Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies.

OBJECTIVE: Cognitive and psychiatric adverse events in patients with epilepsy are important determinants of therapeutic outcomes and patient quality of life. We assessed the relationship between adjunctive cenobamate treatment and selected cognitive and psychiatric treatment-emergent adverse events (TEAEs) in adults with uncontrolled focal epilepsy. METHODS: This was a retrospective analysis of pooled populations of patients with focal epilepsy from two phase 2, randomized, double-blind clinical trials; two open-label extensions (OLEs) of those trials; and a long-term, open-label, phase 3 safety study. Occurrence of cognitive and psychiatric TEAEs in patients treated with adjunctive cenobamate or placebo during double-blind treatment were evaluated. Exposure-adjusted incidence rates of the cognitive and psychiatric TEAEs, defined as the number of TEAEs per patient-year of treatment, during up to 7 years of long-term adjunctive cenobamate treatment, were determined in the pooled OLE and phase 3 patient populations. RESULTS: The pooled randomized trials resulted in a population of 442 patients treated with cenobamate (100 mg/day: n = 108; 200 mg/day: n = 223; 400 mg/day: n = 111) and 216 placebo-treated patients. The combined open-label studies resulted in pooled populations of cenobamate-treated patients ranging from n = 1690 during Year 1 to n = 103 during Year 7. Among cenobamate-treated (all doses) and placebo-treated patients during double-blind treatment, cognitive TEAEs were reported by ≤ 1.9 % (range, 0 %-1.9 %) and ≤ 0.5 % (range, 0 %-0.5 %), respectively, and psychiatric TEAEs by ≤ 3.6 % (range, 0 %-3.6 %) and ≤ 3.2 % (range, 0 %-3.2 %), respectively. During up to 7 years of open-label adjunctive cenobamate treatment, exposure-adjusted incidence rates of cognitive and psychiatric TEAEs were < 0.018 and < 0.038 events per patient-year, respectively. Discontinuation of adjunctive cenobamate due to cognitive or psychiatric TEAEs assessed in this study during double-blind or open-label treatment occurred in ≤ 0.3 % and ≤ 1.7 % of patients, respectively. CONCLUSIONS: Cognitive and psychiatric TEAEs were reported by similar numbers of cenobamate- and placebo-treated patients during double-blind adjunctive cenobamate treatment (< 4 % of patients), and exposure-adjusted incidence rates of these TEAEs remained low during open-label cenobamate treatment for up to 7 years. Treatment discontinuations due to these TEAEs were rare. The results of this post-hoc analysis indicate that adjunctive cenobamate treatment exhibits a low incidence of cognitive or psychiatric TEAEs in patients with uncontrolled focal seizures.

Sudden unexpected death in epilepsy during cenobamate clinical development.

OBJECTIVE: We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program. METHODS: We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ≥1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days that a patient received cenobamate during completed studies or up to June 1, 2022, for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years. RESULTS: A total of 2132 patients (n = 2018 focal epilepsy; n = 114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of .88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130 to 620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% confidence interval [CI] .84-2.0), which was not significantly different from the general population. SIGNIFICANCE: These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy.

Sustainability of seizure reduction and seizure control with adjunctive cenobamate: Post hoc analysis of a phase 3, open-label study.

OBJECTIVE: In this post hoc analysis of a subset of patients from a long-term, open-label phase 3 study, we assessed ≥50%, ≥75%, ≥90%, and 100% seizure reduction and sustainability of these responses with cenobamate using a time-to-event analytical approach. METHODS: Of 240 patients with uncontrolled focal seizures who had adequate seizure data available, 214 completed the 12-week titration phase and received ≥1 dose of cenobamate in the maintenance phase (max dose 400 mg/day) and were included in this post hoc analysis. Among patients who met an initial given seizure-reduction level (≥50%, ≥75%, ≥90%, or 100%), sustainability of that response was measured using a time-to-event methodology. An event was defined as the occurrence of a study visit at which the seizure frequency during the interval since the prior study visit exceeded the initially attained reduction level. Study visits during the maintenance phase occurred at 3-month intervals. RESULTS: Of the 214 patients analyzed, 188 (88%), 177 (83%), 160 (75%), and 145 (68%) met ≥50%, ≥75%, ≥90%, and 100% seizure-reduction responses, respectively, for at least one study visit interval during the maintenance phase. The median (95% confidence interval [CI]) time to first visit without a ≥50% seizure reduction was not reached by 30 months of follow-up (53% of patients maintained their initial ≥50% seizure reduction). Median (95% CI) time to first visit without sustaining the initial ≥75%, ≥90%, or 100% seizure reduction was 13.0 (7.5-21.9) months, 7.5 (5.4-11.6) months, and 7.0 (5.3-10.4) months, respectively. Among the 145 patients who had 100% seizure reduction during at least one study visit, 22% remained seizure-free for at least 30 months and 63% had ≤3 study visits with seizures. SIGNIFICANCE: Adjunctive treatment with cenobamate led to sustained seizure reductions during the maintenance phase of the phase 3 safety study.

Long-term individual retention with cenobamate in adults with focal seizures: Pooled data from the clinical development program.

OBJECTIVE: We determined retention on open-label cenobamate therapy in the clinical development program to assess the long-term efficacy and tolerability of adjunctive cenobamate in individuals with uncontrolled focal seizures. METHODS: Data from two randomized, controlled cenobamate studies and one open-label safety and pharmacokinetic study were pooled. Based on the percentage of participants remaining on treatment, retention rates were estimated using Kaplan-Meier survival analyses. We performed two additional analyses to assess factors contributing to retention, stratifying a robust data set (through 2 years) by cenobamate modal dose and frequently used concomitant anti-seizure medications. Cenobamate discontinuations and treatment-emergent adverse events were summarized. RESULTS: Data from 1844 participants were pooled: 149 from a single-dose randomized trial, 355 from a multi-dose randomized trial, and 1340 from an open-label safety and pharmacokinetic study. Most participants from randomized trials continued in open-label extensions, and pooled data represent >95% of participants exposed to cenobamate. Baseline characteristics and disease and treatment histories were similar across studies. Median duration of cenobamate exposure was 34 months, with a median modal dose of 200 mg/day. Kaplan-Meier estimates of cumulative cenobamate retention rates were 80% at 1 year and 72% at 2 years. Once participants reached the maintenance phase, retention rates were consistently high in participants receiving ≥100 mg/day cenobamate, and concomitant anti-seizure medications did not affect long-term retention. By 2 years, 535 (29%) had actually discontinued cenobamate; the most common reasons for discontinuation were adverse events (37.6%), withdrawal of consent (21.1%), and other (16.8%). SIGNIFICANCE: Treatment retention rates provide a proxy measure for long-term efficacy, safety, tolerability, and adherence. The consistently high retention rates we found suggest that cenobamate may be an effective and well-tolerated new treatment option for people with drug-resistant focal seizures.

Onset of efficacy and adverse events during Cenobamate titration period.

OBJECTIVES: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration. MATERIALS & METHODS: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). RESULTS: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. CONCLUSIONS: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.

Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study.

OBJECTIVE: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). METHODS: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis. RESULTS: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. SIGNIFICANCE: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.

Post hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications.

OBJECTIVE: To report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long-term, open-label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention. METHODS: Patients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut-off, on or after September 1, 2019. RESULTS: A total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut-off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut-off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)-related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months. SIGNIFICANCE: Concomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs.

Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study.

OBJECTIVE: To report long-term post hoc efficacy and safety data from 10 US study sites from an open-label Phase 3 study of adjunctive cenobamate (NCT02535091). METHODS: Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019. RESULTS: Of 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1-4 (12.5-25 mg/day cenobamate) and 61.7% during Weeks 5-8 (50-100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12-month duration of 100% seizure reduction. Common treatment-emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%). SIGNIFICANCE: This post hoc analysis of a subset of patients from the long-term open-label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.

Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy-expert opinion.

Clinical trial results have demonstrated that adjunctive cenobamate (CNB) substantially decreases seizure frequency in adults with uncontrolled focal onset seizures with an acceptable and well-identified safety profile. This manuscript summarizes an expert panel's recommendations regarding optimized CNB treatment of epilepsies with focal onset seizures. Cenobamate, when slowly titrated to the target maintenance dose, represents an effective new antiseizure medication (ASM) with a comparatively high rate of seizure freedom relative to existing treatment options. This paper reviews selection of suitable CNB treatment candidates, realistic treatment expectations and goals, appropriate CNB target doses, and methods to mitigate or avoid potential adverse events. Cenobamate can be a promising therapeutic choice for adult people with epilepsy with focal onset seizures who do not reach adequate seizure control despite treatment with conventional ASMs.

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

OBJECTIVE: During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied in an ongoing, open-label, multicenter study. Also examined were long-term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5 mg/d was initiated and increased at 2-week intervals to 25, 50, 100, 150, and 200 mg/d. Additional biweekly 50 mg/d increases to 400 mg/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin/phenobarbital doses could be decreased by 25%-33%. RESULTS: At data cutoff (median treatment duration = 9 months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n = 137) and consent withdrawn for reason other than adverse event (n = 74); 1339 patients received ≥1 treatment dose (median modal dose = 200 mg). The most common treatment-emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each). No cases of DRESS were identified. In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin/phenobarbital levels were generally comparable to baseline. SIGNIFICANCE: No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start-low (12.5 mg/d), go-slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin/phenobarbital dose reductions (25%-33%), when needed during cenobamate titration, maintained stable plasma levels.

A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.

OBJECTIVE: To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. MATERIALS: Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 – 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 × daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated. RESULTS: 60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. CONCLUSIONS: Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.

Reductions in concomitant antiseizure medication drug load during adjunctive cenobamate therapy: Post-hoc analysis of a subset of patients from a phase 3, multicenter, open-label study.

OBJECTIVE: Many patients with epilepsy require polytherapy, which increases their antiseizure medication (ASM) drug load, a measure that considers the doses of all ASMs a patient is taking. Changes in concomitant ASM drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 study. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient's prescribed dose for each ASM by its defined daily dose, per the World Health Organization, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65-70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency < 3 vs ≥ 3 seizures/28 days. RESULTS: Data from 240 patients were available (mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, the mean concomitant ASM drug load was reduced by 29.4 % at Month 12 % and 31.8 % at Month 24. Reductions occurred in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.2 % at Month 24). Each assessed subgroup exceeded a 30 % reduction in concomitant ASM drug load at Month 24. Over 24 months, maintenance of ≥ 50 % response occurred in 89.3 %, 86.4 %, and 90.6 % of patients with low (-0.25 to <0), moderate (-0.59 to -0.25), or high (-3.3 to -0.59) numerical reductions in concomitant ASM drug load from baseline, respectively, compared with 86.0 % in patients with no change in drug load; maintenance of 100 % response occurred in 80.7 %, 84.3 %, and 70.0 % of patients with low, moderate, or high numerical reductions in concomitant ASM drug load, compared with 82.0 % in patients with no change. CONCLUSIONS: Adding cenobamate led to reduced mean concomitant ASM drug loads during 1 and 2 years of treatment. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics and did not impact maintenance of response rates.

Safety and Efficacy of Cenobamate for the Treatment of Focal Seizures in Older Patients: Post Hoc Analysis of a Phase III, Multicenter, Open-Label Study.

BACKGROUND: Cenobamate is an antiseizure medication (ASM) approved in the US and Europe for the treatment of uncontrolled focal seizures. OBJECTIVE: This post hoc analysis of a phase III, open-label safety study assessed the safety and efficacy of adjunctive cenobamate in older adults versus the overall study population. METHODS: Adults aged 18-70 years with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled in the phase III, open-label safety study; adults aged 65-70 years from that study were included in our safety analysis. Discontinuations due to adverse events and treatment-emergent adverse events (TEAEs) were assessed throughout the study in all patients who received one or more doses of cenobamate (safety study population). Efficacy was assessed post hoc in patients who had adequate seizure data available (post hoc efficacy population); we assessed patients aged 65-70 years from that population. Overall, 100% responder rates were assessed in the post hoc efficacy maintenance-phase population in 3-month intervals. Concomitant ASM drug load changes were also measured. For each ASM, drug load was defined as the ratio of actual drug dose/day to the World Health Organization defined daily dose (DDD). RESULTS: Of 1340 patients (mean age 39.7 years) in the safety study population, 42 were ≥ 65 years of age (mean age 67.0 years, 52.4% female). Median duration of exposure was 36.1 and 36.9 months for overall patients and older patients, respectively, and mean epilepsy duration was 22.9 and 38.5 years, respectively. At 1, 2, and 3 years, 80%, 72%, and 68% of patients overall, and 76%, 71%, and 69% of older patients, respectively, remained on cenobamate. Common TEAEs (≥ 20%) were somnolence and dizziness in overall patients, and somnolence, dizziness, fall, fatigue, balance disorder, and upper respiratory tract infection in older patients. Falls in older patients occurred after a mean 452.1 days of adjunctive cenobamate treatment (mean dose 262.5 mg/day; mean concomitant ASM drug load 2.46). Of 240 patients in the post hoc efficacy population, 18 were ≥ 65 years of age. Mean seizure frequency at baseline was 18.1 seizures/28 days for the efficacy population and 3.1 seizures/28 days for older patients. Rates of 100% seizure reduction within 3-month intervals during the maintenance phase increased over time for the overall population (n = 214) and older adults (n = 15), reaching 51.9% and 78.6%, respectively, by 24 months. Mean percentage change in concomitant ASM drug load, not including cenobamate, was reduced in the overall efficacy population (31.8%) and older patients (36.3%) after 24 months of treatment. CONCLUSIONS: Results from this post hoc analysis showed notable rates of efficacy in older patients taking adjunctive cenobamate. Rates of several individual TEAEs occurred more frequently in older patients. Further reductions in concomitant ASMs may be needed in older patients when starting cenobamate to avoid adverse effects such as somnolence, dizziness, and falls. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT02535091.

Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy.

PURPOSE: To assess the effects of ICA-105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients with epilepsy. METHODS: Male and female patients aged 18-60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single-blind, single-dose, multiple-cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA-105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points. KEY FINDINGS: Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules. SIGNIFICANCE: ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.

Pharmacokinetics of cenobamate as monotherapy compared with adjunctive therapy.

OBJECTIVE: Cenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy. METHODS: A population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8-1.25. RESULTS: In the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816-0.925) for adjunctive carbamazepine and 1.24 (1.147-1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8-1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam. CONCLUSIONS: Based on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients.

Efficacy of cenobamate by focal seizure subtypes: Post-hoc analysis of a phase 3, multicenter, open-label study.

PURPOSE: To report post-hoc efficacy data by focal seizure subtypes from 10 US study sites from a large, global, open-label, phase 3 study of adjunctive cenobamate. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) at 2-week intervals (target dose 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments every other week were allowed. RESULTS: 240 patients were evaluated; 27 (11.3%), 224 (93.3%), and 56 (23.3%) patients had focal aware motor (FAM), focal impaired awareness (FIA), and focal to bilateral tonic-clonic (FBTC) seizures, respectively (patients may have had ≥ 1 seizure subtype). Median baseline seizure frequencies/28 days were 10.5, 2.3, and 0.9 for FAM, FIA, and FBTC seizure subtypes. Reductions in median percent seizure frequency/28 days from baseline were observed during Months 1-3 (55.0%, 52.4%, and 94.1% for FAM, FIA, and FBTC). Greater reductions were observed during Months 4-5 (88.2%, 81.0%, and 100%) and during Months 25-27 (98.1%, 100%, and 100%). The percentage of patients achieving 100% seizure reduction in the FAM, FIA, and FBTC seizure subtypes was 22.2% (6/27), 21.5% (48/223), and 50% (28/56) during Months 1-3 and increased to 47.8% (11/23), 54.3% (88/162), and 90.5% (38/42) during Months 25-27, respectively. The most common treatment-emergent adverse events (≥ 20%) were fatigue, dizziness, and somnolence. No cases of DRESS were reported. CONCLUSIONS: Seizure reductions occurred in all focal seizure subtypes with cenobamate over time through Months 25-27, with the earliest onset in the FBTC group. Results from this subset analysis of the phase 3 study support the long-term efficacy of cenobamate across focal seizure types.

Post hoc analysis of a phase 3 study for treatment of uncontrolled focal seizures: Adjunctive cenobamate dose and seizure reduction by baseline seizure frequency.

This post hoc analysis (n = 240) of a subset of study sites (10 eligible US sites) from an open-label phase 3 study assessed whether baseline seizure frequency (<3 seizures/28 days vs ≥3 seizures/28 days) impacted mean cenobamate dose required to achieve 100% seizure reduction, duration of this response, and responder rates. Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals. Further increases to 400 mg/day by 50-mg/day biweekly increments were allowed during the maintenance phase. Eligible patients were required to have consistent raw seizure data and good-quality data for ≥ 85% of the time spent in the study. Data were assessed until last visit and at data cut-off, on or after September 1, 2019. Among all 240 patients, 127 (52.9%) had < 3 seizures/28 days, and 113 (47.1%) had ≥ 3 seizures/28 days at baseline. Among patients continuing cenobamate at data cut-off (n = 177), 51% (90/177) and 49% (87/177) had < 3 and ≥ 3 seizures/28 days at baseline, respectively. Retention rate at data cut-off was 73.8% (177/240 patients), and these patients had a median time on study of 32.9 months (range: 22.1-43.0 months). 33.9% of patients continuing cenobamate (60/177) achieved 100% seizure reduction for ≥ 12 months at data cut-off, with 44.4% and 23.0% in patients with < 3 and ≥ 3 seizures/28 days at baseline, respectively. Regardless of baseline seizure frequency, responder rates at ≥ 50%, ≥ 75%, and ≥ 90% during the maintenance phase were similar (∼81%, ∼62%, and ∼43%, respectively). Mean±SD cenobamate dose for patients continuing cenobamate was 254.0 ± 82.1 mg/day, with means of 237.9 ± 78.1 mg/day and 270.7 ± 83.1 mg/day in patients with < 3 and ≥ 3 seizures/28 days at baseline, respectively. Among patients who had 100% seizure reduction for ≥ 12 months at data cut-off (n = 60), the mean cenobamate dose was 226.4 ± 75.4 mg/day and 255.1 ± 93.7 mg/day in patients with < 3 and ≥ 3 seizures/28 days at baseline, respectively. The current data suggest that cenobamate was effective regardless of baseline seizure frequency, with both groups having a high number of patients reaching 100% seizure reduction. A higher percentage of patients with less vs more frequent seizures at baseline reached zero seizures, suggesting these patients may reach 100% seizure reduction at lower cenobamate doses than those with more frequent seizures. Cenobamate dose varied slightly (∼30 mg/day) across patients who were stratified by baseline seizure frequency, but future analyses are necessary to determine whether patients with more frequent seizures require higher doses of cenobamate to achieve zero seizures.

Efficacy of cenobamate for uncontrolled focal seizures in patients with previous epilepsy-related surgery: Post hoc analysis of a phase 3, multicenter, open-label study.

OBJECTIVE: This post hoc analysis of 10 US study sites from a long-term open-label phase 3 study of adjunctive cenobamate evaluated the efficacy of cenobamate in patients with prior epilepsy-related surgery. METHODS: Patients with uncontrolled focal seizures despite taking stable doses of 1-3 concomitant antiseizure medications (ASMs) received increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) at 2-week intervals over 12 weeks (target dose, 200 mg/day). Further increases up to 400 mg/day using biweekly 50-mg/day increments were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019. RESULTS: Of the 240 eligible patients, 85 had prior epilepsy-related surgery and 155 were nonsurgical patients. Baseline focal seizure frequency per 28 days was numerically higher among prior surgery (mean=25.9/median=4.1/range=0.3-562.3) versus nonsurgical (mean=13.8/median=2.4/range=0.2-534.2) patients. Among all patients, 100 % seizure reduction ≥ 12 months at any consecutive month interval occurred in 30.6 % (26/85) prior surgery and 39.4 % (61/155; p > 0.05) nonsurgical patients (cenobamate treatment median duration=32.9 months). Among the 177 patients still receiving cenobamate at the data cutoff, 29.2 % (19/65) of prior surgery and 36.6 % (41/112; p > 0.05) of nonsurgical patients had 100 % seizure reduction ≥ 12 months at the data cutoff. Cenobamate was well tolerated. CONCLUSIONS: This post hoc analysis supports the efficacy of cenobamate in patients with refractory focal seizures despite prior surgery. These findings suggest cenobamate may be considered early in the treatment regimen, including, in some patients, before surgery is considered.

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

INTRODUCTION: Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. METHODS: A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. RESULTS: We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. CONCLUSION: The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Some people with epilepsy need to take more than one seizure medicine as part of their treatment. Taking more than one seizure medicine, however, can increase the risk of unwanted side effects. One approach to preventing side effects when adding a new seizure medicine is to lower the amount (dose) of existing seizure medicines. Cenobamate is a newer seizure medicine available in the USA for adults with focal seizures (also referred to as partial-onset seizures). Cenobamate, like many seizure medicines, must be titrated over time to a target dose. A group of epilepsy specialists met and developed recommendations for when and how to change the doses of existing seizure medicines when adding cenobamate. The goal of these recommendations is to prevent or reduce side effects like sleepiness or dizziness. The authors recommend that the dose of specific seizure medicines, including clobazam, lacosamide, phenytoin, and phenobarbital, be lowered as cenobamate is started or as cenobamate's dose is being increased (but before side effects occur). Regular doses of other seizure medicines can be lowered if a side effect occurs because reducing the dose of the other seizure medications can often stop the side effect. These recommendations may help patients successfully reach their optimal dose of cenobamate with fewer side effects, potentially improving their seizure control. Video Abstract: Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.