Ezogabine Reported to Improve Motor Neuron Excitability in ALS


The treatment, previously known as retigabine, was assessed in a phase 2 trial in more than 60 patients with amyotrophic lateral sclerosis.

Dr Brian Wainger

Brian Wainger, MD, PhD

Ezogabine (Potiga, GlaxoSmithKline) has been shown to lessen abnormal neuron excitability in patients with amyotrophic lateral sclerosis (ALS), according to the top-line findings of a phase 2 trial.1

Presented at the 29th International Symposium on ALS/Motor Neurone Disease conference in Glasgow, Scotland, by Brian Wainger, MD, PhD, an assistant professor neurology and anesthesiology at Harvard Medical School and an attending physician at Massachusetts General Hospital, the primary goal of the trial—a reduction in motor neuron excitability—was met following treatment with the anticonvulsant.

"This novel study provides us with a better understanding of neuron hyperexcitability, an important ALS disease pathway, and we are thrilled to be a part of such a powerful collaborative team," Calaneet Balas, MBA, the president and CEO of The ALS Association said in a statement.

The trial (NCT02450552), while not powered to assess clinical outcomes, measured the effects of the Kv7 or KCNQ voltage-gated potassium channel activator on upper and lower motor neuron excitability in 65 people with ALS. This was done by using transcranial magnetic stimulation and threshold tracking nerve conduction studies.

“This is the first clinical trial for ALS that was designed using data based on an iPSC model of ALS and was possible in part due to the availability of a biomarker in people living with disease that measures excitability of motor neurons, also characterized in the iPSC model,” Lucie Bruijn, PhD, MBA, the chief scientist of The ALS Association, said.

Ezogabine was developed in a partnership between GlaxoSmithKline and Valeant Pharmaceuticals (now known as Bausch Health) intended to be used as an add-on treatment for partial-onset seizures in epilepsy. It was withdrawn from the global market in 2017 due to commercial reasons. It had been available in 50-mg, 100-mg, 200-mg, 300-mg, and 400-mg tablets.

Despite this commercially charged withdrawal, the FDA had issued a safety communication and placed a black boxed warning on the drug label in 2013, due to risks of retinal abnormalities, potential vision loss, and blue discoloration of the skin, nail, mucous membrane, and white-of-the-eye. This warning was revised in 2015 based on a review of additional safety reports, in which the agency decided that retinal pigment changes linked with the drug did not seem to impact vision, and skin discoloration appeared to be only cosmetic, without serious adverse effects. At the time, the FDA required GlaxoSmithKline to conduct a long-term observational study to take a further look into the medication’s safety profile.2

Previously, in a 2007 double-blind, randomized, placebo-controlled phase 2 clinical trial of the treatment—then known as retigabine&mdash;tested its efficacy in 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. Seizure frequency was significantly reduced by 23% for its 600-mg dose, 29% for the 900-mg dose, and 35% for the 1200-gm dose (P <.001). Responder rates for ezogabine were 23% (600 mg), 32% (900 mg; P = .021), and 33% (1,200 mg; P = .016), compared to 16% for placebo.3

As well, another phase 2 trial in 2009 which was intended to assess the safety and efficacy of the treatment in postherpetic neuralgia, but it failed to meet its primary end point. Preliminary results were reported by Valeant as inconclusive.4


1. Ezogabine treatment shown to reduce motor neuron excitability in ALS patients [press release]. Boston, MA: Massachusetts General Hospital; Published December 10, 2018. massgeneral.org/News/pressrelease.aspx?id=2320. Accessed December 14, 2018.

2. FDA. FDA Drug Safety Communication: FDA determines 2013 labeling adequate to manage risk of retinal abnormalities, potential vision loss, and skin discoloration with anti-seizure drug Potiga (ezogabine); requires additional study. Published October 31, 2013. Updated June 15, 2015. fda.gov/downloads/Drugs/DrugSafety/UCM451170.pdf. Accessed December 14, 2018.

3. Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology. 2007;68(15):1197-1204. doi: 10.1212/01.wnl.0000259034.45049.00

4. Valeant Pharmaceuticals Announces Preliminary Results From Its Phase IIa Retigabine Study for the Treatment of Postherpetic Neuralgia (PHN) [press release]. Aliso Viejo, CA: Valeant Pharma; Published August 24, 2009. drugs.com/clinical_trials/valeant-pharmaceuticals-announces-preliminary-results-phase-iia-retigabine-study-postherpetic-7947.html. Accessed December 14, 2018.

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