Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

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 PARTICIPANTSThis 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 MEASURESThe 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.

Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation

“…Two Kv7.2/7.3 openers, retigabine and flupirtine, were found to block firing of human motor neurons carrying SOD1, C9ORF72, and FUS mutations in our previous study (Wainger et al, 2014), suggesting the action is not mutation dependent. Retigabine also decreased lower motor neuron hyperexcitability in two recent clinical trials on patients with ALS (Kovalchuk et al, 2018;Wainger et al, 2021), validating the action of Kv7 channels in controlling human motor neuron hyperexcitability in patients. AMPA receptors are glutamate-gated cation channels whose calcium permeability is subject to both posttranscriptional and posttranslational modifications (Weiss, 2011).…”

“…Neuronal hyperexcitability is observed in multiple different ALS models and contributes to cell toxicity by calcium overload ( King et al, 2016 ). In patients, increased motor axonal excitability is revealed by in vivo excitability assessments such as threshold tracking ( Park et al, 2017 ; Wainger etal., 2021 ),which reflects aberrant sodium and potassium currents. An increase in excitability in patients is associated with muscle cramps and fasciculations and most importantly, shorter survival ( Nakata et al, 2006 ; Kanai et al, 2012 ).…”

The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders

“…A Phase II Pharmacodynamic Trial of Ezogabine (Retigabine) on neuronal excitability in ALS (NCT02450552) was conducted from 2015 to 2019 showing a decrease of cortical and spinal MN excitability in participants with ALS. These data suggest that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials (Wainger et al, 2020).…”

Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

“…However, its administration has been associated with side-effects, such as retinal pigmentation, urinary retention, and skin discoloration [ 58 , 67 ]. Although it is known to serve as an activator, it has also been shown to inhibit KCNQ channels at positive potentials [ 68 ]. In addition, retigabine is known to act on other channels, including g-aminobutyric acid receptor channels [ 69 ].…”