Neuro News Roundup: Purple Day

In recent months, the NeurologyLive® team has been covering the news on the latest updates in the clinical care of individuals with neuromuscular disorders, multiple sclerosis, movement disorders, sleep disorders, and more.

For Purple Day — March 26, 2023 —the team has culminated some of the biggest pieces of news to offer updates on new developments in literature in epilepsy to spread awareness on the prevention and treatment of seizures.

Click here for more coverage of the latest epilepsy news from NeurologyLive®.

Latest Literature

Antiseizure Agent EQU-001 Shows Safety, Tolerability, and Preliminary Efficacy in Phase 2 Study

Topline results from a dose-finding, phase 2 clinical trial (NCT05063877) assessing Equilibre’s antiseizure medication EQU-001 showed that the therapy was safe and well tolerated at all tested doses through 60 mg QD.¹ Conducted in the US and Israel, the EQU-201 study evaluated EQU-001 in doses of 10 mg, 20 mg, 40 mg, and 60 mg once daily relative to placebo in a cohort of 43 individuals with epilepsy with focal seizures. Over the course of a 12-week treatment period, no treatment-related serious adverse events (AEs) were reported, all AEs were grade 1 and 2, and AEs occurred at similar rates to that seen in the placebo group.

Although the study was designed to assess safety and tolerability of EQU-001, there was an overall dose response trend in increasing median percent seizure reductions, except for the 40 mg group. In the modified intend-to-treat population, the median percent reduction in focal seizures per 28 days was 41.6% (95% CI, –5.6 to 83.5), 7.4% (95% CI, –51.3 to 29.1), 19.9% (95% CI, –33.6 to 50.2), 12.3% (95% CI, –32.1 to 83.1) and 5.8% (95% CI, –110.0 to 36.9) in the 60 mg, 40 mg, 20 mg, 10 mg, and placebo groups, respectively.

In total, 88.6% of patients across all treatment arms and 75.0% in the placebo arm completed the study, with 37 patients moving on to the open-label extension. One individual in each of the 40 mg and 60 mg treatment arms discontinued the study because of an AE. Patients in the placebo arm also showed higher rates of infections, occurring in 37.5% vs 11% of those on EQU-001 and 0% in the 60 mg treatment arm.

Systematic Study Identifies Association Between Incident Parkinson Disease and Antiepileptic Drug Use

Research using data from the UK Biobank (UKB) found an association between antiepileptic drug (AED) prescription use and incident Parkinson disease (PD) diagnosis.² Carbamazepine, lamotrigine, levetiracetam, and sodium valproate, the 4 most commonly prescribed AEDs in the United Kingdom, were used as the exposure. Logistic regression models, adjusted for age, sex, and Townsend deprivation index, were used to calculate odds ratios (ORs) and 95% Cis.

Data extracted in June 2021 showed an association between AED use and incident PD, as explained by ORs of 1.80 (95% CI, 1.35-2.40). Specifically, sodium valproate showed the highest OR (3.82; 95% CI, 2.41-6.05), followed by levetiracetam (OR, 3.02; 95% CI, 1.51-.6.05), lamotrigine (OR, 2.83; 95% CI, 1.53-5.25), and carbamazepine (OR, 1.43; 95% CI, 0.97-2.11). The odds of incident PD were higher among individuals prescribed more than 1 AED and among individuals with higher number of issues.

Of those with a PD diagnosis, 63.7% had a record of 2 or more issues of a PD medication. Among these individuals, 96% had an HES-coded PD diagnosis, while the remaining 4% were self-reported. With the more stringent definition of PD, strong evidence of an association remained for sodium valproate.

Growing Brivaracetam’s Potential Through the Adaptive, Dose-Finding EXPAND Study

Brivaracetam (BRIVIACT; UCB), an FDA-approved therapy for pediatric patients with partial-onset seizures, is currently being assessed in an innovative, adaptive trial called the EXPAND trial (NCT04666610). It includes individuals with childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE), 2 conditions for which treatment options remain limited. The trial began in 2021 and consists of a dose selection and assessment for futility stage followed by an optimal dose stage after interim analysis.

The 2-stage design allows the investigation of 2 potentially efficacious doses of the therapy, where one dose is dropped in favor of the other with a better benefit-risk profile. The trial is expected to be completed in 2024, and both stages include an up to 2-week screening period, a 2-week placebo-controlled period, and an 11-week active treatment period. The active treatment period includes 10 weeks of initial treatment followed by a 24-hour electroencephalogram (EEG) and an additional week of active treatment for the 24-hour EEG assessment.³

Investigators will assess the percentage of participants who met the criteria for seizure freedom within 4 days prior to or during the 24-hour ambulatory EEG at day 14 as the primary outcome measure. Every 24-hour EEG will include hyperventilation as a standard provocation test at the beginning of the EEG. The parallel-group, multicenter center trial is expected to include 160 participants, aged 2 to 25 years, with a diagnosis of either CAE or JAE, as defined by the International League Against Epilepsy criteria.

Seizure-Free Days and Duration Intervals Increased With Fenfluramine in Dravet Syndrome

News from a recent post-hoc pooled analysis of two clinical trials (NCT02682927, NCT02826863) showed an increase in seizure-free days and increased duration of seizure-free intervals with antiseizure medication, fenfluramine (Fintepla; UCB Pharma), in patients with Dravet syndrome (DS).⁴ All told, there was a significantly higher probability of not reaching the pre-randomization seizure count in both fenfluramine groups, fenfluramine 0.7 mg/kg/day (62.3%) and fenfluramine 0.2 mg/kg/day (35.3%), in comparison with the placebo group (9.1%)(both fenfluramine groups, P <.001).

These results were presented as a late-breaking poster at the 2022 American Epilepsy Society Annual Meeting, held December 2 to 6, in Nashville, Tennessee, by lead investigator Joseph Sullivan, MD, professor of neurology at the University of California San Francisco.⁴ The investigators observed that during the 14-week titration and maintenance period, fenfluramine increased the probability of failing in the count for the pre-randomization convulsive seizures.

The study was conducted as a time-to-event (TTE) analysis, an alternative to routinely used clinical trial endpoints, as a way to provide data on changes in seizure frequency. TTE was defined as the time required during the 14-week combined titration-maintenance period to experience the same number of convulsive seizures as experienced during the baseline period (Kaplan-Meier log-rank test). The participants were patients with DS, 2 to 18 years of age, with no pulmonary hypertension or cardiovascular or cerebrovascular disease history.

At baseline, the average number of convulsive seizures ranged from 22.0 to 28.5 and the average number of seizure-free days per 28 days ranged from 16.3 to 19.3 days. The seizure free days per 28 days with treatment were analyzed by ANCOVA, using age as factors. The log baseline seizure-free days per 28 days was a covariate and a response. The Wilcoxon rank sum test analyzed the longest convulsive seizure-free interval.

Fenfluramine Continues to Show Effectiveness, Safety in Long-Term Analysis of Lennox-Gastaut

Newly published interim findings from the open-label extension of the pivotal phase 3 Study 1601 (NCT03355209) showed that treatment with fenfluramine (Fintepla; UCB Pharma) resulted in sustained reductions in the frequency of motor seizures for patients with Lennox-Gastaut syndrome (LGS) over a median duration of 364 days.

The findings, published in Epilepsia, extend the observations reported in the randomized controlled trial at 14 weeks. Overall, the median percentage change in monthly frequency of seizures associated with a drop was –28.6% over the entire OLE (P <.0001) and –50.5% at month 15 (P <.0001) for fenfluramine-treated individuals. This included generalized tonic-clonic seizures (GTCS), secondary GTCS, focal to bilateral tonic-clonic, tonic seizures, atonic seizures, and tonic-atonic seizures.

In March 2022, the FDA approved the expanded indication for fenfluramine to include the treatment of seizures associated with LGS, marking the second indication for the agent after it received approval for Dravet syndrome in June 2020. The expanded indication was based of Study 1601, which showed that treatment with fenfluramine at a dose of 0.7 mg/kg/day was superior to placebo in reducing monthly drop seizure frequency (MDSF) over a 14-week period. In the original analysis, the primary end point was met, with a 19.9% estimated mean difference (95% CI, –31.0 to –8.7) in MDSF between the fenfluramine 0.7-mg/kg/day group and placebo (P = .001), while the 0.2-mg/kg/day group reported an estimated mean difference of 10.5% (95% CI, –25.0 to 4.0) in MDSF reduction compared with placebo (P = .09).

REFERENCES
1. Equilibre Biopharmaceuticals announces positive topline results from phase 2 clinical trial of EQU-001 (NCT05063877) for safety, tolerability, and preliminary efficacy as adjunctive therapy for focal seizures in adults with epilepsy. News release. Equilibre Biopharmaceuticals. January 30, 2023. Accessed March 23, 2023. https://www.biospace.com/article/releases/equilibre-biopharmaceuticals-announces-positive-topline-results-from-phase-2-clinical-trial-of-equ-001-nct05063877-for-safety-tolerability-and-preliminary-efficacy-as-adjunctive-therapy-for-focal-seizures-in-adults-with-epilepsy/
2. Belete D, Jacobs BM, Simonet C, et a. Association between antiepileptic drugs and incident Parkinson disease in the UK Biobank. JAMA Neurol. Published online December 27, 2022. doi:10.1001/jamaneurol.2022.4699
3. Bast T, Schulz AL, Floricel F, Morita D, Cleveland JM, Elshoff JP. Efficacy and tolerability of brivaracetam monotherapy in childhood and juvenile absence epilepsy: an innovative adaptive trial design. Epilepsia Open. 2022;10.1002/epi4.12628. doi:10.1002/epi4.12628
4. Sullivan J, Specchio N, Devinsky O, et al. Time-to-Event Analysis to Measure Treatment of Fenfluramine Therapy: Pooled Analysis of Two Phase 3 Studies in Dravet Syndrome. Presented at: AES Annual Meeting; December 2-6, 2022; Nashville, TN, and virtual. Poster.
5. Epilepsia publishes interim results of open-label extension study of Fintepla (fenfluramine) oral solution in patients with Lennox-Gastaut syndrome (LGS). News release. UCB Pharma. November 23, 2022. Accessed March 23, 2023. https://www.prnewswire.com/news-releases/epilepsia-publishes-interim-results-of-open-label-extension-study-of-fintepla-fenfluramine-oral-solution-in-patients-with-lennox-gastaut-syndrome-lgs-301685487.html