Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis

Abstract

Objective To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). Methods This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. Results One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [− 8.4 (95% CI − 13.9 to − 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). Conclusions Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

“…However, an open label pilot study, which was conducted to search for the tolerability and safety of perampanel in ALS patients, was terminated owing to the high number of adverse events [ 117 ]. Perampanel was also determined to cause a decline in ALSFRS-R score, along with several adverse events, in a randomized, double-blind, placebo-controlled, multicentre, phase II clinical study [ 118 ].…”

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

“…It is mainly used for epilepsy. However, a 66-patient, phase 2 clinical trial showed that perampanel was not well tolerated and was significantly associated with a decline in the ALSFRS score ( Aizawa et al, 2022 ). Non-AMPA antagonism against voltage-gated sodium channels and M-type potassium currents may exert negative effects ( Lai et al, 2019 ).…”

RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases

“…Moreover, in other studies, perampanel, an FDA-approved noncompetitive AMPA receptor antagonist to manage epilepsy, has prevented ALS-like progressive motor dysfunction in conditional ADAR2 knockout mice and increased the cortical excitability threshold [143,144]. However, with the exception of an improvement in the manual muscle testing score, perampanel did not effectively inhibit disease progression in a recent phase 2 clinical trial on sporadic ALS patients [145,146]. The clinical use of AMPA receptor antagonists is limited by their frequent adverse effects due to the suppression of the physiological function of the CNS neurons; therefore, the development of more sophisticated drugs, such as receptor subunit-specific antagonists, are required in the future.…”