Greater need for treatment optimization in patients with epilepsy initiating adjunctive therapy: Results of a retrospective claims analysis of antiseizure medication drug load in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess changes in antiseizure medication (ASM) drug load for a cohort of patients with epilepsy. METHODS: Adults (≥18 years) with a diagnosis of epilepsy (ICD-10 code G40.xxx) who started new adjunctive ASM treatment with one of 4 branded (brivaracetam, eslicarbazepine, lacosamide, perampanel) or 4 unbranded (carbamazepine, lamotrigine, levetiracetam, topiramate) ASMs between January 1, 2016 and December 31, 2020 were identified from IBM MarketScan® research databases (primary study population). Patients must have been continuously enrolled 360 days before the start of the new ASM (eligibility period). Follow-up was from the start of new ASM until Day 540 (∼18 months). The primary endpoint was concomitant ASM drug load, which included all ASMs except the new (comparator) ASM. A sensitivity analysis population included adults with epilepsy who were continuously enrolled for ≥ 180 days during at least one calendar year in the study period (2016-2020), whether or not the comparator ASM was new or existing during that period. Total ASM drug load, which included comparator ASM and concomitant ASMs, was assessed in the sensitivity analysis population. RESULTS: In total, 21,332 patients were included in the primary study population, of which 5767 initiated branded ASMs and 15,565 initiated unbranded ASMs. A total of 392,426 patients were included in the sensitivity analysis population during at least one calendar year 2016-2020. Concomitant ASM drug load increased in the 360 days prior to new ASM start and slightly declined thereafter. Mean concomitant ASM drug load for the primary population was 1.6 (SD 1.8) at new ASM start. Concomitant drug load was higher among those starting branded ASM comparators compared to those starting unbranded comparators. Mean total ASM drug load for patients increased over time and was approximately double for patients exposed to branded ASMs (mean range 2.1 to 2.7) compared to that of patients exposed to any unbranded ASM (mean range 1.0 to 1.3). CONCLUSION: Concomitant ASM drug load increased prior to addition of new ASM, with higher increases observed among patients starting branded vs unbranded ASMs, followed by slight decreases thereafter. Total drug load increased linearly among all patients. These findings underscore the need for ongoing ASM regimen evaluation and treatment optimization in patients 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.

Incidence of mental health conditions by seizure control among adults with epilepsy in the United States.

BACKGROUND: Mental health conditions (MHCs) are frequent comorbidities among people with epilepsy; however, the influence of seizure control on the incidence of MHCs is not well reported. This retrospective observational cohort study based on claims data evaluated the effects of indicators of poor seizure control on the incidence of MHCs among MHC-naïve people with epilepsy. We hypothesized that poor seizure control is associated with new-onset MHC diagnoses and/or new prescription drugs for MHCs. METHODS: This study utilized a sample of patients from HealthVerity Marketplace, which includes more than 150 US commercial, Medicare, and Medicaid payers, to identify a cohort of adults (age ≥18 years) with prevalent epilepsy. Follow-up started on day 1 (January 1) after a 1-year eligibility assessment period occurring in calendar year 2017 or 2018. Patients were followed up until the occurrence of an incident MHC event (primary outcome), defined as a mental health diagnosis or psychotropic drug prescription. Time from follow-up to incident MHC diagnosis or to a drug prescription specific to depression or anxiety disorder was analyzed as a secondary outcome. Multivariate Cox proportional hazards regressions were estimated with time-varying covariates, measured in 6-month intervals during follow-up. Time-varying covariates were based on the occurrence of 4 variables used as indicators of poor seizure control in the prior period: epilepsy-related emergent care admissions, epilepsy-related inpatient admissions, epilepsy electroencephalography referrals, and exposure to one or more new antiseizure medications (ASMs). RESULTS: From a random sample of 40,000 people with epilepsy, 2563 (mean age 46.1 years; 50.6% male) were included in the analysis. Incident MHC events were observed in 27.7% (incidence rate 24.4 events per 100 person-years over 2,915.7 total person-years of follow-up). Mean (standard deviation [SD]) time to event was 232.7 (186.3) days. Among the 4 variables, epilepsy-related emergent care admissions were associated with an increased risk of incident MHC events in the following 6-month period (hazard ratio [HR] = 1.676, 95% confidence interval [CI]: 1.386, 2.026, p < 0.001) as were prescriptions for new ASMs in the previous period (HR = 1.702, 95% CI: 1.359, 2.132, p < 0.001). Previous epilepsy-related emergent care admissions (HR = 1.650, 95% CI: 1.347, 2.021, p < 0.001) and new ASMs (HR = 1.632, 95% CI: 1.280, 2.081, p < 0.001) also predicted an increased risk of incident depression or anxiety in the following 6-month period. CONCLUSIONS: Previous indicators of poor seizure control, including epilepsy-related emergent care admissions and new ASMs, predicted increased risk of new MHC events, including depression and anxiety, during the following 6-month interval in MHC-naïve patients with prevalent epilepsy. These data suggest that poor seizure control can increase the subsequent risk of new mental health diagnoses and treatment among people with epilepsy.

Incremental burden of mental health conditions in adult patients with focal seizures.

INTRODUCTION: Clinical research has consistently established mental health conditions (MHCs) as frequent comorbidities of epilepsy. However, the extent of economic burden of comorbid MHC in patients with focal seizures has not been systematically investigated. This retrospective cohort analysis of health plan claims compared healthcare use and costs among adult patients with focal seizures with and without comorbid MHC. METHODS: We utilized the Inovalon Medical Outcomes Research for Effectiveness and Economics (MORE2) Registry, longitudinal data from over 150 commercial, Medicare Advantage, and managed Medicaid health plans for the analysis, and identified a cohort of patients with focal (partial-onset) seizure with relevant ICD9/10 diagnosis codes with and without MHC. Mental health conditions were defined as diagnoses for anxiety, bipolar condition/mania, attention-deficit conduct condition, major depression, schizophrenia, and other psychotic conditions, and patients without MHC were propensity score-matched to patients with preexisting MHC on baseline patient characteristics. The assessment examined a series of outcomes, including 1) direct healthcare resource utilization and 2) total provider reimbursement. RESULTS: Patients with preexisting MHC were more likely to receive adjunctive epilepsy therapy as well as broad-spectrum antiepileptic drugs/antiseizure medications (ASMs). Additionally, patients with focal seizures and MHC were significantly more likely to utilize high-cost healthcare services. The presence of MHC was associated with approximately 50% greater utilization of emergency department (ED), physician, and inpatient services. Consequently, healthcare expenditures were significantly higher among patients with MHC ($17,596 vs. $10,857; 62% higher, p < 0.001), with the trend consistent across all care settings. CONCLUSIONS: This analysis illustrates the health service utilization and cost implications of MHC among patients with focal seizures. The data suggest that patients with MHC have a greater overall clinical burden, which may be associated with higher healthcare resource use and expenditures. Because of the potential burden and costs associated with MHC, neurologists should consider screening patients with focal seizures for mental health disorders to identify and initiate treatment for comorbid mental health disorders.

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.

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.

Real-world analysis of retention on cenobamate in patients with epilepsy in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess retention rates on cenobamate compared with four branded antiseizure medications (ASMs) in patients with epilepsy. METHODS: Adults (≥18 years) with prevalent epilepsy (ICD-10 code G40.xx) and ≥ 1 prescription for cenobamate or any of the newer branded ASMs (brivaracetam, eslicarbazepine, lacosamide, or perampanel) between May 1, 2020 and December 31, 2021 were identified from the HealthVerity Marketplace database. At least 360 days of continuous enrollment was required before and after the index date (Day 1 of initiating cenobamate or branded ASM). Patients were followed until cessation of cenobamate or branded ASM or the end of data collection using Kaplan-Meier methods. Retention was compared between cenobamate and the branded ASMs (both as a group and individually) using Chi-square tests. RESULTS: In total, 4109 patients were included (195 cenobamate; 3914 branded ASMs). A higher proportion of patients in the cenobamate group compared with the branded ASMs group had concurrent focal and generalized epilepsy (65.6% vs 40.0%) and were on ≥ 3 concomitant ASMs (48.2% vs 12.8%) at the index date. Median time to discontinuation (i.e., the time that half the patients discontinued) was not quite reached after 12 months in the cenobamate group (50.3% of patients remained on cenobamate) and was 7.7 months in the branded ASMs group. Retention was significantly higher with cenobamate vs the branded ASMs group (p = 0.04545) and vs the individual ASMs lacosamide (p = 0.03044) and perampanel (p = 0.01558). Twelve-month retention rates (95% confidence intervals) were 50.3% (43.1%-57.0%) for cenobamate, 40.5% (38.9%-42.0%) for branded ASMs overall, 42.3% (38.6%-46.0%) for brivaracetam, 44.1% (39.2%-49.0%) for eslicarbazepine, 39.9% (38.0%-41.8%) for lacosamide, and 36.8% (31.9%-41.8%) for perampanel. CONCLUSIONS: In this real-world analysis, retention was significantly higher with cenobamate vs a pooled group of four branded ASMs despite a greater frequency of patients in the cenobamate group having characteristics of more difficult-to-treat epilepsy.