Do real-world clinical practice data confirm the results of cenobamate treatment in the clinical program?
A recent study by Spanish authors presents the largest dataset of patients with published cenobamate treatment results under prolonged observation in real-world clinical practice at the time of article publication. Data are derived from an expanded access program for a population with highly drug-resistant focal seizures.
Study methodology and monitored parameters
This retrospective observational study was conducted in 14 hospitals in Spain. It included adult patients with focal seizures treated within the expanded access program to cenobamate. Patients previously treated with cenobamate in clinical studies were excluded from the study. The authors obtained data from medical records.
The primary efficacy parameters included the proportion of patients who are completely seizure-free or who achieved ≥ 90%, ≥ 75%, and ≥ 50% reduction or increase in seizure frequency. Secondary monitored parameters included the proportion of patients who continued to use cenobamate, and the percentage reduction in the average number of seizures per month.
From a safety perspective, the primary parameter was the proportion of patients with adverse events and the proportion of those whose adverse events led to the discontinuation of cenobamate. Controls in the study were conducted at 3, 6, and 12 months and at its conclusion.
Evaluated patient population
A total of 170 patients were included. Their average age was 40 years, and 52% were males. The average number of seizures per month in this population was 27.6 (median 11.3). The age at epilepsy diagnosis was on average 12 years, and the average duration of epilepsy was 27.8 years.
The average number of previous antiepileptic drugs that patients used was 12, and in 99.4% of them, at least 5 antiepileptic drugs had already failed, defined as absolute pharmacoresistance. Previous medications most commonly included levetiracetam (in 94% of patients), lacosamide (87%), valproate (78%), perampanel (78%), and carbamazepine (75%). Upon entering the study, patients concurrently used a median of 3 antiepileptic drugs with cenobamate, most commonly sodium channel blockers, GABAergic modulators, and SV2A modulators.
Findings
The average dose of cenobamate after 3 months of treatment was 176 mg (median 200 mg, range 25–300 mg), after 6 months it was 200 mg (median 200 mg, range 50–300 mg), and after 12 months it was 250 mg (median 250 mg, 74–400 mg). A low dose of cenobamate (< 200 mg) was used by 36.1% of patients after 3 months, 18.3% after 6 months, 17.5% after 12 months, and 21.1% at the last visit. After 3 months, 98.2% of the included patients continued to use cenobamate, 94.5% after 6 months, and 87% after 12 months.
Reduction of concomitant antiepileptic drugs
The number of concomitant antiepileptic drugs during cenobamate treatment significantly decreased (p < 0.001), already after 3 months (to 2.9), further after 6 months (to 2.6), and after 12 months (to 2.2), while at the last visit it was 2.7. The number of concomitant drugs decreased during cenobamate treatment in 44.7% of patients. Between entering the study and the last control, a significant reduction in the average dose of concomitantly administered antiepileptic drugs was also observed, including valproate, brivaracetam, carbamazepine, clobazam, diazepam, eslicarbazepine, phenytoin, phenobarbital, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, and zonisamide.
Efficacy
At the last control, 13.3% of patients were completely seizure-free. At least 90% reduction in seizure occurrence was achieved in 27.9% of participants, at least 75% reduction in 45.5%, and at least 50% reduction in 63% of participants. Conversely, an increase in seizure frequency was recorded in 7.3% of patients at the 3-month follow-up, in 9.4% at the 6-month follow-up, in 5.1% at the 12-month follow-up, and in 11.5% at the last control. Cenobamate treatment significantly reduced the number of seizures per month compared to study entry, by an average of 44.6%, with a median of 66.7% (p < 0.001). The response to cenobamate treatment persisted regardless of the number of previously or concurrently administered antiepileptic drugs.
Safety
The cumulative proportion of patients with adverse events was 68.2% after 3 months, 74.1% after 6 months, and after 12 months, it no longer increased. Adverse events led to the discontinuation of treatment in 3.5% of patients cumulatively after 3 months, in 4.1% after 6 months, and no more patients discontinued treatment due to adverse events after 12 months. The most common reasons for discontinuation were dizziness, skin reactions, convulsions, headache, and drowsiness. No cases of drug reaction with eosinophilia and systemic symptoms (DRESS) or hypersensitivity syndrome occurred.
Conclusion
Cenobamate demonstrated strong antiepileptic efficacy in the expanded access program in a relatively large population of patients with focal seizures in whom at least 5 previous antiepileptic drugs had already failed. Adverse events were mild to moderate and led to discontinuation of therapy in a small number of patients (compared to the size of the entire evaluated cohort). The benefit of cenobamate in terms of safety could also be the reduction in the number or dose of concomitant antiepileptic drugs, thus reducing the overall drug burden on patients. The results of this real-world practice study are comparable to the findings of registration studies conducted with cenobamate.
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Source: Villanueva V., Santos-Carrasco D., Cabezudo-García P. et al. Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: outcomes from an expanded access program. Epilepsia Open 2023 Sep; 8 (3): 918−929, doi: 10.1002/epi4.12757.
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