Effectiveness, safety and tolerability of perampanel by age group when used to treat people with focal and generalized epilepsy in clinical practice: The PERMIT Extension study.

OBJECTIVE: To assess the effectiveness and safety/tolerability of perampanel (PER) in people with epilepsy (PWE) treated in everyday clinical practice for focal and generalized seizures, both in the total cohort and by age group. METHODS: The PERMIT Extension study was a pooled analysis of data from PWE included in two large previous clinical practice studies (PERMIT and PROVE). Retention was assessed over 12 months. Effectiveness was assessed based on total seizures and by seizure type (focal and generalized) after 3, 6, and 12 months of PER treatment and at final follow-up (last observation carried forward; "last visit"); assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the previous visit). Safety/tolerability was assessed throughout PER treatment by evaluating adverse events (AEs). All assessments were conducted for the total population and by age category (<12, ≥12 to <18, ≥18 to <65, and ≥65 years at baseline). RESULTS: Full Analysis Set included 6,822 PWE (51.1% female; mean age, 36.9 years; mean duration of epilepsy 21.4 years) with 6,433, 4,648, and 6,233 PWE assessed for retention, effectiveness, and safety/tolerability, respectively. The majority of PWE (81.1%) were aged 18-64 at baseline, with 4.5% aged <12 years, 8.4% aged 12-17 years, and 5.9% aged ≥65 years. In the overall population, retention rates at 3, 6, and 12 months were 88.0%, 77.6%, and 61.4%, respectively; responder rates at 12 months were 58.5% for total seizures, 54.6% for focal seizures, and 77.7% for generalized seizures, and corresponding seizure freedom rates were 23.6%, 19.0%, and 51.3%, respectively. PER was effective regardless of age category, although effectiveness was greatest in PWE aged ≥65 years, for both focal and generalized seizures. In the overall population, the incidence of AEs was 49.2% and the most frequent AEs (≥5% of PWE) were dizziness/vertigo (13.4%), somnolence (8.8%), irritability (7.3%), and behavioral disorders (5.3%); AEs led to treatment discontinuation in 18.3% of PWE over 12 months. The incidence of AEs and the discontinuation rate due to AEs increased with increasing age (55.0% and 23.9%, respectively, in PWE aged ≥65 years). CONCLUSION: In this study, the largest pooled analysis of PER clinical practice data conducted to date, PER was shown to be effective and generally well tolerated when used to treat people with focal or generalized epilepsy in everyday clinical practice, regardless of age category. No new or unexpected side effects emerged following long-term use in the real-world setting.

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 efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program.

OBJECTIVE: Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. METHODS: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. RESULTS: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range = 0-74.5), and patients were taking a median of three (range = 0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%). SIGNIFICANCE: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

Perampanel monotherapy for the treatment of epilepsy: Clinical trial and real-world evidence.

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.

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.

Long-term open-label perampanel: Generalized tonic-clonic seizures in idiopathic generalized epilepsy.

OBJECTIVE: Assess the longer-term efficacy and safety of adjunctive perampanel (up to 12 mg/day) in patients aged ≥12 years with generalized tonic-clonic (GTC) seizures from the Open-label Extension (OLEx) Phase of Study 332 to determine whether responses obtained during the Core Study are maintained during long-term treatment. METHODS: Patients with GTC seizures previously enrolled in a randomized placebo-controlled trial of perampanel could enter an OLEx Phase comprising 6-week blinded conversion (during which patients previously randomized to placebo-switched to perampanel) and up to 136-week maintenance periods (maximum perampanel dose of 12 mg/day). A 4-week follow-up period was completed by all patients after the last on-treatment visit during the OLEx. We assessed seizure frequency outcomes from preperampanel baseline and the Core Study Pre-randomization Phase, retention rates, doses selected, and treatment-emergent adverse events (TEAEs). RESULTS: Overall, 138 patients entered the OLEx. Median percent reductions in GTC seizures per 28 days from preperampanel were 77% (Weeks 1-13) and 90% (Weeks 40-52). Retention rates were 88% (6 months) and 75% (12 months). Seizure-freedom rates were maintained for at least 2 years regardless of prior treatment received during the Core Study. Most common modal daily dose was >4-8 mg/day (n = 93). Across the Core and OLEx Phases, 120 (87%) patients experienced TEAEs; the most common was dizziness. SIGNIFICANCE: Perampanel was generally well-tolerated, and the TEAEs reported here are consistent with the known safety profile of perampanel. Perampanel offers a long-term treatment option for patients (aged ≥12 years) with GTC seizures.

PROVE: Retrospective, non-interventional, Phase IV study of perampanel in real-world clinical care of patients with epilepsy.

OBJECTIVE: To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care. METHODS: PROVE was a retrospective, non-interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure-freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme-inducing antiseizure medications (EIASMs). RESULTS: Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24-month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent. SIGNIFICANCE: In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

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.

A multivariable prediction model of a major treatment response for focal-onset seizures: A post-hoc analysis of Phase III trials of perampanel.

OBJECTIVE: Although 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients' health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval. METHODS: Univariate analyses using logistic regression were performed using data from three double-blind, placebo-controlled Phase III studies of adjunctive perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310]), and their open-label extension study (OLEx; Study 307 [NCT00735397]). For the double-blind studies, baseline seizure frequency, number of baseline AEDs, baseline seizure type, baseline concomitant enzyme-inducing AEDs (EIAEDs), baseline carbamazepine, lamotrigine, or valproic acid, age at diagnosis, time since diagnosis, etiology, and perampanel plasma concentration were included individually with study treatment. The same factors were included for the OLEx analysis except for plasma concentration and treatment. Variables found to be significant predictors for a major treatment response in univariate analyses were subsequently included in multivariable analyses using backwards and forwards selection. RESULTS: In the double-blind studies, 175/1374 patients had a major response to placebo (n = 25) or perampanel (n = 150). The best predictors of a major treatment response in multivariable models with forwards and backwards selection were: the presence of FBTC seizures during baseline (P = 0.0002), higher perampanel plasma concentration (P < 0.0001), older age at diagnosis (P = 0.0024 and 0.0045, respectively), and lower baseline seizure frequency (P = 0.0364 and 0.0127, respectively). In the OLEx, 217/1090 patients had a major treatment response. The best predictors of a major treatment response in the final multivariable model, regardless of backwards or forwards selection, were a lower baseline seizure frequency (P = 0.0022), the absence of focal impaired awareness seizures during baseline (P = 0.0011), the presence of FBTC seizures during baseline (P = 0.0164), lower number(s) of baseline AEDs (P = 0.0002), the absence of EIAEDs during baseline (P = 0.0059), an older age at diagnosis (P = 0.0054), and absence of structural etiologies (P = 0.0138). SIGNIFICANCE: These analyses of placebo-controlled and long-term extension trial data identified a number of potential predictive factors for patients with focal-onset seizures achieving a major treatment response. These factors may help guide clinicians when predicting a patient's response to treatment and optimizing individual treatment regimens.

Perampanel in real-world clinical care of patients with epilepsy: Interim analysis of a phase IV study.

Objective: To assess the retention rate, efficacy, safety, and dosing of perampanel administered to patients with epilepsy during routine clinical care in the retrospective phase IV, PROVE Study (NCT03208660). Methods: Exposure, efficacy, and safety data were obtained from the medical records of patients initiating perampanel after January 1, 2014, across 29 US study sites. The cutoff date for this interim analysis was October 10, 2018. The primary efficacy endpoint was retention rate. Secondary efficacy endpoints included median percent changes in seizure frequency, seizure-freedom rate, and overall investigator impression of seizure effect. Results: All enrolled patients (N = 1121) received perampanel. Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 16.6 (14.7) months; overall mean (SD) daily perampanel dose was 5.7 (2.7) mg. Perampanel uptitration occurred weekly (21.1%), biweekly (23.8%), every 3 weeks (1.5%), other (43.3%), and unknown (10.3%). Across the Safety Analysis Set (N = 1121), retention rate on perampanel at 24 months was 49.5% (n = 319/645).At 12 months, the median reduction in seizure frequency per 28 days from baseline in the small number of patients for whom data were available was 75.0% (n = 85), and 30/85 (35.3%) patients were seizure free. Based on investigator impression at the end of treatment, improvement, no change (ie, stable), or worsening of seizures was reported in 54.3%, 33.7%, and 12.0% of patients, respectively.Treatment-emergent adverse events occurred in 500 (44.6%) patients; the most common were dizziness (9.2%), aggression (5.4%), and irritability (4.5%). Serious treatment-emergent adverse events occurred in 32 (2.9%) patients. Significance: Favorable retention and sustained efficacy were demonstrated for ≥12 months following initiation of perampanel during routine clinical care in patients with epilepsy.

Assessment of the long-term efficacy and safety of adjunctive perampanel in tonic-clonic seizures: Analysis of four open-label extension studies.

OBJECTIVE: This post hoc analysis evaluated long-term efficacy and safety in patients with focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who entered open-label extension (OLEx) studies to receive long-term adjunctive perampanel. METHODS: Patients aged 12 years and older who completed phase II or III randomized, double-blind, placebo-controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open-label maintenance period (32-424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. RESULTS: Baseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure-freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long-term treatment. SIGNIFICANCE: This post hoc analysis suggests long-term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.

Adjunctive perampanel and myoclonic and absence seizures: Post hoc analysis of data from study 332 in patients with idiopathic generalized epilepsy.

PURPOSE: This post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332. METHODS: Patients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs). RESULTS: During the double-blind phase, myoclonic and/or absence seizures were reported in 47/163 and 60/163 patients, respectively. Median percent reductions in seizure frequency per 28 days from study baseline were 52.5% and 24.5% (myoclonic seizures) and 7.6 % and 41.2 % (absence seizures) for placebo and perampanel, respectively; seizure-freedom rates were 13.0 % and 16.7 % (myoclonic seizures) and 12.1 % and 22.2 % (absence seizures), respectively. During the OLEx phase, 46/138 and 52/138 patients experienced myoclonic and/or absence seizures, respectively. Responses during the double-blind phase were maintained during long-term (>104 weeks) adjunctive perampanel treatment. The frequency/type of TEAEs was consistent with the known safety profile of perampanel. CONCLUSION: In this post hoc analysis, adjunctive perampanel was not associated with any overall worsening of absence seizures. Further research is needed to investigate the effect of adjunctive perampanel in IGE patients with myoclonic and/or absence seizures.

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.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.

OBJECTIVE: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures. METHODS: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. RESULTS: The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.

Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator.

OBJECTIVE: The objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy. METHODS: Seven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.5 mg PF-06372865, 2 mg lorazepam (active control), and placebo. Standardized photosensitivity ranges (SPRs) to IPS were recorded at screening, predose, and 1, 2, 4, and 6 hours postdose. The primary endpoint was the average least squares mean change in the SPR in the participant's most sensitive eye condition, across all time points. RESULTS: Both doses of PF-06372865 produced a marked and statistically significant mean reduction in SPR compared to placebo, which was similar in degree to lorazepam. There was complete suppression of SPR in 6/7 participants following PF-06372865 or lorazepam administration. PF-06372865 was safe and well-tolerated. CONCLUSION: PF-06372865 demonstrated highly robust efficacy. This demonstrates anticonvulsant activity of a novel α2/3/5-subtype selective GABAA PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted. CLINICALTRIALSGOV IDENTIFIER: NCT02564029. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.

Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up. SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.