Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open‐label safety study

2.1. Study design and patients

This is an ongoing, multicenter, open‐label safety study being conducted at 139 centers in 17 countries (Argentina, Australia, Bulgaria, Chile, Czech Republic, Germany, Hungary, Mexico, Poland, Republic of Korea, Serbia, Spain, Sweden, Russia, Thailand, Ukraine, and USA). Enrollment began on November 3, 2015 and ended on February 8, 2018. This analysis used a data cutoff of April 23, 2018. The study design includes a screening period of up to 21 days and a 12‐month open‐label treatment period, consisting of a 12‐week titration phase followed by a maintenance phase (Figure 1). After 12 months, patients benefiting from treatment may continue on cenobamate per the discretion of the investigator.

Eligible patients were adults 18‐70 years old with a diagnosis of focal (partial onset) epilepsy according to the International League Against Epilepsy's Classification of Epileptic Seizures. ¹⁹ , ²⁰ Patients’ focal seizures had to be uncontrolled despite treatment with at least one ASM within the past 2 years. Patients were required to have an electroencephalographic reading consistent with the diagnosis of focal epilepsy and a computed tomography or magnetic resonance imaging scan performed within the previous 10 years to rule out a progressive cause of epilepsy. Patients must have been currently taking stable doses of one to three concomitant ASMs for at least 3 weeks prior to the start of cenobamate. Vagus nerve stimulation was permitted and did not count as an ASM, but the device must have been implanted at least 5 months prior to screening and the parameters must have been stable for at least 4 weeks prior to baseline. Patients with a history of any drug‐induced rash or hypersensitivity reaction or who had first‐degree relatives with a serious cutaneous, drug‐induced adverse reaction were excluded. Patients taking vigabatrin or ezogabine within the past year or felbamate for less than 18 consecutive months were also excluded. Additional exclusion criteria included a history of status epilepticus within 3 months of screening, history of alcohol or drug abuse within the past 2 years, clinically significant psychiatric illness or history of suicidal ideation within the past 6 months, suicidal behavior in the past 2 years, or more than one lifetime suicide attempt.

During the titration phase, patients initiated cenobamate treatment at 12.5 mg/d for 2 weeks, followed by 25 mg/d for 2 weeks and 50 mg/d for 2 weeks. The dose was then increased by 50‐mg/d increments at 2‐week intervals to the target dose 200 mg/d (Figure 1). Except for patients taking concomitant phenytoin or phenobarbital, patients’ concomitant ASMs could be removed, added, or adjusted, and cenobamate doses could be adjusted during the titration phase, as clinically needed. Monotherapy with cenobamate was not allowed at any point in the study. A minimum cenobamate dose of 50 mg once daily was necessary to continue in the study. For patients receiving concomitant phenytoin or phenobarbital, no dose reduction or interruption of cenobamate titration was allowed and other concomitant ASMs could not be added, removed, or adjusted during titration. If patients were experiencing dose‐related toxicity, a plasma level could be obtained and their dosage of phenytoin or phenobarbital could be reduced by 25%‐33% per clinical discretion. Further reductions in phenytoin or phenobarbital dose up to approximately two‐thirds the total baseline dose were allowed. During the maintenance phase, further cenobamate dose increases to 400 mg/d using biweekly increments of 50 mg/d were allowed for all patients. Downward dose adjustments for tolerability could also occur during the maintenance phase for all patients once the target dose of 200 mg was reached. Concomitant medications, including phenytoin and phenobarbital, could be adjusted during the maintenance phase; concomitant ASMs could also be added (except phenytoin or phenobarbital) or removed.

The study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonisation guidelines ²¹ and all applicable country‐specific regulations. The study protocol was approved by an independent ethics committee or institutional review board at each site according to local regulations. Written informed consent was obtained from each patient prior to participation in the study.

2.2. Safety/tolerability outcomes

Safety assessments included reported adverse events (AEs), coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0, in addition to clinical laboratory tests, 12‐lead electrocardiographic (ECG) measurements, vital signs, physical and neurologic examinations, and Columbia Suicide Severity Rating Scale scores. Monthly reviews of all AEs in the clinical database via Standardized MedDRA Queries for hypersensitivity and DRESS were performed. In addition, physical examinations to identify signs of hypersensitivity were performed every 2 weeks during the first 4 months of treatment, at year 1, and yearly thereafter.

2.3. Pharmacokinetic outcomes

To assess the effect of cenobamate on the pharmacokinetics of phenytoin and phenobarbital, plasma concentrations of phenytoin and phenobarbital were obtained before the start of cenobamate and compared with those obtained during the 12‐week titration phase. Blood samples were collected at baseline (day 1), before the first dose of cenobamate, to assess trough levels of phenytoin and phenobarbital. During the titration phase, scheduled phenytoin and phenobarbital plasma levels were obtained at the end of weeks 4, 6, 8, 10, and 12; two blood samples were collected, one in the morning and one 30 minutes to 2 hours after taking a dose of phenytoin or phenobarbital.

2.4. Data analysis

All patients who enrolled in the study and received at least one dose of cenobamate were included in the safety analysis. To assess the rate of DRESS, at least 1000 patients were planned to be enrolled and treated for at least 6 months. An incidence rate of 0 for DRESS during the treatment period would establish 0.003 (3/1000) as the upper limit of the 95% confidence interval for the rate of DRESS. All patients included in the safety analysis who had at least one blood sample were included in the pharmacokinetic analysis. Safety and pharmacokinetic data were summarized with descriptive statistics.

3.1. Patients

At the data cutoff, 1347 patients were enrolled, and 1339 had received at least one dose of cenobamate and were included in the safety analysis population (Figure 2). The most common reason for discontinuation was AEs (10.2% [137/1347]), followed by withdrawal of consent for reasons other than AEs (5.5% [74/1347]). Because this study was not designed to evaluate efficacy and did not collect seizure counts, “lack of efficacy” was not provided as a choice for discontinuation. Investigators could include information regarding lack of efficacy under comments associated with “withdrew consent” or “other” reasons for discontinuation. Based on investigator comments, 48 of the 1339 patients (3.6%) who took at least one dose of cenobamate discontinued because of lack of efficacy (24 of 74 withdrew consent; 24 of 35 other).

Baseline demographics and patient characteristics are shown in Table 1. Mean epilepsy duration was 22.9 years. Most patients (82% [1098/1339]) were receiving two or three ASMs at baseline (defined as ASMs started prior to and ongoing at the time of first dose of study medication). The most frequently used concomitant ASMs were levetiracetam (39.1%), lamotrigine (33.3%), all forms of valproic acid (30.8%), carbamazepine (27.6%), and lacosamide (24.2%). In addition, 114 patients were receiving concomitant phenytoin and 51 patients were receiving phenobarbital, of whom 83 and 37, respectively, had blood samples and were included in the pharmacokinetic analyses.

3.2. Exposure and retention rate

Median (minimum, maximum) exposure to cenobamate was 9 (0.03, 20.5) months. The majority of patients (82.9% [1110/1339]) were exposed to cenobamate for ≥6 months; 22.9% (306/1339) were exposed for ≥12 months. The median modal daily dose was 200 mg. The last available dose received at or before the cutoff for most patients was 200 mg (35.1%, 470/1339). In 58.2% of patients (779/1339), the last available dose received was between 200 and 300 mg; in 11.2% (150/1339), the last available dose received was >300 mg. The 1‐year retention rate was 79% based on Kaplan‐Meier estimates (Figure 3).

3.3. Safety

At least one treatment‐emergent AE (TEAE) was reported in 1128/1339 patients (84.2%; Table 2). The most frequent TEAEs were somnolence (376 [28.1%]), dizziness (316 [23.6%]), and fatigue (222 [16.6%]). The majority of TEAEs reported during the study were mild or moderate in severity (77.8% [1042/1339]). Skin and subcutaneous tissue disorders were reported in 189 patients (14.1%). Grouped and individual preferred terms reported by at least 1% of patients included rash (grouped terms: rash, erythematous rash, papular rash, etc) in 44 patients (3.3%), pruritis (grouped terms: pruritus and pruritus generalized) in 34 patients (2.5%), dermatitis (grouped terms: dermatitis, dermatitis contact, dermatitis allergic, etc) in 27 patients (2.0%), and alopecia in 15 patients (1.1%).

No cases of DRESS were identified. The rate of DRESS was therefore zero, with an upper bound of the 95% confidence interval of 0.003 among patients exposed to cenobamate for >6 months, and 0.002 among all patients exposed.

At least one serious TEAE was reported in 108 (8.1%) patients (Table S1). Seizure (n = 14, 1.0%) and epilepsy (n = 5, 0.4%) were the most frequently reported serious TEAEs. Additional serious TEAEs reported in more than two patients included fall, pneumonia, and dizziness (n = 4 each, 0.3%) and vomiting, appendicitis, mental status change, suicide attempt, and papular rash (n = 3 each, 0.2%). In addition to papular rash, other serious TEAEs related to skin and subcutaneous tissue disorders occurred in six patients, including allergic dermatitis, erythema, rash, maculopapular rash, facial swelling, and urticaria (n = 1 each). There was no history of rash noted for these patients. One patient had a history of eczema. In each case, the patient recovered following discontinuation of cenobamate.

Psychiatric AEs occurring in ≥1% of patients included anxiety (2.3%, n = 31), irritability (2.2%, n = 29), insomnia (2%, n = 27), depression (1.9%, n = 26), and confusional state (1.2%, n = 16). Three patients had a serious TEAE of suicide attempt (none completed). The first patient was a 52‐year‐old man with a history of ongoing depression. He was not receiving any concomitant medications for depression; concomitant ASMs included phenytoin, lamotrigine, and perampanel. The second patient was a 32‐year‐old woman with a history of ongoing depression and mood disorder (concomitant desvenlafaxine, quetiapine as needed, and diazepam as needed) and prior episodes of self‐harm. Concomitant ASMs included clobazam, oxcarbazepine, and levetiracetam. Both events were considered by the investigator to be unrelated to the study drug. The third patient was a 38‐year‐old man with no history of depression. The patient had a history of vagus nerve stimulator implantation and gastric bypass. Concomitant ASMs included topiramate and clobazam. The investigator considered the event's relationship to the study drug to be remote. One additional patient, a 46‐year‐old woman with a history of ongoing depression, had a serious AE of suicidal ideation. She was receiving concomitant ASM treatment with lacosamide. She did not receive any concomitant medications for depression. The event was considered unrelated to the study drug.

At data cutoff, four deaths had been reported (sudden death with no autopsy, traumatic intracerebral hemorrhage after a fall, fatal injuries after being struck by a car, and respiratory failure in a patient with Angelman syndrome). Three were considered unrelated to the study drug. The relationship between sudden death and the study drug was considered remote by the investigator. TEAEs resulting in discontinuation of cenobamate were reported in 11% (n = 147) of patients (Table S2). The most common TEAEs that led to study discontinuation were nervous system disorders (45 patients [3.4%]), with dizziness (n = 14), seizure (n = 9), and somnolence (n = 9) the most frequently reported, followed by skin and subcutaneous tissue disorders (44 patients [3.3%]), with rash (n = 9), rash erythematous, papular rash, pruritus, and urticaria (all n = 3) the most frequently reported. Most TEAEs leading to discontinuation, including rashes, occurred during the titration period. All were rated as mild or moderate in severity. One patient discontinued due to a TEAE of hypersensitivity. The patient, a 53‐year‐old woman, experienced mild facial erythema with swelling and pruritus following the second dose of cenobamate 12.5 mg. She was afebrile, and symptoms resolved upon discontinuation of the study drug. Concomitant medications included fexofenadine once daily for allergies and concomitant ASM treatment with eslicarbazepine 1800 mg daily.

There were no remarkable changes during the study in hematology, clinical chemistry, laboratory values, ECG readings, vital sign measurements, or physical or neurological examinations.

3.4. Pharmacokinetics

The mean trough plasma level of phenytoin was 11.80 µg/mL at baseline. Morning levels rose slightly at week 4 (12.70 µg/mL) and week 6 (14.92 µg/mL) and remained stable thereafter through week 12 (Figure 4A). The mean trough plasma phenobarbital level was 24.11 µg/mL at baseline and remained stable during titration (Figure 4B). Thirty‐six patients (43.4%) in the phenytoin group and 11 patients (29.7%) in the phenobarbital group had their doses decreased during titration. The mean total daily doses of phenytoin decreased from 330 mg at baseline to 253 mg at the end of the titration phase and beginning of the maintenance phase (week 14); the mean total daily dose of phenobarbital decreased from 138 to 118 mg (Figure S1).