SPECIAL REPORT
AI model predictive of ASM response
Perampanel – PORTABLE study results
Cenobamate mechanism of action
New data for adjunctive cenobamate: three studies
Failed trial of soticlesat in Lennox-Gastaut syndrome (LGS)
Studies examining the efficacy, safety and mode of action of novel antiseizure medications (ASM) were among the highlights of the American Epilepsy Society (AES) annual meeting, held December 6-10, 2024, in Los Angeles, California. The following summarizes some of the key research presented at AES 2024.
AI model predictive of ASM response
An Australian group investigated an artificial intelligence (AI) model for predicting ASM response in newly-diagnosed patients with epilepsy (Kwan et al. AES 2024;P1.428). The fusion AI model used clinical characteristics and EEG findings, three MR images and data on the two most recent regimens to predict the probability of seizure outcome. Overall, 68 of 113 patients (60.2%) were seizure-free. The accuracy of the model was 74% in predicting seizure-free status.
Perampanel – PORTABLE study results
The PORTABLE study investigated the 12-month efficacy of perampanel monotherapy in 61 patients with new-onset/recurrent epilepsy with focal onset seizures in Japan (Akamatsu et al. AES 2024;P2.400). The mean baseline seizure frequency was 2.9/month. Most patients (72.1%) were started on perampanel 2 mg/day; 26.2% started at <2 mg/day. The mean dose during the observation period was 3 mg/day. The seizure-free rate was 67.4% at 12 months. The most common adverse effects were somnolence (14.8%), dizziness (11.5%), and irritability (8.2%).
Cenobamate mechanism of action
The novel ASM cenobamate has been reported to act primarily via blockade of persistent Na+ channels (Nakamura et al. Eur J Pharmacol 2019;855:175-182); and modulation of GABA-induced currents mediated by GABAA receptors (Sharma et al. Eur J Pharmacol 2020:879:173117) (see also Cenobamate as adjunctive therapy for partial-onset seizures: a review, NeuroSens, October 24, 2024). A new review analysed preclinical data to further clarify the mechanism of action of cenobamate (Sankar et al. AES 2024;P1.437). The data showed that blockade of persistent Na+ channels contributed to a paroxysmal depolarization shift and regulation of neurons in the hippocampus after epileptogenic stimuli. Selective blockade of the fast Na+ channel was enhanced by cenobamate’s modulation of GABAA receptor-mediated tonic currents. Allosteric modulation of GABAA appeared to occur via non-benzodiazepine binding sites. Cenobamate spared the transient Na+ channel and did not interfere with GABAergic interneuron function, which may preserve network inhibition. This selective inhibition of the persistent Na+ channel versus the transient Na+ channel appeares to be a unique feature that is not found in other ASMs such as phenytoin and carbamazepine.
New data for adjunctive cenobamate: three studies
Time to efficacy onset: A study examined the time to achieve treatment efficacy during the initial titration phase in Asian patients with focal seizures (Pradhan et al. AES 2024;P1.404). A total of 446 patients were randomized to placebo or cenobamate 100 mg, 200 mg or 400 mg once-daily. The starting dose was 12.5 mg/day up-titrated every two weeks according to the standard titration schedule. There was a significant median reduction in 28-day seizure frequency starting at week 5-6 (titrated dose 50 mg/day) with cenobamate versus placebo (42.9% vs. 15.4%); the median seizure reduction at weeks 7-8 (dose 100 mg/day) was 55.6% vs. 20.0%, respectively.
Real-world dosing: A U.S. health database analysis (N-4306) examined the maintenance dose of cenobamate that was most commonly used in practice (Wade et al. AES 2024;P1.436). In the subgroup receiving cenobamate for >180 days, most (50.9%) were taking a dose of 200 mg/day. Other commonly-used maintenance doses were 150 mg/day (16.1%) and 100 mg/day (21.5%). Few patients received a maintenance dose of 50 mg/day (8.9%) or required doses >200 mg/day (2.6%).
Efficacy and safety: A single-centre retrospective study analysed the efficacy and safety of adjunctive cenobamate at one year in 170 patients with focal epilepsy (Loushy et al. AES 2024;P1.418). For the subgroup with higher frequency seizures, response rates were 47% for focal impaired awareness seizures (FIAS) and 58% for focal to bilateral tonic-clonic seizures (FBTCS). In the lower frequency seizure group, response rates were 53% and 68%, respectively. Factors associated with seizure-freedom were lower seizure frequency at baseline, failing fewer prior ASMs, and concomitant clobazam use. Most patients in the seizure-freedom group were receiving a dose of cenobamate 200 mg/day. The 12-month retention rate was 82.4%. The most common adverse effect was drowsiness (32%). There was one case of depression requiring hospitalization.
Failed trial of soticlesat in Lennox-Gastaut syndrome (LGS)
Soticlestat is a selective inhibitor of cholesterol 24-hydroxylase that reduces glutaminergic hyperexcitability. In the phase II ELEKTRA trial, adjunctive soticlestat showed a significant reduction in seizure frequency in patients with Dravet syndrome or LGS (Hahn et al. Epilepsia 2022;63:2671-2683). In the phase III SKYWAY trial, there was no significant difference between active therapy and placebo in reduction in major motor drop seizure frequency (Auvin et al. AES 2024;P1.489). The median reduction from baseline in MMD seizure frequency per 28 days was -6.11% with soticlestat and -6.69% with placebo. No differences were seen with soticlestat versus placebo for most of the key secondary endpoints.