Uncontrolled Focal Seizures Research Articles

Effectiveness and Safety of Adjunctive Cenobamate in People with Focal-Onset Epilepsy: Evidence from the First Interim Analysis of the BLESS Study.

Despite new anti-seizure medications (ASMs) being introduced into clinical practice, about one-third of people with epilepsy do not reach seizure control. Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. In randomized controlled trials, adjunctive cenobamate reduced the frequency of focal seizures in people with uncontrolled epilepsy. Studies performed in real-world settings are useful to complement this evidence and better characterize the drug profile. The Italian BLESS ("Cenobamate in Adults With Focal-Onset Seizures") study is an observational cohort study aimed to evaluate the effectiveness, tolerability, and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy in the context of real-world clinical practice. The study is ongoing and conducted at 50 centers in Italy. This first interim analysis includes participants enrolled until June 2023 and with 12-week outcome data available. Forty participants with a median age of 36.5 (interquartile range [IQR] 26.0-47.5) years were included. The median monthly seizure frequency at baseline was 6.0 (IQR 2.5-17.3) seizures and 31 (77.5%) participants had failed four or more ASMs before cenobamate. At 12 weeks from starting cenobamate, the median reduction in monthly seizure frequency was 52.8% (IQR 27.1-80.3%); 22 (55.0%) participants had a ≥ 50% reduction in baseline seizure frequency and six (15.0%) reached seizure freedom. The median number of concomitant ASMs decreased from 3 (IQR 2-3) at baseline to 2 (IQR 2-3) at 12 weeks and the proportion of patients treated with > 2 concomitant ASMs decreased from 52.5% to 40.0%. Seven (17.5%) patients reported a total of 12 adverse events, 11 of which were considered adverse drug reactions to cenobamate. In adults with uncontrolled focal seizures, the treatment with adjunctive cenobamate was well tolerated and was associated with improved seizure control and a reduction of the burden of concomitant ASMs. NCT05859854 (ClinicalTrials.gov Identifier).

Efficacy and safety of adjunctive cenobamate based on patient etiology: Post-hoc analysis of YKP3089C017 randomized clinical trial

IntroductionAdjunctive cenobamate was effective and safe for the treatment of uncontrolled focal onset seizures in a randomized, double-blind, placebo-controlled, phase 2 study (YKP3089C017; NCT01866111). This post-hoc analysis assessed the efficacy of adjunctive cenobamate in the treatment of patients with different epileptic etiologies during the study. MethodsAdult patients with uncontrolled focal seizures who previously received 1 to 3 antiseizure medications (ASMs) were randomly assigned in a ratio of 1:1:1:1 to receive placebo or cenobamate 100, 200 or 400 mg/day. Patients were further stratified based on their etiologic causes as genetic/presumed genetic, unknown cause, structural cause, and not reported (NR) groups. The frequency per 28 days for an 18-week double-blind treatment period, responder rates (≥50 %, ≥75 %, ≥90 %, and 100 %) during the maintenance phase (12 weeks), and safety were assessed. ResultsA total of 394 patients were categorized into the genetic/presumed genetic (n = 9; 2.28 %), unknown cause (n = 199; 50.51 %), structural cause (n = 177; 44.92 %), and NR (n = 13; 3.30 %) groups, with 4 patients were classified into either of the two etiological causes each. The baseline characteristics were comparable. The percentage of reduction in seizure frequency per 28 days was significantly higher in the cenobamate-treated structural (p = 0.01) and unknown cause (p = 0.0003) groups compared with the placebo group. Responder rates of ≥50 %, ≥75 %, ≥90 %, and 100 % were also higher with cenobamate therapy. Notably, no serious treatment-emergent adverse events (TEAEs) were observed in the genetic/presumed genetic group treated with cenobamate. The most common TEAEs (≥10 %) occurring in patients treated with cenobamate were nervous system disorders by system organ class, and somnolence was the most commonly reported TEAE. ConclusionCenobamate reduces seizures in adult patients previously treated with ASMs, with high responder rates and acceptable safety, regardless of underlying causes.

Dose Reduction Timing for Concomitant Antiseizure Medications: Post-hoc Analysis of a Phase 3, Open-label Study of Cenobamate for Treatment of Uncontrolled Focal Seizures (P8-1.003)

Dose Reduction Timing for Concomitant Antiseizure Medications: Post-hoc Analysis of a Phase 3, Open-label Study of Cenobamate for Treatment of Uncontrolled Focal Seizures (P8-1.003)

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

ObjectiveCognitive 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. MethodsThis 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. ResultsThe 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. ConclusionsCognitive 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.

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

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. 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. 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. Adjunctive treatment with cenobamate led to sustained seizure reductions during the maintenance phase of the phase 3 safety study.

Predictors of Achievement of Response With Cenobamate: Post-hoc Subset Analysis From a Phase 3, Open-Label Safety Study (S44.006)

Predictors of Achievement of Response With Cenobamate: Post-hoc Subset Analysis From a Phase 3, Open-Label Safety Study (S44.006)

Predictors of Sustainability of Response With Cenobamate: Post-hoc Subset Analysis of a Phase 3, Open-Label, Study (P14-1.005)

Predictors of Sustainability of Response With Cenobamate: Post-hoc Subset Analysis of a Phase 3, Open-Label, Study (P14-1.005)

Concomitant Drug Load Reduction During Adjunctive Cenobamate Therapy: Post-hoc Analysis of a Phase 3, Open-Label Study (P11-1.006)

<h3>Objective:</h3> Changes in concomitant antiseizure medication (ASM) drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 safety study. <h3>Background:</h3> Many patients with epilepsy require adjunctive therapy, which can increase their ASM drug load. <h3>Design/Methods:</h3> Patients 18–70 years old with uncontrolled focal seizures taking stable doses of 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, a World Health Organization standardized daily maintenance dose, 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 &lt;3 vs ≥3 seizures/28 days. <h3>Results:</h3> Data from 240 patients were available (median exposure duration 30.2 months, mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, mean percent reductions in concomitant ASM drug load occurred at Month 12 (29.44%) and 24 (31.82%), and in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.24% at Month 24). All assessed patient subgroups exceeded 30% reduction in concomitant ASM drug load at Month 24. Patients with low (−0.25 to &lt;0), moderate (−0.59 to −0.25), or high (−3.3 to −0.59) change in concomitant ASM drug load vs no change, respectively, had similar maintenance of ≥50% (89.29%, 86.42%, 90.57% vs 85.99%) and 100% response rates (80.65%, 84.29%, 70.00% vs 82.00%). <h3>Conclusions:</h3> Adding cenobamate led to reduced mean concomitant ASM drug load during Year 1 and Year 2. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics. Reductions in ASM drug load did not impact maintenance of response rates. See also abstract by O’Dwyer et al. <b>Disclosure:</b> Dr. Aboumatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Aboumatar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Aboumatar has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. Louis Ferrari has received personal compensation for serving as an employee of SK Life science. Mr. Stern has received personal compensation for serving as an employee of SK Life Science. Mr. Wade has nothing to disclose. Dr. Weingarten has received personal compensation for serving as an employee of SK Life Science. The institution of Dr. Connor has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for SK Life Sciences. The institution of Dr. Connor has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for SK Life Sciences. The institution of Dr. Rosenfeld has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for SK Life Science. Dr. Rosenfeld has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for SK Life Science. The institution of Dr. Rosenfeld has received research support from SK Life Science. The institution of Dr. Rosenfeld has received research support from UCB Pharma.

Safety and Efficacy of Cenobamate for the Treatment of Focal Seizures in Older Patients (P4-1.002)

<h3>Objective:</h3> Safety (treatment-emergent adverse events [TEAEs] and efficacy with cenobamate were analyzed post-hoc for older adults aged 65–70 in a phase 3, open-label safety study. <h3>Background:</h3> Cenobamate is an antiseizure medication (ASM) approved in the US and EU for the treatment of uncontrolled focal seizures. <h3>Design/Methods:</h3> Adults 18–70 years old with uncontrolled focal seizures taking stable doses of 1–3 ASMs were enrolled. Concomitant ASM drug load changes from baseline to 1 year were measured (drug load defined as ratio of actual drug dose per day to the defined daily dose by the World Health Organization). <h3>Results:</h3> Of 1340 patients (mean age 39.7 years) who received ≥1 dose of cenobamate, 42 were aged 65–70 years (mean age 67.0 years). Median duration of exposure was 36.1 and 36.9 months for overall patients and older patients. 80%, 72%, and 68% of patients overall, and 76%, 71%, and 69% of older patients remaining on cenobamate at 1, 2, and 3 years, respectively. Discontinuation rates due to TEAEs were 13.6% (183/1340) in patients overall and 26.2% (11/42) in older patients. TEAEs reported in ≥20% of older patients were dizziness, somnolence, fall, fatigue, balance disorder, and upper respiratory tract infection. Efficacy (100% seizure reduction) was assessed in 240 patients with adequate seizure data available (n=18, ≥65 years). Rates of 100% seizure reduction within a 3-month interval during the maintenance phase increased over time for the overall population and older adults, reaching 52% and 77%, respectively by 24 months. Mean percent change in concomitant ASM drug load, not including cenobamate, was reduced in the overall population (29.44%) and older patients (31.18%). <h3>Conclusions:</h3> Results from this post-hoc analysis showed notable rates of efficacy in older patients when treated with adjunctive cenobamate. Further reductions in concomitant ASMs may be needed in older patients when starting cenobamate. See also abstract by Aboumatar et al. <b>Disclosure:</b> Dr. O’Dwyer has nothing to disclose. Mr. Stern has received personal compensation for serving as an employee of SK Life Science. Mr. Wade has nothing to disclose. Dr. Guggilam has received personal compensation for serving as an employee of SK Life Science, Inc. The institution of Dr. Rosenfeld has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for SK Life Science. Dr. Rosenfeld has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for SK Life Science. The institution of Dr. Rosenfeld has received research support from SK Life Science. The institution of Dr. Rosenfeld has received research support from UCB Pharma.

Long-term Cenobamate for Uncontrolled Focal Seizures in Patients Living in a Group Home or With Developmental Disability (P4-1.006)

Long-term Cenobamate for Uncontrolled Focal Seizures in Patients Living in a Group Home or With Developmental Disability (P4-1.006)

Concomitant Antiseizure Medication Dose Reduction and Discontinuation After Starting Cenobamate: a Retrospective Review (P4-1.004)

<h3>Objective:</h3> This investigator-initiated study examined discontinuations and dose reductions of concomitant ASMs following cenobamate initiation in patients with epilepsy treated at MetroHealth (Cleveland, OH). <h3>Background:</h3> The treatment goal for people with epilepsy who receive polytherapy is seizure control with the lowest possible drug load (lowest numbers and doses). Cenobamate is an antiseizure medication (ASM) approved in the US and EU for uncontrolled focal seizures. <h3>Design/Methods:</h3> Adults with focal epilepsy who started adjunctive cenobamate between 9/2020 and 5/2022 were analyzed by retrospective chart review (target enrollment n=75). Data on concomitant ASMs and doses were collected. <h3>Results:</h3> Eighty-one patients received cenobamate as of 5/2022. Two discontinued because of side effects. Seventy-nine continued on cenobamate as of the data cutoff (mean [range] age, 44.1 [19–74] years; 48% women). Seventy-five started cenobamate because of uncontrolled seizures. Four other patients were seizure-free but started cenobamate to taper off their current ASMs, which were causing intolerable side effects. Among those continuing cenobamate, 34.2% (27/79) discontinued concomitant ASMs, including clobazam (n=15), levetiracetam (n=5), phenytoin (n=3), lacosamide (n=2), lamotrigine (n=1), and oxcarbazepine (n=1). Nine patients achieved cenobamate monotherapy, and 15.2% (12/79) of patients were in the process of tapering off concomitant ASMs, including phenytoin (n=8) and clobazam (n=4). Divalproex sodium dose reductions occurred in 4 patients. At data cutoff, 34.2% (27/79) of patients were seizure-free ≥3 months (range, 3–10 months), including all 4 patients who were seizure-free prior to starting cenobamate and 23 patients with uncontrolled seizures prior to cenobamate. No patients had worsening seizure frequency on cenobamate. <h3>Conclusions:</h3> Initiating cenobamate led to a reduction in concomitant ASM drug load (discontinuation or dose reduction) in 53.1% (43/81) of patients, and some were able to transition to monotherapy. Seizure control was maintained or improved during treatment. These data suggest that cenobamate therapy may allow a reduction or elimination of polytherapy in some patients. <b>Disclosure:</b> Dr. Becker has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurelis, Inc. Dr. Becker has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sk life Science. Dr. Becker has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Supernus Pharmaceuticals. Dr. Becker has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurelis, Inc. Dr. Becker has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sk Life Science. Dr. Becker has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz pharmaceuticals. Dr. Becker has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for UBC. Dr. Becker has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for LivaNova. Dr. Becker has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neuropace. Dr. Becker has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Supernus Pharmaceuticals. Mrs. Demko has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Mrs. Demko has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SK Life Sciences. Mrs. Demko has received research support from SK Life Sciences.

Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms

Antiseizure medication is the mainstay of treatment for seizures, and adjunctive therapy is widely used to achieve adequate seizure control in patients with epilepsy who fail to respond to the first monotherapy. The newly developed antiepileptic drug cenobamate (YKP3089) as an adjunctive therapy improved seizure control in patients with uncontrolled focal seizures. Cenobamate is thought to reduce neuronal excitability through action on multiple targets, including GABA A receptors (GABAARs) and voltage-gated sodium channels. However, its effects on brain function and synaptic plasticity are unclear. Here, we explored the behavioral, synaptic, and cellular actions of cenobamate. Cenobamate influenced novel object recognition, object location memory, and Morris water maze performance in mice. Cenobamate enhanced inhibitory postsynaptic potentials by prolonging inhibitory postsynaptic current (IPSC) decay without affecting presynaptic GABA release or the peak amplitude of IPSCs. In addition, cenobamate suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation. A reduction in neuronal excitability induced by cenobamate was associated with an elevation of action potential (AP) threshold, and which progressively increased in later APs during repetitive firing, indicating the activity-dependent modulation of neuronal sodium currents. Cenobamate suppressed neuronal excitability under the condition that GABAergic neurotransmission is excitatory, and administration of cenobamate rapidly enhanced the phosphorylation of eukaryotic elongation factor 2 in the hippocampus of adult and neonatal mice. Collectively, these results suggest that the combined action of cenobamate on sodium currents and GABAAR-mediated synapse responses results in reduced excitability in neurons.

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.

Onset of efficacy and adverse events during Cenobamate titration period.

ObjectivesCenobamate 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 & MethodsAdult 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]).ResultsOnset 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.ConclusionsReductions 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.

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

ObjectiveThis 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. MethodsPatients 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. ResultsOf 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. ConclusionsThis 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.

157 Efficacy of adjunctive cenobamate: post-hoc analysis in patients grouped by concomitant anti-epileptic drug type

PurposeThere has been little success with polytherapy for patients with drug-resistant epilepsy. The need for optimizing AED combinations is high. Cenobamate is a novel AED with a unique, dual, complementary mechanism of action (MoA) combining GABA-A positive allosteric modulation (via a binding site different from benzodiazepines) together with broad spectrum sodium channel blockage. Here we assessed the efficacy of cenobamate when combined with AEDs grouped by MoA.MethodsA post-hoc exploratory analysis of the study C017, in adult epilepsy patients with uncontrolled focal onset seizures who had ≥4 seizures/month despite treatment with stable doses of 1–3 AEDs.ResultsIn the maintenance phase, 183/397 (46%) patients were receiving at least one GABA modulator (felbamate, valproate, topiramate, tiagabine, vigabatrin) and 329/397 (82%) a sodium channel blockers (carbamazepine, oxcarbazepine, lamotrigine, lacosamide, eslicarbazepine). Added onto GABA modu- lators, cenobamate 100/200/400mg achieved seizure freedom rates (SFR) of 7.3%/15.6%/30.6% vs 2.1% for placebo; when added onto sodium channel blockers, cenobamate 100/200/400mg/day showed SFR of 2.3%/9.3%/17.5% vs 1.2% for placebo. Both results were statistically significant for 200 and 400mg. A consistent SFR with cenobamate for a subset of patients receiving background levetiracetam (11% 200mg and 25% 400 mg vs 2.5% placebo) as well as those with background benzodiazepines (20% 400 mg vs 0% placebo) occurred.ConclusionsAdjunctive cenobamate achieved significant dose-dependent SFR when combined with AEDs across multiple MoAs in patients with uncontrolled FOS.lee.finlan@arvelletx.com

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

PurposeTo 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. MethodsPatients 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. Results240 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. ConclusionsSeizure 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.

Cenobamate for Uncontrolled Focal Seizures in Patients With Previous Epilepsy-Related Surgery: A Post-hoc Analysis (P13-8.003)

Cenobamate for Uncontrolled Focal Seizures in Patients With Previous Epilepsy-Related Surgery: A Post-hoc Analysis (P13-8.003)

Cenobamate for Uncontrolled Focal Seizures in Patients Living in a Group Home or With a Developmental Disability (P1-8.006)

Cenobamate for Uncontrolled Focal Seizures in Patients Living in a Group Home or With a Developmental Disability (P1-8.006)

Adjunctive Brivaracetam in Older Patients with Focal Seizures: Evidence from the BRIVAracetam add‑on First Italian netwoRk Study (BRIVAFIRST).

BackgroundThe management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug’s profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy.ObjectiveThe aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting.MethodsThe BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age (‘older’) vs those aged <65 years (‘younger’).ResultsThere were 1029 patients with focal epilepsy included in the study, of whom 111 (10.8%) were aged ≥65 years. The median daily dose of brivaracetam at 3 months was 100 [interquartile range, 100–175] mg in the older group and 100 [100–200] mg in the younger group (p = 0.036); it was 150 [100–200] mg in both groups either at 6 months (p = 0.095) or 12 months (p = 0.140). At 12 months, 49 (44.1%) older and 334 (36.4%) younger patients had a reduction in their baseline seizure frequency by at least 50% (p = 0.110), and the seizure freedom rates were 35/111 (31.5%) and 134/918 (14.6%) in older and younger groups, respectively (p < 0.001). During the 1-year study period, 20 (18.0%) patients in the older group and 245 (26.7%) patients in the younger group discontinued brivaracetam (p = 0.048). Treatment withdrawal because of insufficient efficacy was less common in older than younger patients [older: n = 7 (6.3%), younger: n = 152 (16.6%); p = 0.005]. Adverse events were reported by 24.2% of older patients and 30.8% of younger patients (p = 0.185); the most common adverse events were somnolence, nervousness and/or agitation, vertigo, and fatigue in both study groups.ConclusionsAdjunctive brivaracetam was efficacious, had good tolerability, and no new or unexpected safety signals emerged when used to treat older patients with uncontrolled focal seizures in clinical practice. Adjunctive brivaracetam can be a suitable therapeutic option in this special population.