As many as 1 in 5 patients experienced ZERO seizures1
Secondary outcome
Percentage of patients who achieved seizure reductions of 100%
(12-week, maintenance phase)1,2
Secondary outcome
Percentage of patients who achieved seizure reductions of ≥50%, ≥75%, and ≥90%
(12-week, maintenance phase)1,2
Study design1
The efficacy of XCOPRI® (cenobamate tablets) CV as adjunctive therapy in partial-onset seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled studies in adult patients (Study 1 and Study 2). Patients had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant ASMs. Study 1 (N=221) compared XCOPRI 200 mg/day with placebo. Study 2 (N=434) compared XCOPRI 100 mg/day, 200 mg/day, and 400 mg/day with placebo. The double-blind treatment period consisted of a titration phase (6 weeks) and a maintenance phase (6 weeks for Study 1 and 12 weeks for Study 2). In both studies, patients were started on a higher starting dosage and/or faster titration than the Prescribing Information recommendation. The primary outcome was median percentage reduction in 28-day seizure frequency during the double-blind treatment period.
In Study 1, patients were started on a daily dosage of 50 mg (a higher starting dosage than currently recommended) and subsequently increased by 50 mg/day every 2 weeks, until the final daily target dosage of 200 mg/day was achieved. In Study 2, patients were started on a daily dosage of 50 mg (a higher starting dosage than currently recommended) and subsequently increased by 50 mg/day every week (a faster titration than currently recommended) until 100 mg/day or 200 mg/day was reached and then increased by 100 mg/day every week in patients randomized to 400 mg/day.
EFFICACY RESULTS FOR PATIENTS WITH 1-2 SEIZURES
Post hoc analysis of an open-label safety study: Percentage of patients with 1-2 seizures/28 days at baseline achieving zero seizures for ≥12 months5
Limitations
This post hoc analysis of an open-label study of XCOPRI did not include a control arm. These data are descriptive and representative of an enriched population with a relatively small number of patients. Appropriate multiplicity adjustments were not applied.
Early Titration Data
Post hoc analysis of an open-label safety study:
Percentage of patients with 1-2 seizures/28 days at baseline who achieved zero seizures during titration5
0
Limitations
This post hoc analysis of an open-label study of XCOPRI did not include a control arm. These data are descriptive and representative of an enriched population with a relatively small number of patients. Appropriate multiplicity adjustments were not applied.
References: 1.XCOPRI [package insert]. Paramus, NJ: SK Life Science, Inc.
2.Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020;19(1):38-48.
3.Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311-e2322.
4.Data on file. SK Life Science, Inc.
5.Aboumatar S, Biton V, Wechsler R, Ferrari L, Rosenfeld WE. Post hoc analysis of a phase 3 study for treatment of uncontrolled focal seizures: Adjunctive cenobamate dose and seizure reduction by baseline seizure frequency. Epilepsy Res. 2022;186:107014. doi:10.1016/j.eplepsyres.2022.107014
PM-US-XCOP-1069
Study 2
Primary outcome
Median percentage reduction in 28-day seizure frequency
(18-week, double-blind period)
Study details on concomitant ASMs
Patients in the placebo arm remained on their current ASM(s)2,3
1-3 concomitant ASMs were not adequately controlling patients at baseline*
*The more frequently used ASMs were levetiracetam, lamotrigine, valproate or valproic acid, carbamazepine, oxcarbazepine, clobazam, lacosamide, and topiramate.1-3
†Statistically significant compared with placebo.
Study design1
The efficacy of XCOPRI® (cenobamate tablets) CV as adjunctive therapy in partial-onset seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled studies in adult patients (Study 1 and Study 2). Patients had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant ASMs. Study 1 (N=221) compared XCOPRI 200 mg/day with placebo. Study 2 (N=434) compared XCOPRI 100 mg/day, 200 mg/day, and 400 mg/day with placebo. The double-blind treatment period consisted of a titration phase (6 weeks) and a maintenance phase (6 weeks for Study 1 and 12 weeks for Study 2). In both studies, patients were started on a higher starting dosage and/or faster titration than the Prescribing Information recommendation. The primary outcome was median percentage reduction in 28-day seizure frequency during the double-blind treatment period.
In Study 1, patients were started on a daily dosage of 50 mg (a higher starting dosage than currently recommended) and subsequently increased by 50 mg/day every 2 weeks, until the final daily target dosage of 200 mg/day was achieved. In Study 2, patients were started on a daily dosage of 50 mg (a higher starting dosage than currently recommended) and subsequently increased by 50 mg/day every week (a faster titration than currently recommended) until 100 mg/day or 200 mg/day was reached and then increased by 100 mg/day every week in patients randomized to 400 mg/day.
Study 1
Primary outcome
Median percentage reduction in 28-day seizure frequency
(12-week, double-blind period)
Study details on concomitant ASMs
Patients in the placebo arm remained on their current ASM(s)2,3
1-3 concomitant ASMs were not adequately controlling patients at baseline*
*The more frequently used ASMs were levetiracetam, lamotrigine, valproate or valproic acid, carbamazepine, oxcarbazepine, clobazam, lacosamide, and topiramate.1-3
†Statistically significant compared with placebo.
Secondary outcome/post-hoc analysis
Percentage of patients who achieved seizure reductions of ≥50%, ≥75%, ≥90%, and 100%3,4*†‡
(6-week maintenance phase)
*Secondary outcome: Percentage of patients achieving a seizure reduction of ≥50%.
†Post hoc analysis: Percentage of patients achieving seizure reductions of ≥75%, ≥90%, and 100%.
‡Results not statistically significant.
As many as 1 in 5 patients experienced ZERO seizures1
Study design1
The efficacy of XCOPRI® (cenobamate tablets) CV as adjunctive therapy in partial-onset seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled studies in adult patients (Study 1 and Study 2). Patients had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant ASMs. Study 1 (N=221) compared XCOPRI 200 mg/day with placebo. Study 2 (N=434) compared XCOPRI 100 mg/day, 200 mg/day, and 400 mg/day with placebo. The double-blind treatment period consisted of a titration phase (6 weeks) and a maintenance phase (6 weeks for Study 1 and 12 weeks for Study 2). In both studies, patients were started on a higher starting dosage and/or faster titration than the Prescribing Information recommendation. The primary outcome was median percentage reduction in 28-day seizure frequency during the double-blind treatment period.
In Study 1, patients were started on a daily dosage of 50 mg (a higher starting dosage than currently recommended) and subsequently increased by 50 mg/day every 2 weeks, until the final daily target dosage of 200 mg/day was achieved. In Study 2, patients were started on a daily dosage of 50 mg (a higher starting dosage than currently recommended) and subsequently increased by 50 mg/day every week (a faster titration than currently recommended) until 100 mg/day or 200 mg/day was reached and then increased by 100 mg/day every week in patients randomized to 400 mg/day.
Study population treated yet uncontrolled
XCOPRI® (cenobamate tablets) CV was studied across 2 multicenter, randomized, double-blind, placebo-controlled studies in adult patients with partial-onset seizures with or without secondary generalization1
concomitant anti‑seizure medications (ASMs) were not adequately controlling patients at baseline*
Patients in the placebo arm remained on their current ASM(s)2,3
of patients were taking 2 or more concomitant ASMs1
was the approximate mean duration of epilepsy for patients in both studies1
per 28 days was the median baseline seizure frequency for patients in both studies1
*The more frequently used ASMs were levetiracetam, lamotrigine, valproate or valproic acid, carbamazepine, oxcarbazepine, clobazam, lacosamide, and topiramate.1-3
Study design5
A multicenter, open-label safety study in patients 18 to 70 years old with uncontrolled focal seizures despite taking a stable dosage of 1 to 3 ASMs. The study included a screening period of up to 21 days was followed by an open-label treatment period consisting of a 12-week titration phase, followed by an open-label maintenance phase. The maintenance phase continued for the length of the study (total study duration up to 43 months). Patients initiated XCOPRI treatment using the FDA-approved titration schedule. After reaching 200 mg/day, further increases up to 400 mg/day using biweekly increments of 50 mg/day were allowed during the maintenance phase. Reductions below 200 mg were allowed at investigators’ clinical judgment (minimum allowed dosage 50 mg/day). XCOPRI monotherapy was not allowed. Patient visits occurred every 2 weeks for 16 weeks and then every 1 to 3 months.
A post hoc analysis in a subset of patients (N=240) evaluated the impact of baseline seizure frequency (<3 seizures/28 days vs ≥3 seizures/28 days) on mean XCOPRI dosage required to achieve 100% seizure reduction, duration of this response, and responder rates. To be eligible for the post hoc analysis, the following criteria must have been met: patients must have had at least 1 focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure per 13 weeks baseline prior to screening visit; seizure data while on treatment; and consistent documentation of good-quality, raw seizure data for ≥85% of the time spent in the study. Responder rates (≥50%, ≥75%, ≥90%, and 100%) were assessed during the entire treatment period, during the titration phase, and during the maintenance phase.
INDICATION
XCOPRI® (cenobamate tablets) CV is indicated for the treatment of partial-onset seizures in adult patients.
Important Safety Information and indication
CONTRAINDICATIONS
XCOPRI® is contraindicated in any patients with known hypersensitivity to the compound or any of the components of the drug product.
XCOPRI is contraindicated in patients with Familial Short QT syndrome.
IMPORTANT SAFETY INFORMATION and INDICATION for XCOPRI® (cenobamate tablets) CV
CONTRAINDICATIONS
XCOPRI® is contraindicated in any patients with known hypersensitivity to the compound or any of the components of the drug product.
XCOPRI is contraindicated in patients with Familial Short QT syndrome.
WARNINGS AND PRECAUTIONS
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including XCOPRI. DRESS has been reported, including one fatality, when XCOPRI is titrated rapidly (weekly or faster titration). No cases of DRESS were reported in an open-label safety study of 1339 partial-onset seizure patients when XCOPRI was initiated at 12.5 mg/day and titrated every two weeks. This finding does not establish that the risk of DRESS is prevented by a slower titration; however, XCOPRI should be initiated at 12.5 mg once daily and titrated every two weeks. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement. Eosinophilia is often present. If such signs or symptoms are present, the patient should be evaluated immediately. XCOPRI should be discontinued immediately and not restarted if an alternative etiology for the signs or symptoms cannot be established.
QT Shortening: XCOPRI can cause shortening of the QT interval. Caution should be used when administering XCOPRI and other drugs that shorten the QT interval as there may be a synergistic effect on the QT interval that would increase the QT shortening risk.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including XCOPRI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Advise patients, their caregivers, and/or families to be alert for these behavioral changes and report them immediately to a healthcare provider.
Neurological Adverse Reactions: XCOPRI causes dose-dependent increases in the neurologic adverse reactions including, dizziness, diplopia, disturbance in gait and coordination, somnolence, and fatigue.
Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of XCOPRI is known.
Withdrawal of AEDs: As with all antiepileptic drugs, XCOPRI should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
MOST COMMON ADVERSE REACTIONS
In adult adjunctive therapy placebo-controlled clinical studies, the most common adverse reactions that occurred in XCOPRI-treated patients (incidence at least 10% and greater than placebo) were somnolence, dizziness, fatigue, diplopia, headache.
DOSING CONSIDERATIONS
Dosage adjustment of XCOPRI or other concomitant medications may be necessary.
Consider gradually reducing phenytoin dosages by up to 50% during initial titration.
Consider reducing dosages of phenobarbital and clobazam as needed when used concomitantly with XCOPRI. When XCOPRI and carbamazepine or lamotrigine are taken concomitantly, consider increasing dosages as needed of carbamazepine or lamotrigine.
Consider increasing dosages as needed of drugs which are CYP2B6 and CYP3A substrates and decreasing dosages as needed of drugs which are CYP2C19 substrates.
Effectiveness of hormonal oral contraceptives may be reduced when administered concomitantly with XCOPRI. Women should use additional or alternative non-hormonal birth control.
Dosage reduction of XCOPRI may be considered in patients with mild to moderate and severe renal impairment. XCOPRI use is not recommended in end‑stage renal disease.
The maximum recommended daily dose is 200 mg for patients with mild or moderate hepatic impairment. XCOPRI use is not recommended in patients with severe hepatic impairment
DRUG ABUSE
XCOPRI is a Schedule V controlled substance.
INDICATION
XCOPRI is indicated for the treatment of partial-onset seizures in adult patients.
