Assistant professor in anesthesiology and neurology, Harvard Medical School; and attending physician, Massachusetts General Hospital

Brian Wainger, MD, PhD

"All of a sudden there’s more powerful tools in the hands of more people. Some of these tools are things that can be adapted and brought into clinic quickly. Overall, it’s a really exciting time for translational medicine in neuroscience and degenerative diseases in particular.”

Ezogabine, once FDA-approved for the treatment of adjunctive treatment for partial-onset seizures, was found in a recent study to decrease cortical and spinal motor neuron (MN) excitability in patients with amyotrophic lateral sclerosis (ALS). Strong clinical evidence that supported hyperexcitability as a prominent phenotype in both familial and sporadic ALS helped investigators move directly from pluripotent stem cell (iPSC) modeling to a clinical trial using neurophysiological metrics of MN excitability as pharmacodynamic biomarkers.

The uniqueness of going from iPSC modeling straight to a phase 2 clinical trial raises questions about the boundaries of researching ALS, and the outside-the-box thinking needed to counteract a disease that has a limited number of treatment options. Lead author of the trial Brian Wainger, MD, PhD, feels as though researchers need to find creative ways to try to better understand ALS, while keeping in mind the lengthy process that encompasses traditional drug development.

Wainger, assistant professor of neurology and anesthesiology, Harvard Medical School, sat down with 

 to detail how the study came about, and the types of strategies needed to grow the understanding of ALS and how it progresses.

Wainger BJ, Macklin EA, Vucic S, et al. Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: a randomized clinical trial. 

. Published online November 23, 2020. doi: 10.1001/jamaneurol.2020.4300

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The assistant professor of neurology and anesthesiology at Harvard Medical School discussed non-traditional ways ALS research is changing and where the focus should continue to be.

Expanding the Understanding of ALS With New Methods: Brian Wainger, MD, PhD

"I’m hoping that it sets this paradigm for repurposing drugs quickly from stem cell work to patients and having confidence that the stem cell models can be predictive. For me, that’s the big value.”

Ezogabine, once FDA-approved as an adjunctive therapy for partial-onset seizures uncontrolled by medications in patients with epilepsy, was recently found to 

decrease cortical and spinal motor neuron (MN) excitability

 in patients with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial. Despite the drug not showing any changes in cognition or slowing progression of the disease, researchers suggested that the MN excitability may be used as a pharmacodynamic biomarker in future clinical studies.

Spinal MN axonal hyperexcitability, which has been indicated by strength-duration time constant (SDTC) measured using threshold tracking nerve conduction studies (TTNCSs) has been previously found in patients with sporadic and familial ALS, according to study authors Brian Wainger, MD, PhD, and his colleagues. The additional TTNCS parameters of depolarizing threshold electrotonus, super-excitability, and latency were all affected with ezogabine treatment.

Wainger claims that he and his colleagues were not disappointed by the lack of effect ezogabine had on survival functions, but were content that it was able to show a proof of mechanism for opening this particular potassium channel and potassium channels in general. He sat down with 

 to provide details on the potential next steps of ezogabine, how clinicians can build off the data observed, and whether a phase 3 trial would be on the way.

The assistant professor of neurology and anesthesiology at Harvard Medical School detailed the future outlook of ezogabine and whether it may be studied again in patients with ALS.

Brian Wainger, MD, PhD: Future Studies Evaluating Motor Neuron Excitability in ALS

"In basic science literature, there’s more connecting of 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.”

Recently published results from a phase 2 study showed a decrease in motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) when they were receiving treatment with ezogabine. The data suggested that these neurophysiological metrics have potential and may be used a pharmacodynamic biomarker in future clinical trials.

Change in short-interval intracortical inhibition, the primary outcome of the study, increased by 53% in the 900-mg/day ezogabine group when compared to those on placebo (

 = .009). This was the first study done using ezogabine—a once FDA-approved treatment for partial-onset seizures uncontrolled by medications—in patients with ALS. 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.

Lead investigator Brian Wainger, MD, PhD, feels as though abnormal excitability remains a consistent factor among patients with ALS. Wainger, 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, sat down with 

 to provide background on the study and the importance of his results.

The assistant professor of neurology and anesthesiology at Harvard Medical School provided context on the potential of motor neuron excitability in patients with ALS. 

Brian Wainger, MD, PhD

Articles

Expanding the Understanding of ALS With New Methods: Brian Wainger, MD, PhD

Brian Wainger, MD, PhD: Future Studies Evaluating Motor Neuron Excitability in ALS

Brian Wainger, MD, PhD: Motor Neuron Excitability in ALS

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