Third-Generation Antiseizure Medications: Adjunct Therapy for Partial-Onset Seizures
Epilepsy is a neurological disorder affecting approximately 70 million individuals worldwide; it is characterized by recurrent, unprovoked seizures.1,2 Despite the prevalence, not all seizures are epileptic, with some triggered by factors such as emotional stress or movement disorders.2 Moreover, seizures significantly impact patients’ health-related quality of life (HRQOL), affecting such aspects as physical function, cognitive function, social interaction, and emotional well-being. Depression, prevalent in up to 35% of patients with epilepsy, is a significant predictor of HRQOL.3 As a result, epilepsy imposes substantial economic and social burdens, including reduced educational and job opportunities, psychological distress, and stigma.4 Figure 1 discusses the epidemiology of epilepsy.1,3,5
With an estimated global prevalence ranging from 2.7 to 17.6 per 1000 individuals and an incidence rate of 16 to 51 per 100,000 people, epilepsy is a significant public health concern.1 In the United States alone, an estimated 3.4 million individuals are affected by epilepsy.5 The economic impact of epilepsy varies based on disease severity, treatment response, and healthcare infrastructure, with out-of-pocket expenses and productivity losses imposing significant strains on affected households.4
Understanding Seizures and Epilepsy
Seizures can be broadly categorized into provoked seizures, which are triggered by identifiable causes such as trauma or infection, and epileptic seizures, which arise from an imbalance in neuronal excitation and inhibition. This imbalance can be caused by various factors, including gene mutations, aberrant signaling, or dysfunctional neural networks. Notably, immature brains are more susceptible to seizure development due to delayed inhibitory synaptic function and excitatory gamma-aminobutyric acid (GABA) effects.2
Epilepsy demonstrates a bimodal distribution in its incidence, peaking in infants and children under 4 years old, decreasing through childhood and early adulthood, and stabilizing until around the age of 50. However, the prevalence of epilepsy is notably highest among older adults, affecting approximately 1 in 67 individuals aged 65 years or older. In older patients, treatment outcomes may be influenced by physical frailty, cognitive impairments, and the presence of dementia and neurodegenerative diseases, with up to 20% of cases linked to these conditions. Additionally, older individuals often have more medical comorbidities, leading to increased medication usage and a higher risk of drug interactions. Reduced drug clearance due to age-related changes in liver and renal function makes older patients more susceptible to drug side effects.6
Partial-Onset Seizures in Adults
Neurophysiological identification of partial (focal) seizures involves electroencephalography (EEG) and presurgical depth electrode recordings. Common EEG patterns aid in diagnosis, enabling tailored treatment plans to improve patient quality of life.2
In adults, partial-onset seizures account for about 60% of all cases, with approximately 30% of patients experiencing refractory epilepsy, where seizures persist despite treatment.3,5 Understanding the associations between changes in seizure severity, patient characteristics, alterations in seizure frequency, and HRQOL is crucial for optimizing medication therapy in patients with epilepsy.
Treatment Landscape
The cornerstone of epilepsy management revolves around symptomatic relief, primarily achieved through antiseizure medications (ASMs), which aim to control seizures while preserving or enhancing HRQOL.3 While many patients achieve seizure freedom with proper ASM therapy, about 30% of patients continue to experience recurrent seizures, leading to elevated morbidity and mortality rates, decreased quality of life, and heightened healthcare utilization.5 This highlights the persistent challenge of drug-resistant epilepsy and underscores the urgent need for innovative treatment modalities.
Recent advancements in third-generation ASMs, such as eslicarbazepine acetate, brivaracetam, cenobamate, lacosamide, and perampanel, have received US Food and Drug Administration (FDA) approval as adjunctive therapy for managing partial-onset seizures in adults.4,7 These third-generation ASMs, distinguished by novel mechanisms of action or enhanced tolerability, expand clinicians’ options in epilepsy management, offering improved efficacy and tolerability profiles.7
Below is an overview of the current evidence regarding the efficacy and tolerability of these third-generation ASMs as adjunctive therapies for partial-onset seizures in adults.
Third-Generation ASMs
Lacosamide
Approved by the FDA in 2008, lacosamide marked a milestone in the treatment of partial-onset seizures in patients aged 1 month or older.8
Efficacy
Lacosamide’s efficacy as an adjunctive therapy for partial-onset seizures was validated through three 12-week randomized, double-blind, placebo-controlled trials involving adult patients (studies 2, 3, and 4). These trials enrolled patients who had not achieved satisfactory seizure control with 1 to 3 concurrent ASMs and were experiencing an average of 4 or more partial-onset seizures every 28 days with no seizure-free interval exceeding 21 days. With an average epilepsy duration of 24 years and a median baseline seizure frequency ranging from 10 to 17 seizures per 28 days, approximately 84% of patients were concurrently taking 2 to 3 ASMs, with or without concurrent vagal nerve stimulation.8
Dosing and Titration
The trials compared various lacosamide doses (200, 400, and 600 mg/day) with a placebo. During the titration phase, treatment started at 100 mg/day (50 mg twice daily) and increased weekly until reaching the target dose, with a possible back-titration to 100 mg/day or placebo in cases of intolerable adverse reactions. The titration phase lasted 6 weeks in study 2 and study 3, and 4 weeks in study 4. Following titration, patients entered a 12-week maintenance phase where they maintained a stable lacosamide dose.8
Outcome Measures
The primary measure across all trials was the reduction in 28-day seizure frequency compared with the placebo group. Statistically significant reductions were observed with lacosamide doses of 200 mg/day (in study 4), 400 mg/day (in studies 2, 3, and 4), and 600 mg/day (in studies 2 and 3). Subgroup analyses showed no significant differences in seizure control based on sex; data on race were limited.8
Perampanel
Approved by the FDA in 2012, perampanel is a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist that is one option in the armamentarium for managing partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy who are aged 4 years and older.9
Efficacy Evaluation
Perampanel’s efficacy in treating partial-onset seizures, regardless of secondary generalization, was scrutinized in 3 pivotal multicenter trials (studies 1, 2, and 3), encompassing both adult and pediatric patients aged 12 years and older. These trials enrolled patients with inadequate seizure control despite using 1 to 3 concurrent ASMs. Eligible patients, identified during a 6-week baseline period, entered a 19-week treatment period comprising a 6-week titration phase followed by a 13-week maintenance phase. With an average epilepsy duration of approximately 21 years, patients experienced a median baseline seizure frequency ranging from 9 to 14 seizures every 28 days. More than 85% of enrolled patients were on 2 to 3 concurrent ASMs, sometimes alongside concurrent vagal nerve stimulation. Notably, around 50% of patients were prescribed at least 1 ASM known to induce CYP3A4, which is an enzyme crucial for the metabolism of perampanel, potentially affecting its serum concentration.9
Dosing Regimen
Patients in all trials received placebo or various perampanel dosages. During the titration phase, patients initiated perampanel at 2 mg once daily and increased weekly by 2 mg/day until reaching the final prescribed dose. Those who reported intolerable adverse reactions had the option to reduce their dose to the previously tolerated level.9
Outcome Measures
Primary assessment in studies 1, 2, and 3 focused on the percentage change in seizure frequency per 28 days during the treatment period compared with the baseline period, with statistical significance set at P <.05. Notable reductions in seizure rate were observed across doses ranging from 4 to 12 mg/day, with a discernible dose-response relationship particularly evident at 4 to 8 mg, showcasing marginal additional reduction at 12 mg/day.9
Eslicarbazepine Acetate
Eslicarbazepine acetate received FDA approval in 2013 as an adjunctive therapy for partial-onset seizures in patients aged 4 years and older.10 This approval marked a pivotal moment in epilepsy management, offering a new avenue of treatment for patients with uncontrolled seizures.
Clinical Trials Overview
The efficacy of eslicarbazepine acetate as adjunctive therapy in partial-onset seizures stems from 3 pivotal clinical trials (studies 3, 4, and 5) designed to evaluate its performance in managing partial-onset seizures. These trials enrolled adult patients with epilepsy with inadequate seizure control despite using 1 to 3 other ASMs. Study participants had an average epilepsy duration of 19 years and a median baseline seizure frequency of 8 seizures every 28 days. Notably, the majority (69%) of participants were concurrently using at least 2 ASMs.10
Study Designs and Dosages
Using a comparative approach, studies 3 and 4 assessed various dosages of eslicarbazepine acetate — 400, 800, and 1200 mg once daily — against placebo. Meanwhile, study 5 explored dosages of 800 and 1200 mg once daily vs placebo. Following an initial 8-week baseline phase aimed at establishing baseline seizure frequency, participants were randomly assigned to treatment groups and entered a treatment period comprising a titration phase (2 weeks) followed by a maintenance phase (12 weeks). Patients initiated therapy with a daily dosage of 400 mg or 800 mg, with incremental increases of 400 mg/day after 1 or 2 weeks until reaching the final target daily dose.10
Primary and Secondary Endpoints
The primary efficacy endpoint across all trials was standardized seizure frequency during the maintenance phase over 28 days. Eslicarbazepine acetate treatment — particularly at doses of 800 mg/day in studies 3 and 4, and at doses of 1200 mg/day in all 3 studies — consistently demonstrated significant reductions in seizure frequency. 10
Global Phase 3 Trial
A pivotal global phase 3 trial (Study 304; ClinicalTrials.gov identifier: NCT00988429) delved deeper into eslicarbazepine acetate’s therapeutic landscape. Focusing on patients aged 16 years and older with refractory focal seizures, this trial yielded promising outcomes, showcasing a reduction in standardized seizure frequency with eslicarbazepine acetate compared with placebo. The study also showed that eslicarbazepine acetate was well tolerated, underpinning its suitability as a viable adjunctive therapy option for individuals with refractory focal seizures.3
Post Hoc Analyses
Insights from additional analyses shed more light on the various clinical effects of eslicarbazepine acetate. Particularly interesting is the link found between treatment with eslicarbazepine acetate 1200 mg and improvements in seizure severity, which is a crucial aspect of epilepsy management that is often overlooked. Additionally, the correlation between reduced seizure frequency and improved HRQOL highlights the broader benefits of eslicarbazepine acetate therapy beyond just seizure control, extending to other aspects of patient well-being. However, the lack of significant associations between eslicarbazepine acetate treatment and changes in depressive symptoms suggests the need for further investigation into how ASM therapy interacts with mood regulation.3
Brivaracetam
Approved by the FDA in 2016, brivaracetam is indicated for the management of partial-onset seizures in patients aged 1 month and older. The precise mechanism of action of brivaracetam for anticonvulsant activity is unknown, but it is thought to work via is high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain.11
Efficacy Assessment
The effectiveness of brivaracetam in treating partial-onset seizures, with or without secondary generalization, was confirmed through 3 fixed-dose, randomized, double-blind, placebo-controlled multicenter studies (studies 1, 2, and 3) involving 1550 patients. These patients, whose seizures were inadequately controlled with 1 to 2 concurrent ASMs, had a median baseline seizure frequency of 9 seizures per 28 days, with an average epilepsy duration of approximately 23 years. Notably, 72% to 86% of participants were concurrently using 2 or more ASMs, with or without vagal nerve stimulation.11
Study Design
Each trial comprised an 8-week baseline period, during which patients experienced at least 8 partial-onset seizures, followed by a 12-week treatment period without titration. Study 1 compared brivaracetam doses of 50 mg/day and 100 mg/day with placebo; study 2 compared a dose of 50 mg/day with placebo; and study 3 compared doses of 100 mg/day and 200 mg/day with placebo. Brivaracetam was administered in equally divided doses twice daily, and upon completion of treatment, patients were tapered off over 1, 2, or 4 weeks, depending on their dosage regimen.11
Primary Outcomes
In studies 1 and 2, the primary efficacy outcome was the percentage reduction in 7-day partial-onset seizure frequency compared with placebo, while in study 3, it was the percentage reduction in 28-day partial-onset seizure frequency compared with placebo. Statistical significance across all studies was determined with a criterion of P <.05.11
Levetiracetam Combination
In studies 1 and 2, where daily brivaracetam doses of 50 mg and 100 mg were assessed, about 20% of patients were concurrently using levetiracetam. However, there was no observable additional benefit noted with the addition of brivaracetam to levetiracetam. In study 3, participants concurrently using levetiracetam were excluded, although approximately 54% had prior exposure to it.11
Cenobamate
Cenobamate gained FDA approval in 2020 to treat partial-onset seizures in adults. It can be given as monotherapy or adjunctive therapy12
Clinical Trials
Two randomized, double-blind, placebo-controlled trials (studies 1 and 2) established cenobamate’s efficacy in managing partial-onset seizures among adult patients with insufficient control using 1 to 3 other ASMs. Patients enrolled in these trials had an average epilepsy duration of approximately 24 years, with a median baseline seizure frequency of 8.5 seizures per 28 days. Notably, more than 80% of participants were concurrently using 2 or more ASMs.12
Study Design
Study 1 compared cenobamate doses of 200 mg/day with placebo, while study 2 compared doses of 100 mg/day, 200 mg/day, and 400 mg/day with placebo. Both trials began with an 8-week baseline period to establish seizure frequency before randomization. Subsequently, patients underwent a 6-week treatment period involving titration followed by a maintenance phase (6 weeks in study 1 and 12 weeks in study 2).12
Titration Process
During the titration phase, patients in study 1 initiated cenobamate at a daily dose of 50 mg (which is a higher starting dose than currently recommended) and increased by 50 mg/day every 2 weeks until reaching the target dose of 200 mg/day. In study 2, patients began with 50 mg/day and increased by 50 mg/day every week (which is a faster titration than currently recommended) until reaching 100 mg/day or 200 mg/day. For those assigned to 400 mg/day, the dose increased by 100 mg/day weekly.12
Primary Outcomes
The primary efficacy endpoint in both studies was the percentage change from baseline in seizure frequency per 28 days during the treatment period. Cenobamate demonstrated a significant reduction in seizure frequency compared with placebo.12
Maintenance Phase
In study 2’s maintenance phase, a noteworthy proportion of patients across cenobamate dosage groups reported no partial seizures.12
Table 1 outlines the indications, potential adverse reactions, mechanism of action, and pharmacokinetics of the approved third-generation ASMs.8-12
Indirect Treatment Comparisons via Meta-Analyses
In the landscape of partial-onset epilepsy treatment, the dearth of head-to-head randomized controlled trials (RCTs) comparing all available ASMs underscores the necessity for alternative evidence sources. Indirect treatment comparisons via systematic reviews utilizing network meta-analysis methodology emerge as vital tools, offering clinicians valuable insights into the relative effectiveness of these medications and aiding in informed treatment decisions. Augmenting such analyses with real-world data offers additional perspectives into the clinical characteristics and therapeutic potentials of these ASMs.1,13,14
Data from 16 RCTs involving 6753 participants unveiled that all ASMs demonstrated superior seizure response rates compared with placebo. Regarding seizure freedom, brivaracetam, cenobamate, eslicarbazepine acetate, and perampanel all exhibited greater efficacy than placebo, with no statistically significant differences observed between ASMs.4
In terms of tolerability, all ASMs were associated with higher rates of treatment-emergent adverse events (TEAEs) compared with placebo. Regarding TEAEs leading to discontinuation, all ASMs were less tolerated than placebo, with no significant differences observed between ASMs. Nonetheless, it is crucial to acknowledge the inherent limitations of such analyses, including potential study heterogeneity and sponsorship biases inherent in industry-funded trials.4
References
1. Lattanzi S, Zaccara G, Giovannelli F, et al. Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand. 2019;139(1):33-41. doi:10.1111/ane.13025
2. Latimer D, Le D, Falgoust E, et al. Brivaracetam to treat partial onset seizures in adults. Health Psychol Res. 2023;10(5):56782. doi:10.52965/001c.56782
3. Cramer JA, Colman S, Anastassopoulos KP, Grinnell T, Mehta D, Williams GR. Associations between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life in patients with focal seizures treated with adjunctive eslicarbazepine acetate: post hoc analyses of clinical trial results. Epilepsy Behav. 2020;112:107312. doi:10.1016/j.yebeh.2020.107312
4. Lattanzi S. New evidence in adjunctive treatment of focal-onset seizures in adults: a critical appraisal. Glob Reg Health Technol Assess. 2022;9(Suppl 2):14-19. doi:10.33393/grhta.2022.2420
5. Ostendorf AP, Ahrens SM, Lado FA, et al. United States epilepsy center characteristics: a data analysis from the National Association of Epilepsy Centers. Neurology. 2022;98(5):e449-e458. doi:10.1212/WNL.0000000000013130
6. Andermann E, Rosenfeld W, Penovich P, et al. Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (≥60 years) and younger (18-59 years) adults. Epilepsy Res. 2021;169:106478. doi:10.1016/j.eplepsyres.2020.106478
7. Kwok CS, Johnson EL, Krauss GL. Comparing safety and efficacy of “third-generation” antiepileptic drugs: long-term extension and post-marketing treatment. CNS Drugs. 2017;31(11):959-974. doi:10.1007/s40263-017-0480-6
8. Vimpat®. Prescribing information. UCB, Inc; 2022. Accessed March 31, 2024. https://www.ucb-usa.com/vimpat-prescribing-information.pdf
9. Fycompa®. Prescribing information. Catalyst Pharmaceuticals, Inc; 2023. Accessed March 31, 2024. https://www.fycompa.com/media/media/Files/Fycompa/Fycompa_Prescribing_Information.pdf
10. Aptiom®. Prescribing information. Sumitomo Pharma America, Inc; 2019. Accessed March 31, 2024. https://www.aptiom.com/Aptiom-Prescribing-Information.pdf
11. Briviact®. Prescribing information. UCB, Inc; 2023. Accessed March 31, 2024. https://www.briviacthcp.com/briviact-PI.pdf
12. Xcopri®. Prescribing information. SK Life Science, Inc; 2024. Accessed March 31, 2024. https://www.xcopri.com/pdf_file/xcopri_cenobamate_prescribing_information_medication_guide_combined.pdf
13. Privitera M, Richy FF, Schabert VF. Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures. Epilepsy Behav. 2022;126:108429. doi:10.1016/j.yebeh.2021.108429
14. Thieffry S, Klein P, Baulac M, et al. Understanding the challenge of comparative effectiveness research in focal epilepsy: a review of network meta-analyses and real-world evidence on antiepileptic drugs. Epilepsia. 2020;61(4):595-609. doi:10.1111/epi.16476
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Reviewed April 2024
