NeuroVoices: Brian Wainger, MD, PhD, on Ezogabine and Stem Cells in ALS

December 23, 2020
Marco Meglio
Marco Meglio

Marco Meglio, Associate Editor for NeurologyLive, has been with the team since October 2019. Follow him on Twitter @marcomeglio1 or email him at

The assistant professor of neurology and anesthesiology at Harvard Medical School detailed the findings of a phase 2 trial using ezogabine, a drug once FDA-approved to treat epilepsy, in patients with ALS.

Recently published data from a phase 2 randomized controlled trial demonstrated that ezogabine can decrease cortical and spinal motor neuron (MN) excitability in patients with amyotrophic lateral sclerosis (ALS), suggesting that neurophysiological metrics may be used as a pharmacodynamic biomarker in future clinical studies.

Strong clinical evidence that supported hyperexcitability as a prominent phenotype in both familial and sporadic ALS helped investigators move directly from induced pluripotent stem cell (iPSC) modeling to a clinical trial using these metrics as biomarkers. Brian Wainger, MD, PhD, assistant professor, neurology and anesthesiology, Harvard Medical School, and physician scientist and principal investigator, Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, claims this abnormal excitability is 1 of the most consistent factors in patients with ALS.

Ezogabine, once FDA-approved as an adjunctive therapy for partial-onset seizures uncontrolled by medications, has helped open the door on the importance of researching MN excitability, according to Wainger. In the latest segment of NeuroVoices, Wainger discussed the trial in full detail, how ezogabine was chosen for this patient population, and what the current treatment needs are for patients with ALS.

NeurologyLive: Can you provide more detail on your results? Were you shocked by any of your findings?

Brian Wainger, MD, PhD: We identified ezogabine as a candidate using work in stem cells made from ALS patients. Those findings showed that motor neurons from ALS patients tended to fire more compared to motor neurons from control neurons. That fit nicely with the existing neurophysiological studies in ALS patients, using both transcranial magnetic stimulation to look at upper motor neurons that have the shell bodies in the brain, and the lower motor neurons that have their cell bodies in the spinal cord. Those lower motor neuron excitability studies were done using a technique called threshold tracking nerve conduction, which was developed by Hugh Bostock, PhD, in the United Kingdom. Both of these sort of separate, but parallel, groups of neurophysiology studies in ALS patients had shown increased excitability.

Although it should be noted that this is controversial, and that there’s been a bunch of other studies involving motor neurons that have shown similar things and some that have shown opposite things. But that finding was similar between the stem cell motor neurons and the patient and pointed towards ezogabine as a way of correcting that propensity to fire too much. Uniquely, many medicines that affect the firing of neurons or muscle work by blocking specific ion channels work by affected the sodium or calcium ion channels, but this was 1 of the first drugs that affects the potassium channels. That may be important because those potassium channels are open a lot more compared to some of the sodium or calcium channels. It may be an effective or powerful way to control the excitability and firing of these neurons.

For the study, we brought this drug straight from stem cell to work to patients without using mouse models. That in itself, in my opinion, was pretty novel, and reflected a few things. First was the lack of predictive mouse models for most ALS variants, and the second was the fact that this was a drug already FDA approved for epilepsy, so we knew a lot about its pharmacodynamics, how it gets into the central nervous system, and what are its optimal doses.

The other novel component of the study was the development of these neurophysiology metrics which had just been used at specialized single sites and relatively small studies, and then applying them more broadly throughout the Northeast ALS Association network of clinical trial sites and doing this in 12 different locations. That involved a lot of rigor being applied in these tests, which took a lot of time. We were surprised by how clean some of the neurophysiology data was with a relatively small subgroup of patients.

I was also surprised by the magnitude of the effect, particularly in the motor neuron excitability. The effect of the drug reduced the full extent of the abnormal excitability in patients with ALS. The study was designed to assess from a pharmacodynamic side, the effect of the drug on the neurophysiology. There’s still this remaining, "so what?" question that gets asked. Does correcting this excitability matter? We showed that we could affect it briefly for about 8 weeks, but would that persist in a longer study? The other question is, how much does that matter in the disease progression? Would blocking abnormal excitability be sufficient to alter the disease course? We don’t have the answer to that.

In basic science literature, there’s more connecting different ALS disease processes to this abnormal excitability. Aside from the clinical diagnosis, motor and muscle weakening and things of that sort, it’s really 1 of the strongest signals. I shouldn’t over-speak, but it is definitely a consistent feature among a broad range of pathologically different ALS.

How did ezogabine go from being an approved medication for partial-onset seizures to being studied in patients with ALS?

It really was the work in the ALS stem cell models which showed that there was an increased firing in the motor neurons from ALS, and that reducing that firing promoted the survival of those motor neurons. That is the crux of the argument in that it would matter, or rather it could matter. But that hasn’t been fully assessed yet. This was a big step in the translation because it was the first sort of study where you had an identified treatment involving stem cell drug neurons and then moving it straight to patients. There’s a lot of novelty in the development and upscaling of these metrics to a format that could be useful. That was the scope of it.

What does the treatment landscape for patients with ALS look like right now?

There’s never been a more hopeful time for treatments for ALS. That’s particularly true for some of the familial variants, including those with the SCA1 mutation or the C9orf72 expansion, where the power of gene therapy in antisense oligonucleotides is being brought to bear in those cases of ALS. It’s also a very exciting time for understanding sporadic ALS and advancing treatments for this patient population. That includes better mechanistic understanding, better development of biomarkers, and innovation in clinical trial design. Those all have the potential to contribute to improving treatment. Not that it is necessarily more heterogenous, but sporadic ALS doesn’t have as clear handle of the heterogeneity and the genetic variance that you have with familial. If treatments are efficacious in some subgroups of sporadic ALS, but not others, then it may be harder to identify.

Transcript edited for clarity.

Related Content:

News | NeuroVoices | Neuromuscular | Clinical