory board member, an Inventram advisory board member, and a Partners Therapeutics advisory board member; personal fees from serving as consultant to Lavin Consulting and Myolex Inc. outside the submitted work. Dr Vucic reported receiving consultancy fees from Biogen Idec Australia and Merck Serono Pty Ltd Australia. Dr Paganoni reported receiving grants from the ALS Association during the conduct of the study; grants from ALS Association, ALS Finding a Cure, the Spastic Paraplegia Foundation, the Salah Foundation, the Muscular Dystrophy Association, the American Academy of Neurology, Amylyx, Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia; and personal fees from Orion outside the submitted work. Dr Maragakis reported serving as consultant to Orion, Apellis Pharmaceuticals, Seneca Biopharmaceuticals, Inc., Amylyx Pharmaceuticals, and Orphazyme. Dr Bedlack reported receiving personal fees from Biogen, Brainstorm Cell, Alexion Pharmaceuticals, the ALS Assocation, Mallinkrodt, Amylyx, MT Pharma; grants from Orion; and personal fees from New Biotic, and Woolsey Pharma outside the submitted work. Dr Goyal reported receiving research support from Brainstorm Cell Therapeutics, Cytokinetics, Fulcrum, Kezar, Octapharma, Orion, and Orphazyme; serving on Advisory Boards for Acceleron, Alexion Pharmaceuticals, Argenx, CSL Behring, MT Pharma, Sanofi Genzyme, Sarepta, and UCB; serving on the speaker’s bureau for CSL Behring. Dr Rivner reported grants from Alexion Pharmaceuticals, Catalyst Pharmaceuticals, Analixis, Medicinova, UBC, Apellis, Momenta, Ra, Takeda, Seikagaku, and Orion outside the submitted work; and personal fees from Alexion Pharmaceuticals and Allergan Pharmaceuticals. Dr Goutman reported receiving grants from the ALS Association during the conduct of the study; grants from NIH/National Institute of Environmental Health Sciences, the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry, and Target ALS; and personal fees from Biogen scientific advisory board, ITF Pharma scientific advisory board, and Watermark Research Partners data safety monitoring board service outside the submitted work. Dr Baloh reported receiving personal fees from Mitochondria in Motion and Acurastem outside the submitted work. Dr Simmons reported receiving personal fees from Amylyx, grants and personal fees from Biogen and Biohaven, and personal fees from Cytokinetics outside the submitted work. Ms Hall reported receiving grants from the ALS Association. Dr Oskarsson reported receiving personal fees from Medicinova, Mitsubishi, Biogen, Columbia University/Tsumura Inc.; and grants from Biogen, Mitsubishi, Medicinova, Genentech, Cytokinetics. Dr Lewis reported receiving personal fees from CSL Behring, Pfizer, Argenx, Momenta, Pharnext, Sanofi, Annexon, Takeda Pharmaceuticals, Akcea, and Alnylam outside the submitted work. Dr Kiskinis is a Les Turner ALS Research Center Investigator and a New York Stem Cell Foundation-Robertson Investigator and had patent US9517223B2 issued for use of potassium channel openers in neurodegenerative diseases. Dr Woolf reported receiving grants from MassLifeSciences, TargetALS, and GSK during the conduct of the study; being a co-founder of Quralis; and had patent US9517223B2 issued for use of potassium channel openers in neurodegenerative diseases. Dr Eggan reported receiving grants from GlaxoSmithKline; personal fees, consulting fees, and founder equity from Quralis, Q-State Biosciences, and Enclear Therapeutics; stock grant from BioMarin Stock grant outside the submitted work; and had patent US9517223B2 issued for use of potassium channel openers in neurodegenerative diseases. Dr Weiss reported receiving grants from the ALS Association and ALS Finding a Cure; personal fees from Biogen, Ra Pharmaceuticals, Argenx, NuFactor, and Mitsubishi Tanabe Pharma outside the submitted work. Dr Berry reported receiving personal fees from Biogen, Clene Nanomedicine, and Alexion Pharmaceuticals; grants from MT Pharma of America, Brainstorm Cell Therapeutics, Genentech, Amylyx Therapeutics, Alexion Pharmaceuticals, Biogen, Clene Nanomedicine, ALS One, ALS Finding A Cure, the Muscular Dystrophy Association, and the ALS Association outside the submitted work. Dr Camprodon reported receiving stocks from Apex Neuroscience outside the submitted work. Dr Pascual-Leone reported receiving personal fees from Starlab, Neuroelectrics, and Magstim outside the submitted work; and had a patent to Integration TMS with EEG and MRI issued. Dr Kiernan reported service as Editor-in-Chief of the Journal of Neurology, Neurosurgery & Psychiatry (BMJ Publishers); and receiving a grant from the National Health and Medical Research Council of Australia. Dr Shefner reported receiving grants from the ALS Association during the conduct of the study; grants and personal fees from Cytokinetics, Brainstorm, Amylyx, Biogen, and MT Pharma America; and personal fees from Neurosense, Immunity Pharma, Sanofi, Apic Bio, Avexis, Orphazyme; grants from Alexion Pharmaceuticals. Dr Atassi is a full-time employee of Sanofi-Genzyme. Dr Cudkowicz reported serving as an advisory board chairperson for Lily, and as a consultant to Biogen, Pharmnext, Treeway, Avexis, Revalasio, Aclipse, Mt Pharma, Biohaven, Sunovian, Anelixis, Cytokinetics, ALS Pharma, RRD International, Disarm, and Immunity Pharm outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

ALS indicates amyotrophic lateral sclerosis; NCS, nerve conduction study; RMT, resting motor threshold; SICI, short-interval intracortical inhibition; and TMS, transcranial magnetic stimulation.

Figure 2.. Effect of Ezogabine Treatment on Multiple Measurements of Upper and Lower Motor Neuron Excitability

Plots show treatment- and visit-specific estimates with 95% CIs from a shared baseline, random-slopes model for short-interval intracortical inhibition (SICI) (A), resting motor threshold (RMT) (B), motor evoked potential (MEP) amplitude at 120% of RMT (C), MEP amplitude at 120% of RMT normalized by peak compound muscle action potential (CMAP) (D), peak CMAP (E), strength-duration time constant (SDTC) (F), rheobase (G), depolarizing threshold electrotonus (TEd) (H), and superexcitability (I).