Study of Perampanel for ALS Stopped Due to Adverse Events
A small open-label study evaluating the epilepsy medication perampanel in adults with amyotrophic lateral sclerosis (ALS) was halted due to adverse events that affected behavior.
Despite the findings, larger clinical trials investigating perampanel in ALS patients are ongoing, which might determine if the medication contributed to behavioral side effects.
The study, “An open label pilot study of the safety and tolerability of perampanel in amyotrophic lateral sclerosis,” was published in the journal Muscle & Nerve.
Perampanel, sold under the brand name Fycompa, is a medicine approved to treat epileptic seizures. Long-term trials in epilepsy patients have shown a favorable tolerability profile, with headache, dizziness, and sleepiness being the main side effects.
In animal models, the therapy also has been shown to reduce motor function impairment and prevent the loss of motor neurons, which are the nerve cells that control voluntary movements and are lost in people with ALS.
Perampanel is known to block a protein receptor called AMPA, which plays a role in motor neuron function. Talampanel is a similar AMPA-blocker that has shown promise in a clinical trial in ALS patients.
Earlier this year, a Phase 2 study (NCT03019419) in Japan testing perampanel in 66 ALS patients was completed, and a pilot study (NCT03020797) in the U.S. for perampanel in ALS is enrolling.
A team of scientists based at the American University of Beirut Medical Center, in Lebanon, also conducted an open-label trial (NCT03377309) to test the safety and tolerability of perampanel in adults with ALS who were diagnosed in the past three years.
“To date, no clinical data [have] been published on the safety or efficacy of the short or long term use of perampanel in people living with ALS,” the team wrote.
A total of six men, average age 55 years, were enrolled in the trial. All were treated with either the approved ALS therapy riluzole (marketed as Rilutek, Tiglutik, and Exservan), or no treatment for at least 30 days before the study.
The primary goal was tolerability and safety. Secondary measures included disease progression, as defined by the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as lung function, assessed with the forced vital capacity (FVC) test — the amount of air that can be exhaled forcibly from the lungs.
Enrolled patients started on perampanel at 2 mg/day; then, the dose was increased by 2 mg/day every week to a maximum of 8 mg/day. Treatment was followed by a washout period in which the dose was reduced by 2 mg/day every five days over a period of 15 days.
Participants were examined every four weeks until the end of the treatment phase, for a total of 12 weeks (three months), then weekly throughout the washout period.
All participants experienced adverse events, with two completing the trial. One was withdrawn from the study by the research team due to recurrence of adverse events, and the others withdrew on their own due to side effects.
The most common adverse events included somnolence (drowsiness), aggression, and anger. The sleepiness was resolved by taking the medicine at bedtime. Other adverse events experienced by patients who withdrew included dizziness, imbalance, speech problems, irritability, and gait (walking) disturbances.
Although the upper extremity strength of the two participants who completed the trial remained stable, their lung function declined.
Some study participants also reported worsening of existing symptoms such as speech impairment and imbalance, “raising the possibility that these symptoms are due to disease progression rather than being treatment-related adverse events,” the researchers wrote.
All adverse events were resolved after participants discontinued perampanel. Due to the high number of these events and the low tolerability experienced by patients, the study was stopped.
“The participants in our study did not tolerate perampanel and the trial was halted,” the researchers concluded. “Side effects were mainly behavioral and psychiatric.”
The investigators also noted that “most participants were enrolled in the study during the early stages of the disease, with the median time of symptom onset being 14 months. This raises concerns whether the administration of perampanel has triggered or accelerated the appearance of non-motor and psycho-behavioral symptoms.”
“Future studies using a randomized controlled design could help determine the true contributors to the behavioural events,” they added.
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