Dr. Brian Wainger from the Massachusetts General Hospital (MGH) presented initial top-level results from a recently completed phase II clinical trial of ezogabine (retigabine) on motor neuron excitability (NCT02450552). The study, supported by The ALS Association, met its main goal of quantifying a reduction in motor neuron excitability in people with ALS following treatment. Results were presented during the 29th International Symposium on ALS/MND in Glasgow, Scotland, last week.
“This novel study provides us with a better understanding of neuron hyperexcitability, an important ALS disease pathway, and we are thrilled to be part of such a powerful, collaborative team,” stated Calaneet Balas, president and CEO of The ALS Association.
This trial, conducted by investigators from the MGH Neurological Clinical Research Institute (NCRI) at Northeast ALS Consortium (NEALS) trial sites, focuses on hyperexcitability of motor neurons. It was previously shown that people living with ALS have motor neurons (both upper and lower) that fire too many signals, meaning they are hyperexcitable. Too much firing leads to motor neuron damage. These “hyperexcitable neurons” are thought to play a role in ALS.
Ezogabine is an agonist (activator) of the Kv7 or KCNQ family of voltage-gated potassium channels in cell membranes. It is designed to reduce the over firing of motor neurons that can cause seizures.
To physiologically test motor neuron hyperexcitability in trial participants in real time, the investigators used techniques called transcranial magnetic stimulation (TMS) and nerve conduction studies. These specialized tests are a way to measure the connections between motor neurons and muscles.
TMS works by stimulating the motor cortex (part of the brain that controls muscle movement) with a magnet and recording the response of the muscles in the hand. Nerve conduction studies evaluate the ability of motor neurons to conduct signals to muscles.
The investigators used TMS and threshold-tracking nerve conduction studies to measure the effect of ezogabine on upper and lower motor neuron excitability in 65 people with ALS. They found a reduction of motor neuron excitability. The study was not powered to assess clinical outcomes.
Preclinical studies in human-induced pluripotent stem cells leading up to the clinical trial were supported by The ALS Association, Harvard Stem Cell Institute (HSCI), the New York Stem Cell Foundation, and Target ALS. Dr. Wainger is a New York Stem Cell Foundation – Robertson Investigator.
“This is the first clinical trial for ALS that was designed using data based on an iPSC model of ALS. It 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,” stated Dr. Lucie Bruijn, chief scientist of The ALS Association.
This trial was also supported by GlaxoSmithKline, HSCI, and NCRI at MGH.
Read full press release here.
Read more about the phase II ezogabine trial here.