Summary: Ezogabine, an antiepileptic drug, reduces the excitability of cortical and spinal motor neurons associated with ALS.
Source: Mass General
The antiepileptic drug ezogabine reduced pathologic excitability of cortical and spinal motor neuron cells that are early signs of clinical dysfunction in people with amyotrophic lateral sclerosis (ALS), according to a study conducted by the Neurological Clinical Research Institute of Massachusetts General Hospital (MGH).
In addition to providing a clearer understanding of motor neuron excitability as an important disease pathway for ALS, the multi-site study, published in JAMA Neurology, involves the first clinical investigation of ALS (also known as Lou Gehrig’s disease) using a drug identified through an induced pluripotent stem cell (iPSC) model.
“The stem cell approach allowed us to capture the hyperexcitability of motor neurons — a prominent disease phenotype — and to then show ezogabine was able to reduce it in people with ALS,” says lead author Brian Wainger, MD, PhD, of the Healey Center for ALS at MGH. “Our findings could have important implications for the field of ALS research both by demonstrating the effect of ezogabine on excitability in people with the disease and by showing that the metrics of cortical and spinal motor neuron excitability may be used as drug biomarkers in multi-site clinical trials.”
ALS is a progressive neurodegenerative disorder that leads to the death of neurons in the brain and spinal cord that control speech, swallowing and limb movements. Named after the famous baseball player Lou Gehrig, who was diagnosed with the disease in 1939, there are around 20,000 people in the U.S. with ALS, and another 5,000 newly diagnosed cases each year. Currently, there are three approved drugs in the U.S. for treating ALS, each with limited benefit, creating an urgent need for new therapies that could change the course of the fatal disease.
The MGH study of ezogabine was not designed to assess the long-term effects of the drug on the neurodegenerative disorder, but rather to unravel the biological processes that go awry and identify novel molecular targets for drug intervention. To that end, the ten-week, phase 2 study of 65 participants with ALS at 12 U.S. sites investigated the feasibility of using neuron excitability metrics as predictors of disease progression. “We demonstrated for the first time that these neurophysiological assays can be effectively deployed across multiple study sites, which is important in trials of diseases like ALS where investigators rely on many sites for recruitment,” explains Wainger. “That finding could be useful in evaluating other drugs to treat ALS, or even for other diseases where motor neuron metrics could serve as key biomarkers.”
Ezogabine (also known as retigabine) had been previously approved by the U.S. Food and Drug Administration (FDA) for treating epilepsy with a unique mechanism of action: facilitating potassium channels in cell membranes that play a central role in controlling neuron excitability, particularly important in the control of seizures. Researchers from MGH’s Neurological Clinical Research Institute began evaluating the drug’s potential in the context of ALS, using transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS) to measure the effects of ezogabine on motor neuron excitability. They learned that ezogabine did indeed calm the excitability of motor neurons.
“Further studies are needed to determine if longer treatment will sustain the effects of reduced excitability and, if so, whether that may slow disease progression,” says Wainger. “Through our study we’ve hopefully established a new research paradigm for using iPSC-based in vitro models for identifying novel disease targets and compounds, and rapidly repurposing drugs for clinical trials.”
Wainger is assistant professor in Neurology, Anesthesia, Critical Care and Pain Medicine at Harvard Medical School (HMS). Senior author Merit Cudkowicz, MD, MSc, is chief of Neurology at MGH, director of the MGH Neurological Clinical Research Institute, and the Julieanne Dorn Professor of Neurology at HMS. Co-author Eric Macklin, PhD, is a biostatistician at the MGH Biostatistics Center.
Funding: The study was supported by the ALS Association, GlaxoSmithKline, the Harvard Stem Cell Institute and the MGH Neurological Clinical Research Institute.
About this ALS research news
Source:Mass General Contact: Michael Morrison – Mass General Image: The image is in the public domain
Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
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.
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.
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.
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−1increased 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.