Ezogabine Decreases Motor Neuron Excitability in ALS Clinical Trial

The anticonvulsant ezogabine can significantly reduce abnormal motor neuron excitability in people with amyotrophic lateral sclerosis (ALS), a clinical trial has found.

The findings support further investigation of ezogabine, and into the possible utility of neuron excitability as a measurement of disease in ALS, researchers said.

The study, “Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis,” was published in JAMA Neurology.

ALS is characterized by the progressive death of motor neurons — the nerve cells that control muscle movements — in the brain and spinal cord. One of the hallmark changes in these neurons is that they become more excitable, that is, they are more likely to become activated to send an electrical signal.

Ezogabine reduces abnormal neuronal electrical activity by activating certain proteins, called voltage-gated potassium channels, in the membranes of motor neurons.

The therapy was developed by GlaxoSmithKline and Valeant Pharmaceuticals (now Bausch Health). It was sold under the name Trobalt (retigabine) in Europe as an add-on therapy for seizures, but was withdrawn from all markets for commercial reasons in 2017.

A recently completed clinical trial (NCT02450552) evaluated the effect of ezogabine on motor neuron excitability in people with sporadic and familial ALS. Top-line results from the study were announced in late 2018. Now, the detailed results have undergone peer review and been published.

The trial enrolled 65 patients (45 men and 20 women, mean age 58.3 years) and randomly assigned them to receive either a low dose of ezogabine (600 mg/day), a high dose (900 mg/day), or a placebo.

Participants were given the respective treatment for 10 weeks. At the start of treatment (baseline), and after six and eight weeks of treatment, participants underwent clinical evaluations, as well as measurements of motor neuron excitability in the brain and spinal cord.

The trial’s main goal was to determine changes in short-interval intracortical inhibition (SICI), in which an increase in SICI is linked with lower neuron excitability.

In the high-dose group, SICI increased significantly by nearly 40%, over the course of the trial. In the placebo and low-dose ezogabine groups, SICI did not significantly change during the trial.

Overall, “the increase in SICI that we observed during a 900 mg/d dose ezogabine treatment corrected about half the heightened excitability separating participants with ALS from healthy control participants,” the investigators wrote.

Other electrical measurements, including measurements of spinal cord motor neurons, also suggested that ezogabine treatment reduced motor neuron excitability in participants.

“Treatment with ezogabine decreased both cortical [brain] and spinal MN excitability in participants with ALS,” the researchers concluded.

Measures of disease progression, such as the revised ALS Functional Rating Scale, did not change significantly over the course of the trial; given that this was a fairly short trial, such changes were not expected.

“The effect of ezogabine on clinical progression and the association between [SICI and other electrical measurements] and clinical progression are not yet known,” the researchers wrote, pointing to a need for more research.

Four serious adverse events (side effects) were reported over the course of the trial. Three of these were deemed unrelated to the study treatment. The fourth, an instance of decreased alertness in a person in the high-dose ezogabine group, was deemed likely related to treatment.

Nearly all (97%) participants in the trial reported at least one adverse event. The most frequent adverse events among participants given ezogabine were fatigue and dizziness.

None of the participants given placebo discontinued treatment, whereas 12 participants across the two ezogabine groups discontinued the therapy. Almost all discontinuations were associated with adverse events.

“Drug tolerability rates were similar to the rates in studies of ezogabine for epilepsy,” the researchers wrote.

Beyond supporting ezogabine as a potential ALS therapy, this study supports the use of electrical measurements related to motor neuron excitability in ALS research, though the investigators noted that more research will be needed to understand how best to apply these measurements.

“Larger trials with longer treatment durations will be necessary to ascertain whether measures of SICI and [related metrics] can act as surrogates for ALS progression, and whether sustained modulation of these biomarker metrics will yield disease improvement,” they wrote.

This study was funded by the ALS Association, GlaxoSmithKline, Harvard Stem Cell Institute, and the Neurological Clinical Research Institute at Massachusetts General Hospital.