Regulatory submission: NDA submitted September 2026

“VANCOUVER, BC and BOSTON, MA, Sept. 17, 2026 (GLOBE NEWSWIRE) -- Xenon Pharmaceuticals Inc. (Nasdaq: XENE), a neuroscience-focused biopharmaceutical company dedicated to drug discovery, clinical development, and commercialization of life-changing therapeutics for patients in need, today announced it has submitted a New Drug Application (NDA) for azetukalner in focal seizures (FS) to the U.S. Food and Drug Administration (FDA).” (opens the source at this quote in a new tab)
“We are very pleased to announce completion of the NDA submission for azetukalner in focal seizures in epilepsy.” (opens the source at this quote in a new tab)

Launch

No evidence found.

Investigational status: no approved product

“The Company has no products approved for sale and has not generated any revenue from product sales.” (opens the source at this quote in a new tab)

Pre-NDA meeting and planned submission quarter

“We remain on track to submit our New Drug Application (NDA) for azetukalner in FOS in the third quarter of 2026, having completed a pre-NDA meeting with the U.S. Food and Drug Administration (FDA).” (opens the source at this quote in a new tab)

Clinical basis of the New Drug Application

“The NDA submission is based on positive clinical data from two global, randomized, double-blind, placebo-controlled trials for azetukalner in focal seizures, including the Phase 2b X-TOLE study and Phase 3 X-TOLE2 study. Across the two studies, treatment with all four doses of azetukalner demonstrated a statistically significant reduction from baseline in monthly seizure frequency compared with placebo, and azetukalner was generally well-tolerated with a consistent safety profile observed in both studies. These safety results are comparable with the long-term safety observed in the X-TOLE open label extension (OLE) study, with the entire epilepsy program generating more than 1,500 patient-years of safety and exposure data.” (opens the source at this quote in a new tab)

Studies supporting submissions outside the United States and in a second seizure type

“The ongoing Phase 3 X-TOLE3 and X-ACKT studies of azetukalner in focal seizures and primary generalized tonic-clonic seizures (PGTCS), respectively, continue to enroll patients to support expansion of use across seizure types and global regions.” (opens the source at this quote in a new tab)

Japanese regulatory interaction

“In support of a potential regulatory submission in Japan, Xenon has completed an ethnobridging study and shared the results in a recent meeting with Japan’s Pharmaceutical and Medical Devices Agency (PMDA). Xenon has aligned with PMDA to enroll approximately 60 of the planned 360 X-TOLE3 participants in Japan.” (opens the source at this quote in a new tab)

First-in-class positioning if approved

“If approved, azetukalner would be the only KV7 potassium channel opener available for the treatment of epilepsy.” (opens the source at this quote in a new tab)

Commercial readiness activities

“With a strong body of clinical evidence from two large placebo-controlled trials and more than 800 patient-years of exposure data, we are focusing next on submitting our new drug application to the FDA later this year, as well as advancing our commercial-readiness activities in anticipation of our first commercial launch.” (opens the source at this quote in a new tab)

FDA expedited program designations, filing acceptance, and action date

No evidence found.

Manufacturer: Xenon Pharmaceuticals

“Xenon Pharmaceuticals (Nasdaq: XENE) is a neuroscience-focused biopharmaceutical company dedicated to drug discovery, clinical development, and commercialization of life-changing therapeutics for patients in need. Xenon's lead molecule, azetukalner, is a novel, potent KV7 potassium channel opener in late-stage clinical development for the treatment of epilepsy, major depressive disorder and bipolar depression.” (opens the source at this quote in a new tab)

Development history and prior product codes

“Originally described in a patent by Valeant Pharmaceuticals in 2008, azetukalner was acquired by First-Order Pharmaceuticals in 2015 and later obtained by Xenon Pharmaceuticals in 2017. It was formerly known as encukalner, XEN1101, 1OP-2198, or VRX621698” (opens the source at this quote in a new tab)

Therapeutic class: KV7 potassium channel opener

“Azetukalner is a novel, potent KV7 potassium channel opener currently in development for the treatment of epilepsy, major depressive disorder and bipolar depression. It represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development.” (opens the source at this quote in a new tab)

Molecular target and seizure type addressed

“XEN1101 is a novel, small-molecule, selective Kv7.2/Kv7.3 potassium channel opener being developed for the treatment of FOSs, the most common type of seizures experienced by individuals with epilepsy.” (opens the source at this quote in a new tab)

Brand name

No evidence found.

Oral capsule formulation used in the Phase 2b study

“This was a multicenter, randomized, double-blind, parallel-group, dose-ranging, placebo-controlled adjunctive-therapy clinical trial in which XEN1101 was administered once daily with food as a 10-, 20-, or 25-mg oral capsule.” (opens the source at this quote in a new tab)

Immediate-release capsules used in Phase 1

“After single doses ranging from 5 to 30 mg (immediate-release capsules) administered in the fasting state, peak plasma azetukalner concentrations are achieved at 3.2–4.5 h on average.” (opens the source at this quote in a new tab)

Strengths evaluated in the Phase 3 focal seizure studies

“The completed X-TOLE2 study and the ongoing X-TOLE3 study were both designed as multicenter, randomized, double-blind, placebo-controlled studies to evaluate the clinical efficacy, safety, and tolerability of 15 mg or 25 mg of azetukalner administered orally with food as adjunctive treatment in approximately 360 patients per study with FOS.” (opens the source at this quote in a new tab)

Registry record of the dosage form

“XEN1101 Capsules” (opens the source at this quote in a new tab)

Announced price for azetukalner

No evidence found.

No approved product and no product revenue

“We have no products approved for commercial sale and have not generated any revenue from product sales to date, and we will continue to incur significant research and development and other expenses related to our clinical development and ongoing operations.” (opens the source at this quote in a new tab)
“Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we obtain regulatory approval.” (opens the source at this quote in a new tab)
“In order to obtain and maintain acceptable reimbursement levels and access for patients at copay levels that are reasonable and customary, we may have to offer discounts or rebates from list prices or to implement other unfavorable pricing modifications.” (opens the source at this quote in a new tab)

Branded adjunctive antiseizure medication comparators: United States National Average Drug Acquisition Cost, week of 16 September 2026

Product and strength	Quoted record description	Quoted acquisition cost per unit	Quoted effective date
Cenobamate 200 mg tablet	“XCOPRI 200 MG TABLET”	“39.86819”	“2026-08-19”
Brivaracetam 100 mg tablet	“BRIVIACT 100 MG TABLET”	“24.07624”	“2026-08-19”
Perampanel 12 mg tablet	“FYCOMPA 12 MG TABLET”	“39.07764”	“2026-08-19”

United States brand and generic antiseizure medication price levels, 2013 to 2023

“This study utilized National Average Drug Acquisition Cost (NADAC) data from November 2013 to July 2023.” (opens the source at this quote in a new tab)
“From 2013-2016 to 2020-2023, accounting for standard deviations (SD), the average price of brand-name ASMs increased from $8.71 (SD 5.9) to $15.43 (SD 10.7), while generic ASMs saw a slight decrease from $1.39 (SD 1.8) to $1.26 (SD 1.6).” (opens the source at this quote in a new tab)
“Consequently, the price gap between brand-name and generic ASMs surged from 1452.39 % to 3399.26 %.” (opens the source at this quote in a new tab)

Cenobamate list price, United Kingdom

“Titration packs of 14 to 28 tablets are available in different doses ranging from 12.5 mg to 200 mg and costing between £85.54 to £165.62 per pack.” (opens the source at this quote in a new tab)
“Maintenance packs of 28 tablets are available in doses ranging from 50 mg to 200 mg costing £91 to £182 per pack.” (opens the source at this quote in a new tab)
“Estimated cost for the maintenance phase of treatment is £206 per person every 28 days (£7.37 per day).” (opens the source at this quote in a new tab)

Mechanistic classification

“On the basis of these data, azetulkalner can be classified as a selective opener of neuronal Kv7.2/7.3 channels, with no effects on cardiac (Kv7.1) channels.” (opens the source at this quote in a new tab)

AHFS classification

No evidence found.

Indication sought in the United States New Drug Application

“today announced it has submitted a New Drug Application (NDA) for azetukalner in focal seizures (FS) to the U.S. Food and Drug Administration (FDA).” (opens the source at this quote in a new tab)

Indication described at the Phase 3 readout

“Xenon plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the treatment of focal onset seizures in the third quarter of 2026.” (opens the source at this quote in a new tab)

Adjunctive use in adults, as studied in the registration trial

“A Randomized, Double-blind, Placebo-Controlled, Multicenter Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Focal-Onset Seizures” (opens the source at this quote in a new tab)

Potassium channel opening and neuronal hyperpolarization

“Azetukalner is designed to open potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarizing neurons. This process helps reduce excessive neuronal firing, which is a key contributor to several neurologic and psychiatric disorders.” (opens the source at this quote in a new tab)

Stabilization of the open channel state

“By stabilizing the open state of these channels, it promotes a hyperpolarized resting membrane potential, thereby reducing rapid action potential spiking.” (opens the source at this quote in a new tab)

In vitro potency at KV7.2 and KV7.2/7.3 channels

“In these systems, azetukalner was found to activate Kv7.2 channels with half-maximal effective concentrations (EC50) of 11 and 15 nM, respectively. In a Xenopus oocyte expression system, azetukalner activated channels Kv7.2, Kv7.5, Kv7.4, and Kv7.2/7.3 heteromer with EC50 values of 0.45, 0.35, 0.63, and 0.35 µM, respectively” (opens the source at this quote in a new tab)

Subtype selectivity within the KV7 family

“In in vitro studies in CHO cell lines expressing heteromeric Kv7.2/7.3 and Kv7.3/7.5 channels and homomeric Kv7.4 channels, azetukalner showed 3.4-fold greater selectivity for Kv7.2/7.3 over Kv7.3/7.5 and Kv7.4 channels, with EC50 values of 27 nM versus 94 nM and 113 nM, respectively” (opens the source at this quote in a new tab)

Selectivity over other ion channels and the GABA system

“Azetukalner reportedly exerts no activity on other ion channels or the GABA system at concentrations > 100-fold greater than those active on Kv7.2 channels” (opens the source at this quote in a new tab)

Relative rather than absolute selectivity

“Reported selectivity is subtype-relative rather than absolute: in heterologous expression assays azetukalner is approximately fourfold more potent at KV7.2/7.3 than at KV7.3/7.5 or KV7.4, with screening selectivity over unrelated channels and receptors reported as greater than 100-fold, including absence of the GABAA activity seen with retigabine.” (opens the source at this quote in a new tab)

Potency relative to ezogabine

“In studies with human embryonic kidney (HEK) cells expressing Kv7.2/7.3 channels, azetukalner (EC50, 42 nM) was 20 times more potent than ezogabine (EC50, 920 nM) in causing an approximate 40 mV leftward (negative) shift in the half-maximal voltage of channel activation, while causing a similar increase in maximal conductance” (opens the source at this quote in a new tab)

Structural difference from ezogabine

“The novel structure differs from that of ezogabine.” (opens the source at this quote in a new tab)

Structural basis for bypassing the pigment-forming pathway

“It was designed to bypass the pigment-forming pathway associated with retigabine” (opens the source at this quote in a new tab)
“Unlike retigabine, which bears a secondary aromatic amino group, the amino functionality of azetukalner is incorporated within a tetrahydroisoquinoline ring system, which sterically and electronically constrains the nitrogen atom and prevents 1 from participating in oxidative dimerization.” (opens the source at this quote in a new tab)

Preclinical antiseizure activity in rodent seizure models

“In the MES test, azetukalner has ED50 values of 1.1 mg/kg in rats at 60 min after per os (p.o.) dosing, and 2.2 mg/kg in mice at 120 min after i.p. dosing. In mice, azetukalner is also effective in protecting against seizures induced by subcutaneous (s.c.) pentylenetetrazole, s.c. picrotoxin, s.c. bicuculline, and 6 Hz stimulation, with ED50 values < 10 mg/kg i.p., which correspond to a > 3–19-fold greater potency compared with ezogabine (Table 2 )” (opens the source at this quote in a new tab)

Transcranial magnetic stimulation biomarkers of cortical excitability

“Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15–55 msec after TMS) and at late (150–250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration.” (opens the source at this quote in a new tab)

Concentration-effect relationship for resting motor threshold

“Mean plasma azetukalner concentrations (± SD) at 2, 4, and 6 h after dosing were 15.7 ± 21.5 ng/mL, 30.2 ± 21.9 ng/mL, and 42.1 ± 19.1 ng/mL, respectively. At the time of individual peak drug concentrations, plasma azetukalner levels correlated significantly with changes in RMTs, but not with changes in TEPs.” (opens the source at this quote in a new tab)

Use of the transcranial magnetic stimulation study for target engagement and dose selection

“In addition, data from a Phase 1b transcranial magnetic stimulation, or TMS, study – which was designed to assess azetukalner’s ability and potency to modulate cortical excitability – demonstrated activity in the target central nervous system, or CNS, tissue and helped inform dose selection for our Phase 2b clinical study.” (opens the source at this quote in a new tab)

In vivo additive effects with other antiseizure medications

“Additionally, a new poster highlighting the mechanistic characterization of azetukalner will also be presented, including KV7 binding, enhanced channel opening, and rational polytherapy potential. This poster will include in vivo data demonstrating the potential additive effects of azetukalner when used in combination with commonly prescribed antiseizure medications (ASMs), reinforcing its opportunity to enhance seizure control through the application of rational polytherapy in clinical practice.” (opens the source at this quote in a new tab)

Absorption and time to peak concentration

“After single doses ranging from 5 to 30 mg (immediate-release capsules) administered in the fasting state, peak plasma azetukalner concentrations are achieved at 3.2–4.5 h on average. Thereafter, the drug concentration declines with a biphasic profile. Azetukalner AUC increases about 1.8-fold after co-administration with food” (opens the source at this quote in a new tab)

Food effect and dose proportionality

“Absorption in the fed state was relatively slow, with peak drug concentrations occurring at 4–6 h after dosing. When azetukalner is administered in the fasting state, exposure is less than dose proportional. However, after 10 days of once-daily (q.d.) dosing with food, exposure increases proportionally with dose” (opens the source at this quote in a new tab)

Half-life and steady state

“The half-life of azetukalner is about 1–2 days, which implies a modest (about 25%) peak-to-trough fluctuation in serum drug concentration on a q.d. dosing schedule” (opens the source at this quote in a new tab)
“After multiple dosing, azetukalner elimination shows a late terminal phase with an average half-life of 4–10 days” (opens the source at this quote in a new tab)
“Steady state (defined as no statistical difference between trough levels on successive days) is reached after 7–10 days, even though complete steady state is expected to occur after about 3 weeks” (opens the source at this quote in a new tab)

Terminal half-life supporting once-daily dosing without titration

“The pharmacokinetic properties of XEN1101, including a long terminal elimination half-life (approximately 10 days), support once-daily oral dosing without the need for titration at initiation of dosing or tapering at termination of dosing.” (opens the source at this quote in a new tab)

Phase 1 single- and multiple-ascending-dose results

“Single- and multiple-ascending-dose studies were conducted in healthy volunteers to evaluate PK and tolerability, including an evaluation of food effects. Testing included single doses of 5 mg, 15 mg, 20 mg, and 30 mg, as well as multiple doses of 15 mg once daily for 7 days. Key PK findings revealed peak plasma concentrations (Cmax) of 31.5 ng/mL (20 mg) and 35.5 ng/mL (30 mg), with corresponding half-lives of 41 h and 63.4 h. Elimination followed a biphasic pattern, characterized by a functional half-life of 1–2 days and a terminal half-life exceeding 5 days.” (opens the source at this quote in a new tab)

Metabolism and elimination

“After 10 days of dosing at 25 mg q.d., only 0.01% of the administered dose is excreted in urine as unchanged drug over a 24 h collection period, indicating that azetukalner renal clearance is negligible” (opens the source at this quote in a new tab)
“Azetukalner is cleared by CYP3A4-mediated metabolism, with other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6) playing little or no role” (opens the source at this quote in a new tab)
“A major oxidative metabolite detected in plasma at concentrations of approximately 20% of those of the parent drug has been found to be inactive on Kv7 channels after preliminary testing” (opens the source at this quote in a new tab)

FDA-approved prescribing information, contraindications, and boxed warnings

No evidence found.

Absence of tissue discoloration in the Phase 2b study

“No TEAEs of tissue discoloration were reported. Two nonserious TEAEs of urinary retention were reported in the active treatment groups, 1 of which required a dose reduction; both patients continued to receive the study medication with no other changes or interventions, including no need for catheterization.” (opens the source at this quote in a new tab)
“There were no cardiovascular signals of concern in electrocardiograms or vital signs, no allergic skin rashes, and no deaths in the study. Urinary problems were infrequent and mild; no catheterization was required. Moreover, tissue discoloration was not observed in this limited duration trial nor in an interim analysis of the ongoing 5-year, open-label extension study.” (opens the source at this quote in a new tab)

Urinary retention during long-term open-label treatment

“Three participants reported urinary retention, 1 reported it as mild and 2 as moderate; no dose changes were made in any case.” (opens the source at this quote in a new tab)
“Serious AEs were infrequent at 12.7%, as were TEAEs related to urinary retention (1.1%), which have been reported with the use of KV7 channel openers.” (opens the source at this quote in a new tab)

Urinary retention as a possible class effect of KV7 openers

“Urinary retention has been reported in a small minority of patients receiving chronic treatment with ezogabine and azetukalner” (opens the source at this quote in a new tab)
“urinary retention may be considered a class effect of these medications.” (opens the source at this quote in a new tab)

Absence of the ophthalmological and pigmentary pattern seen with retigabine

“However, azetukalner lacks the recognizable pattern of drug-induced organ toxicity, specifically the urinary retention and ophthalmological abnormalities (e.g., retinal pigmentation and visual acuity changes), that limited the clinical use of retigabine” (opens the source at this quote in a new tab)

Absence of the phenazinium dimers implicated in ezogabine pigmentation

“Azetukalner lacks a secondary aniline structure and reportedly does not generate the phenazinium dimers considered to be responsible for ezogabine-induced pigmentation” (opens the source at this quote in a new tab)

Central nervous system adverse events

“The most common (>10%) TEAEs across all XEN1101 dose groups were dizziness (24.6%), somnolence (15.6%), and fatigue (10.9%).” (opens the source at this quote in a new tab)
“The adverse event of confusional state was reported in 4.7% of the treated groups (2.2% receiving 10 mg, 5.9% receiving 20 mg, and 5.3% receiving 25 mg) and in 0.9% of the placebo group. No allergic rashes occurred.” (opens the source at this quote in a new tab)

Neuropsychiatric adverse events observed in the psychiatry studies

“In addition, the Company announced today that it has implemented a voluntary pause on enrollment for new patients in its ongoing clinical studies in major depressive disorder (MDD) and bipolar depression (BPD), following an analysis of neuropsychiatric adverse events in these studies. Participants currently enrolled in the randomized controlled psychiatry studies and associated OLE studies will continue on study. The observed events, the rate of these events and their severity, are consistent with the known safety and tolerability profile of azetukalner and its mechanism; however, such adverse events had not previously been seen in the Phase 2 X‑NOVA clinical study in MDD.” (opens the source at this quote in a new tab)
“This voluntary action does not impact ongoing epilepsy studies.” (opens the source at this quote in a new tab)

Adolescents in the generalized tonic-clonic seizure and open-label studies

“A similar trial ( NCT05667142 ) is being conducted in patients with generalized tonic-clonic seizures, assessing doses of 25 mg q.d. (participants aged ≥ 18 years) and 15 mg or 25 mg q.d (participants aged from 12 to < 18 years).” (opens the source at this quote in a new tab)

Age eligibility in the Phase 3 open-label extension

“This study will evaluate the long term safety, tolerability, pharmacokinetics (PK), and efficacy of XEN1101 in subjects with Focal Onset Seizures (FOS) or Primary Generalized Tonic-Clonic Seizures (PGTCS) for the treatment of seizures for up to 6 years.” (opens the source at this quote in a new tab)

Negligible renal elimination

“After 10 days of dosing at 25 mg q.d., only 0.01% of the administered dose is excreted in urine as unchanged drug over a 24 h collection period, indicating that azetukalner renal clearance is negligible” (opens the source at this quote in a new tab)

Hepatic impairment, renal impairment, pregnancy, and lactation

No evidence found.

CYP3A4 inhibition: itraconazole

“In healthy subjects, a single 400 mg oral dose of the CYP3A4 inhibitor itraconazole given after 10 days of treatment with azetukalner (20 mg q.d.) was associated with an approximately 10% increase in peak plasma azetukalner concentration and a < 30% increase in azetukalner exposure” (opens the source at this quote in a new tab)
“Longer treatment with itraconazole, however, would be required to adequately assess the effect of CYP3A4 inhibition on azetukalner pharmacokinetics.” (opens the source at this quote in a new tab)

Modelled effect of CYP3A4 inhibitors and inducers

“Modeling pharmacokinetic data from the phase 2b efficacy and safety study (see below) predicted a 32% increase in steady-state plasma azetukalner levels in the presence of CYP3A4 inhibitors. The same model predicted a 22% decrease in azetukalner exposure in the presence of concomitant treatment with a single CYP3A4 inducer, and a 39% decrease in the presence of two or more CYP3A4 inducers” (opens the source at this quote in a new tab)

Enzyme-inducing antiseizure medications and trial stratification

“Azetukalner is primarily metabolized by cytochrome P450 3A4 (CYP3A4), with minimal involvement from other cytochrome P450 enzymes, and plasma levels of azetukalner may decrease in the presence of CYP3A4 inducers.” (opens the source at this quote in a new tab)

Randomization stratified by enzyme-inducing background medication

“XEN1101 is primarily metabolized by cytochrome P450 3A4 isozyme (CYP3A4) without substantial involvement of other CYPs, and plasma levels of XEN1101 may decrease in the presence of CYP3A4 inducers. To ensure balanced distribution across groups, randomization was stratified by background use of CYP3A4 inducer medications (eg, carbamazepine, eslicarbazepine acetate, oxcarbazepine, phenytoin, topiramate, or phenobarbital).” (opens the source at this quote in a new tab)

In vitro cytochrome P450 inhibition and induction

“At in vitro concentrations of 3 μmol/L, which are much higher than those anticipated to be clinically efficacious, azetukalner did not cause direct inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor did it cause time-dependent inhibition” (opens the source at this quote in a new tab)
“Likewise, no clinically meaningful induction of the pregnane X nuclear receptor (PXR), which is associated with CYP3A4 expression levels, was observed at azetukalner concentrations of 0.1–1 μmol/L” (opens the source at this quote in a new tab)

Low potential for drug interactions in clinical use

“A mechanism of action that differs from that of currently marketed ASMs and a low potential for drug–drug interactions make azetukalner a good candidate for adjunctive therapy in focal-seizure patients receiving any type of concomitant medication. Additional advantages include the feasibility of once daily dosing without titration.” (opens the source at this quote in a new tab)

No dose adjustment of concomitant antiseizure medications

“Azetukalner has the potential to deliver much needed innovation to treat people living with focal seizures, with strong efficacy, a differentiated mechanism of action that may enable rational polytherapy, once-daily dosing with no dose adjustments for other antiseizure medications, and a consistent and generally well-tolerated safety profile” (opens the source at this quote in a new tab)

Effect on hormonal contraceptives

No evidence found.

Doses evaluated in the Phase 3 focal seizure studies

“The completed X-TOLE2 study and the ongoing X-TOLE3 study were both designed as multicenter, randomized, double-blind, placebo-controlled studies to evaluate the clinical efficacy, safety, and tolerability of 15 mg or 25 mg of azetukalner administered orally with food as adjunctive treatment in approximately 360 patients per study with FOS.” (opens the source at this quote in a new tab)

No titration at initiation or tapering at discontinuation

“Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used.” (opens the source at this quote in a new tab)
“which enables gradual self-titration associated with a rapid onset of effect, with nearly the maximum seizure reduction achieved in each arm by the first week of treatment, which was sustained throughout the 8-week DBP in the 20- and 25-mg groups.” (opens the source at this quote in a new tab)

Dose used in long-term open-label treatment

“Participants who completed the DBP with a minimum of 80% study medication compliance and no important protocol deviations were eligible to enter the OLE phase, during which participants from all DBP arms began treatment with azetukalner 20 mg taken once daily with food (Figure 1 ). Azetukalner dose adjustments and changes in concomitant ASMs were allowed during the OLE.” (opens the source at this quote in a new tab)

Oral once-daily administration with food

“The X-TOLE2 clinical trial (NCT05614063) was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study evaluating the efficacy, safety, and tolerability of azetukalner, administered as an oral, adjunctive therapy once-daily with food in adult patients with FOS.” (opens the source at this quote in a new tab)

Rationale for administration with food and timing of the dose

“XEN1101 was administered as a once-daily adjunctive treatment in capsule formulation by mouth. Because the oral bioavailability of XEN1101 is enhanced by coadministration with food, patients were instructed to take the study medication with the evening meal.” (opens the source at this quote in a new tab)

Administration in the Phase 3 studies

“During the DBP, subjects will be instructed to orally take XEN1101 or placebo once daily with an evening meal.” (opens the source at this quote in a new tab)

Absence of an existing commercial and distribution infrastructure

“We do not have a sales or marketing infrastructure and, as a company, have no sales, marketing or distribution experience. Our strategy involves building our own commercial infrastructure to selectively commercialize future products in certain commercial markets which will be expensive and time consuming. For certain products, including azetukalner, and/or specific commercial markets, we evaluate commercial partners from time to time.” (opens the source at this quote in a new tab)

Reliance on contract manufacturers for commercial supply

“We do not own or operate manufacturing or testing facilities for the production of clinical or commercial quantities of our product candidates, and we lack the resources and the capabilities to do so. As a result, we currently rely on third parties for the manufacture and supply of the active pharmaceutical ingredients, or APIs, in our product candidates and the final drug product formulation” (opens the source at this quote in a new tab)

Adjunctive use on a background of one to three antiseizure medications

“Treatment with a stable dose of 1 to 3 allowable current ASMs for at least one month prior to screening, during baseline, and throughout the duration of the DBP” (opens the source at this quote in a new tab)

Concomitant antiseizure medication use in the Phase 3 trial population

“Participants had highly treatment-resistant epilepsy, with a median of five prior ASMs, a baseline seizure frequency of 12.75 per month, and 51.3% using three concomitant ASMs.” (opens the source at this quote in a new tab)

Concomitant antiseizure medication use in the Phase 2b trial population

“A total of 8.9% of the patients received 1 stable ASM at baseline and concomitantly throughout the DBP of the study, 40.6% of the patients received 2, and 50.5% of the patients received 3. Patients had tried and stopped a median of 6 previous ASMs before study entry. More than half of the patients (57.8%) were taking a CYP3A4 inducer at baseline.” (opens the source at this quote in a new tab)

Polytherapy in routine epilepsy management

“Epilepsy is often managed with polytherapy – or concurrent use of multiple antiseizure medications (ASMs) – to improve seizure control. However, despite more than 30 available epilepsy treatments, up to half of people with focal epilepsy still live with uncontrolled seizures.” (opens the source at this quote in a new tab)

Rationale for combining distinct mechanisms of action

“Currently, healthcare professionals only have a handful of MOAs to choose from when treating epilepsy, and patients who do not respond to or tolerate an ASM with a specific MOA may be less likely to benefit from others with a similar MOA. Therefore, it is imperative that different MOAs be introduced to the treatment armamentarium to give more people living with epilepsy the opportunity to achieve seizure control.” (opens the source at this quote in a new tab)

Comparison with ezogabine: potency and daily dose

“azetukalner was estimated to be approximately 50 times more potent than ezogabine” (opens the source at this quote in a new tab)

Comparison with retigabine: daily dose and metabolic burden

“This is evident in the contrasting profiles of retigabine (600–1200 mg/day) and azetukalner (25 mg/day), where the significantly lower dose of azetukalner may reduce the burden on detoxification pathways.” (opens the source at this quote in a new tab)

Comparison with ezogabine: dosing schedule and tolerability limits of the predecessor

“Ezogabine was approved for the treatment of focal seizures in 2011 but, because of the risk of pigmentary changes affecting the retina and the skin, and the consequent need for intensive ophthalmological monitoring, it was never used widely.” (opens the source at this quote in a new tab)
“One factor that probably contributed to ezogabine suboptimal tolerability was its short half-life, which results in considerable fluctuations in serum drug concentrations at steady state. The need for a t.i.d. regimen limited its acceptability in the clinical setting, and retention on treatment was generally lower than that reported for other second-generation ASMs” (opens the source at this quote in a new tab)

Comparison with retigabine: metabolic stability and brain penetration

“This structural analog of retigabine exhibits improved metabolic stability, increased potency, and enhanced blood–brain barrier penetration compared with its predecessor.” (opens the source at this quote in a new tab)

Comparison with currently marketed antiseizure medications: confusional state

“The most frequent TEAEs (dizziness, balance disorder, dysarthria, and gait disturbance) were related to the central nervous system and were similar to those associated with other commonly used ASMs. Some of these TEAEs were dose related and occurred at the highest dose. The adverse event of confusional state occurred at an overall rate of 4.7% in the treated group, which was 3.8% higher than placebo. These rates are similar to the frequencies of the rates observed in placebo-controlled phase 3 trials of lacosamide and oxcarbazepine, and less than the rates in trials of eslicarbazepine, pregabalin, perampanel, and topiramate.” (opens the source at this quote in a new tab)

Mechanistic position relative to the available treatment armamentarium

“Despite a large number of approved epilepsy treatments, there are only a handful of distinct mechanisms of action available, and the data from X-TOLE2 reinforce the value that azetukalner and its KV7 mechanism may bring to the treatment armamentarium for focal seizures” (opens the source at this quote in a new tab)

Comparison with other potassium channel modulators in development

“Related developments include BHV-7000 (BNP-25203), a KV7.2/7.3 modulator in phase II/III for both KCNQ2-DEE (precision use) and focal epilepsy; XEN496, a pediatric retigabine formulation repurposed as precision therapy for KCNQ2-DEE; and AUT-00206, a KV3.1/3.2 modulator in phase II for fragile X syndrome that enhances cortical network synchronization consistent with restored parvalbumin-interneuron function” (opens the source at this quote in a new tab)

Direct comparison with another active antiseizure medication

No evidence found.

Operational definition of epilepsy

“Seizures are defined as transient symptoms and signs due to abnormal excessive or simultaneous neuronal activity of a population of neuronal cells in the brain.” (opens the source at this quote in a new tab)
“The diagnosis of epilepsy requires at least two unprovoked seizures occurring greater than twenty-four hours apart.” (opens the source at this quote in a new tab)
“Therefore, the definition of epilepsy has been revised and expanded from having two or more unprovoked seizures more than twenty-four hours apart to including those with one seizure and a high likelihood (more than 60%) of having another” (opens the source at this quote in a new tab)
“More than 60% was taken because it is the lower limit of the confidence interval for the individual with two unprovoked seizures having another seizure” (opens the source at this quote in a new tab)

Resolved epilepsy

“It is said to be resolved after ten years of the seizure-free period with the last five years spent without medications, or the patient is no longer at risk for age-related epilepsy syndrome” (opens the source at this quote in a new tab)

Definition of focal seizures and the seizure classes

“Focal seizures are defined as originating within networks limited to one hemisphere.” (opens the source at this quote in a new tab)
“They may be discretely localized or more widely distributed and may originate in cortical or subcortical structures.” (opens the source at this quote in a new tab)
“The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified.” (opens the source at this quote in a new tab)
“This updated classification comprises four main classes and 21 seizure types.” (opens the source at this quote in a new tab)

Definition of drug-resistant epilepsy

“Failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication (ASM) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (opens the source at this quote in a new tab)
“The number of people for whom treatment fails to control their seizures remains at about 30%” (opens the source at this quote in a new tab)

Predictors of drug resistance and its association with focal epilepsy

“Some syndromes respond better to medication, e.g. the idiopathic generalized epilepsies or the childhood onset self-limited epilepsies which are less associated with resistance than the focal epilepsies or most of the DEEs.” (opens the source at this quote in a new tab)
“The two most robust epidemiological predictors of resistance are the number of previous ASMs tried (irrespective of the class of medication) and the number of seizures prior to starting medication, which is more likely a measure of disease severity rather than seizures influencing drug response.” (opens the source at this quote in a new tab)

Etiologic categories

“Etiology (structural, genetic, metabolic, infectious, immune, unknown)” (opens the source at this quote in a new tab)

Age distribution of etiologies

“Epilepsy incidence has a bimodal age distribution with the highest risk in infants (genetic, metabolic, and obstetrical causes) and older people (higher risk for stroke and neurodegenerative diseases)” (opens the source at this quote in a new tab)

Incidence of focal compared with generalized seizures

“Focal seizures are more common than generalized seizures.” (opens the source at this quote in a new tab)
“The median focal seizure incidence rate is 30.4 per 100,000 per year, compared to 19.6 per 100,000 per year for generalized seizures” (opens the source at this quote in a new tab)
“The most common type of focal seizures are focal impaired awareness seizures, accounting for approximately a third of all cases” (opens the source at this quote in a new tab)

Estimated incidence of epilepsy among European adults

“Epilepsy has an unequal distribution” (opens the source at this quote in a new tab)
“Based on the age-specific incidence rates in European studies, the estimated number of new cases per year among European adults aged 20−64 is 960,000 (incidence rate 30 per 100,000) and 85,000 in the ≥ 65 years population (incidence 100 per 100,000)” (opens the source at this quote in a new tab)

Proportion of the epilepsy population with focal epilepsy

“Focal epilepsy comprises about 55.7–61.1% of the overall epilepsy patient population.” (opens the source at this quote in a new tab)

United States prevalence of active epilepsy, 2015

“In 2015, 1.2% of the U.S. population (3.4 million persons: 3 million adults and 470,000 children) reported active epilepsy (self-reported doctor-diagnosed epilepsy and under treatment or with recent seizures within 12 months of interview) or current epilepsy (parent-reported doctor-diagnosed epilepsy and current epilepsy).” (opens the source at this quote in a new tab)

United States prevalence of active epilepsy among adults, 2021

“In 2021, 1.1% of U.S. adults, (approximately 2,865,000 adults) reported active epilepsy” (opens the source at this quote in a new tab)

Current national estimates of active epilepsy

“CDC estimates that about 2.9 million U.S. adults had active epilepsy” (opens the source at this quote in a new tab)
“An estimated 456,000 U.S. children 17 or younger had active epilepsy in 2022” (opens the source at this quote in a new tab)

Treated prevalence of epilepsy and seizures in the United States, 2010 to 2018

“Treated prevalence was .38% (95% confidence interval [CI] = .34–.41) for epilepsy, .76% (95% CI = .71–.81) for seizure, and 1.14% (95% CI = 1.08–1.20) for epilepsy or seizure.” (opens the source at this quote in a new tab)

Global prevalence of active epilepsy

“In 2016, there were 45·9 million (95% UI 39·9–54·6) patients with all-active epilepsy (both idiopathic and secondary epilepsy globally; age-standardised prevalence 621·5 per 100 000 population; 540·1–737·0).” (opens the source at this quote in a new tab)
“Prevalence of active epilepsy increased with age, with peaks at 5–9 years (374·8 [280·1–490·0]) and at older than 80 years of age (545·1 [444·2–652·0]).” (opens the source at this quote in a new tab)

Proportion of prevalent epilepsy that is focal

“The prevalence of focal epilepsy was 3.70 per 1000, accounting for 61% of epilepsy” (opens the source at this quote in a new tab)
“Overall, estimates in 2016 for France, Germany, Italy, Spain, and the UK show that two-thirds of people with epilepsy had focal seizures, equating to over 1.3 million people” (opens the source at this quote in a new tab)

Proportion of people with epilepsy who are drug resistant

“approximately 40% of people with epilepsy are drug-resistant, further increasing the risks associated with epilepsy” (opens the source at this quote in a new tab)

Persistent seizures among United States adults with focal epilepsy

“The proportion of patients with persistent seizures (>1 per year) among AED users was higher in the U.S. (66.4%) than the 5EU (53.0%) and Brazil + 5EU (52.3%) datasets” (opens the source at this quote in a new tab)

Standardized mortality ratios in epilepsy

“All of these nine showed significant elevations of their SMRs ranging from 1.6 to 3.0.” (opens the source at this quote in a new tab)
“Among six of these population-based studies representing incidence cohorts including all ages, the weighted median SMR was 2.3.” (opens the source at this quote in a new tab)
“Standard mortality ratios are especially high among people with epilepsy aged <50 years, among those whose epilepsy is categorized as structural/metabolic, those whose seizures do not fully remit under treatment, and those with convulsive seizures.” (opens the source at this quote in a new tab)
“Among deaths directly attributable to epilepsy or seizures, important immediate causes include sudden unexpected death in epilepsy (SUDEP), status epilepticus, unintentional injuries, and suicide.” (opens the source at this quote in a new tab)

Incidence of sudden unexpected death in epilepsy

“SUDEP risk in children with epilepsy (aged 0–17 years) is 0.22/1,000 patient-years (95% CI 0.16–0.31) (high confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64–2.32) (low confidence in evidence).” (opens the source at this quote in a new tab)
“The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence).” (opens the source at this quote in a new tab)
“Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected.” (opens the source at this quote in a new tab)
“Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.” (opens the source at this quote in a new tab)

Sudden unexpected death in epilepsy in treatment-resistant populations

“Nine clinic-based studies, mainly representing people with treatment-resistant epilepsy, yielded higher estimates of SUDEP occurrence, ranging from 1.2 to 6.3 cases of SUDEP annually per 1,000 individuals.” (opens the source at this quote in a new tab)

Mortality by seizure control status in drug-resistant focal epilepsy

“An Austrian study found that the standardized mortality ratio for those not seizure free was 3.3 (95% CI 2.6−4.4) compared to 1.4 (95% CI 0.8−2.3) for those seizure free 2 years after diagnosis” (opens the source at this quote in a new tab)
“Clinic-based studies report an estimate of SUDEP in people with drug-resistant focal epilepsy of up to 6.3 per 1000 people” (opens the source at this quote in a new tab)
“People with epilepsy are at a 27-fold higher risk of sudden death than controls, but this falls to a 16-fold risk when adjusted for sex, comorbidities, and the Charlson comorbidity score” (opens the source at this quote in a new tab)

Seizure-related injury, drowning, and suicide

“An observational study of people with epilepsy and convulsive seizures found that ∼60% of the population experienced at least one accidental injury associated with convulsions over 12 months; common injuries in this population included head injuries (35.5%), dental injuries (4.9%), and burns (4.9%)” (opens the source at this quote in a new tab)
“The risk of drowning is also higher in people with epilepsy, with an estimated relative risk ranging from 13- to 19-fold” (opens the source at this quote in a new tab)
“Attempted and completed suicides are estimated to occur in 5−14.3% of people with epilepsy” (opens the source at this quote in a new tab)
“the suicide-specific standardized mortality ratio among those with epilepsy is estimated to be 3.3 (95% CI: 2.8−3.7)” (opens the source at this quote in a new tab)

Global mortality attributable to idiopathic epilepsy

“Global age-standardised mortality rates of idiopathic epilepsy were 1·74 per 100 000 population (1·64–1·87; 1·40 per 100 000 population [1·23–1·54] for women and 2·09 per 100 000 population [1·96–2·25] for men).” (opens the source at this quote in a new tab)

Neuronal hyperexcitability and epileptogenesis

“Epilepsy represents a condition in which abnormal neuronal discharges or the hyperexcitability of neurons occur with synchronicity, presenting a significant public health challenge.” (opens the source at this quote in a new tab)
“This transformation presupposes the hyperexcitability of neuron groups, which become prone to discharge abnormally” (opens the source at this quote in a new tab)

Epileptiform synchronization in focal epileptic disorders

“Intracellular recordings from neurons located in these foci demonstrated that interictal events were associated with paroxysmal depolarizing shifts (PDSs) of the neuron membrane potential causing bursts of action potential firing followed by a hyperpolarization” (opens the source at this quote in a new tab)
“These findings provide insights into the mechanisms of seizure initiation and maintenance, thus leading to the development of specific pharmacological treatments for focal epileptic disorders.” (opens the source at this quote in a new tab)

Excitatory signaling in temporal lobe seizure generation

“In contrast to NMDA receptors, which contribute but are not indispensable for seizure generation, AMPA receptors appear to be a key component to triggering seizures.” (opens the source at this quote in a new tab)

KV7 channels and the M-current in the control of neuronal excitability

“Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current.” (opens the source at this quote in a new tab)
“Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons.” (opens the source at this quote in a new tab)
“Kv7 channels locate to key areas for the control of action potential initiation and propagation.” (opens the source at this quote in a new tab)
“Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits.” (opens the source at this quote in a new tab)

Role and yield of routine electroencephalography

“The electroencephalogram (EEG) is the most direct measure of electrical brain activity and the most specific test for the evaluation of epilepsy” (opens the source at this quote in a new tab)
“Patients most commonly receive a 20 min routine EEG recorded from 19 scalp electrodes placed according to the 10–20 electrode placement.” (opens the source at this quote in a new tab)
“Studies show that the initial routine EEG fails to record IEDs in approximately 47–50% of epileptic patients.” (opens the source at this quote in a new tab)
“To improve the yield of EEG, subsequent EEG recording should include sleep deprivation, sleep recording, prolonged hyperventilation, optimized light stimulation, addition of an inferior temporal electrode chain, extended EEG duration, and continuous video-EEG monitoring, all measures known to activate IEDs.” (opens the source at this quote in a new tab)

Role of magnetic resonance imaging

“Similarly, magnetic resonance imaging (MRI) has become the gold standard imaging technique for identifying epileptogenic structural brain abnormalities.” (opens the source at this quote in a new tab)

Classification of focal seizures by state of consciousness

“Focal seizures and those of unknown origin are further classified by the patient’s state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness.” (opens the source at this quote in a new tab)
“If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin).” (opens the source at this quote in a new tab)
“Consciousness is used as a classifier instead of awareness, with consciousness operationally defined by awareness and responsiveness.” (opens the source at this quote in a new tab)

Consistency of ictal onset in focal seizures

“For each seizure type, ictal onset is consistent from one seizure to another, with preferential propagation patterns that may involve the contralateral hemisphere.” (opens the source at this quote in a new tab)

Review of the diagnosis when seizures continue

“Review the diagnosis of epilepsy if seizures continue despite an optimal dose of a first-line antiseizure medication.” (opens the source at this quote in a new tab)

Assessments that trigger referral to a tertiary epilepsy service

“further assessment and treatment approaches are indicated, such as: video electroencephalogram (EEG) telemetry, neuropsychology or neuropsychiatry, specialised neuroimaging, specialised treatments (for example, medication that can only be prescribed by a tertiary epilepsy service or a ketogenic diet), epilepsy surgery or vagus nerve stimulation” (opens the source at this quote in a new tab)

Investigations used to classify seizure type and epilepsy type

“Classification of seizure type and epilepsy type both take into account the results of investigations such as electroencephalography (EEG) and neuroimaging studies together with other studies exploring the underlying etiology of the epilepsy.” (opens the source at this quote in a new tab)

Seizure semiology: focal aware and focal impaired awareness seizures

“Temporal lobe epilepsy (TLE) is the commonest form of focal epilepsy and represents almost 2/3 of cases of intractable epilepsy managed surgically.” (opens the source at this quote in a new tab)
“Seizure auras occur in many TLE patients and often exhibit features that are relatively specific for TLE but few are of lateralizing value.” (opens the source at this quote in a new tab)
“Automatisms represent coordinated involuntary motor activity that is stereotyped and virtually always accompanied by altered consciousness and subsequent amnesia.” (opens the source at this quote in a new tab)
“Automatisms occur in almost two thirds of CPSs of mesial temporal lobe onset” (opens the source at this quote in a new tab)

Seizure semiology: focal to bilateral tonic-clonic seizures

“focal seizures in which the ictal activity propagates to both hemispheres, while the semiology evolves to impairment and eventually complete loss of consciousness and bilateral tonic muscle activation” (opens the source at this quote in a new tab)

Seizure semiology: ictal and postictal amnesia

“Individuals with CPSs may be unaware that they had a seizure minutes earlier. They may also be unable to recall events which occurred before seizure onset. The degree of retrograde and anterograde amnesia is variable.” (opens the source at this quote in a new tab)
“Postictal amnesia likely results from bilateral impairment of hippocampal function.” (opens the source at this quote in a new tab)

Cognitive symptoms: memory, executive function, and language impairment

“The proportion with generalized cognitive impairment, another unexpected phenotype for a focal epilepsy, ranged from 15–44% (mean 29%), and the remaining individuals exhibited more focal cognitive patterns, involving reduced executive function and/or speed, and memory and/or language impairments” (opens the source at this quote in a new tab)

Cognitive symptoms: effect of seizures and medication on learning and memory

“Aside from severe learning disabilities, epilepsy can impact learning through memory impairment. Seizures can reduce alertness and interfere with short-term information storage. Frequent uncontrolled or night-time seizures can impair new information learning, disrupt memory consolidation, and affect language function” (opens the source at this quote in a new tab)
“Cognitive impairments, such as learning difficulties, behavior change, and memory impairment, can be induced or exacerbated by ASMs, particularly those with impaired cognition, depending on dose and individual susceptibility” (opens the source at this quote in a new tab)

Psychiatric symptoms: mood and anxiety disorders in newly diagnosed focal epilepsy

“A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts.” (opens the source at this quote in a new tab)
“Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%).” (opens the source at this quote in a new tab)
“In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy.” (opens the source at this quote in a new tab)

Psychiatric symptoms: pooled prevalence of depression in epilepsy

“Nine studies reported on 29,891 PWE who had an overall prevalence of active (current or past-year) depression of 23.1% (95% confidence interval [CI] 20.6%–28.31%).” (opens the source at this quote in a new tab)
“Five of the 14 studies reported on 1,217,024 participants with an overall OR of active depression of 2.77 (95% CI 2.09–3.67) in PWE.” (opens the source at this quote in a new tab)

Psychiatric symptoms: other psychiatric comorbidity

“The most prevalent psychiatric comorbidities are depression (23.1%) and anxiety (20.2%)” (opens the source at this quote in a new tab)
“People with epilepsy may also present with alcohol abuse (8.7%), drug abuse (7.8%), and interictal psychosis (5.2%)” (opens the source at this quote in a new tab)

Comorbidity burden in adults with active epilepsy

“Approximately 50% of adults with active epilepsy have one or more comorbid conditions, with several conditions, such as depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis being eight times more common in people with epilepsy compared to the general population” (opens the source at this quote in a new tab)
“Among people with intellectual disability, approximately one in five will also have epilepsy, with prevalence increasing with increasing severity of the intellectual disability” (opens the source at this quote in a new tab)

Accelerated brain ageing and cognitive decline in drug-resistant epilepsy

“A study found that people with DRE presented a difference between predicted brain age and chronological age that was on average 4.5 years older than healthy controls” (opens the source at this quote in a new tab)
“DRE is related to cognitive decline, and this phenomenon has been conceptualized as accelerated cognitive ageing” (opens the source at this quote in a new tab)

Seizure-related injury in refractory focal epilepsy

“Another US study found that hospitalization and pharmacy costs in people with focal seizures were twice as high in the refractory cohort versus the nonrefractory cohort. This was mainly due to the higher prevalence of injuries, including fractures, sprains and strains, and wounds” (opens the source at this quote in a new tab)
“People may injure themselves during a seizure resulting in fractures, head injury, sprains, and open wounds” (opens the source at this quote in a new tab)

Employment and unemployment

“Unemployment and underemployment are markedly more common in PwE compared with the general population.” (opens the source at this quote in a new tab)
“Unemployment rates range from similar to twice or three times the rates of the general population, depending on the countries and years examined.” (opens the source at this quote in a new tab)
“Developing specific legislation and programs to include PwE in the workplace could help their social integration.” (opens the source at this quote in a new tab)

Unemployment in drug-resistant focal seizures

“Among people with drug-resistant focal seizures in Europe, high unemployment rates have been shown compared to a matched control population (46% vs. 19%)” (opens the source at this quote in a new tab)
“Productivity loss and unemployment among people with epilepsy are the primary sources of the individual and societal burden” (opens the source at this quote in a new tab)

Driving restrictions

“This consensus statement recommends that in order to be able to drive PWE should have a SFI of at least 3 months, but PWE with focal aware seizures, consistent and prolonged auras, or nocturnal seizures may still drive on a case-by-case basis.” (opens the source at this quote in a new tab)
“Due to unique state laws and variable physician awareness regarding these, patients may receive the wrong advice regarding driving.” (opens the source at this quote in a new tab)

Instruments used to measure health-related quality of life in focal epilepsy

“Ten instruments evaluating HRQOL in people with focal epilepsy were identified, of which four were epilepsy-specific” (opens the source at this quote in a new tab)
“HRQOL was also worse, often significantly so, in people with epilepsy and psychiatric disorders, particularly depression, than in those without psychiatric disorders.” (opens the source at this quote in a new tab)

Quality of life by treatment response in focal epilepsy

Population	Quoted mean QOLIE-31-P total score with standard deviation
Focal epilepsy, drug resistant (n = 184)	“56.4 (18.7)”
Focal epilepsy, drug responsive (n = 53)	“70.8 (13.3)”
Comparison of the two groups	“<0.0001”

Stigma

“Almost one quarter (23.8%) of people with epilepsy reported having felt enacted stigma” (opens the source at this quote in a new tab)
“Stigma was associated with family and social support and employment; with increasing perceptions of stigma associated with worse family functioning or unemployment/low employability.” (opens the source at this quote in a new tab)
“Perceived stigma was experienced similarly by both people with epilepsy and their caregivers.” (opens the source at this quote in a new tab)

Seizure freedom and quality of life

“People seizure-free for more than 1 year have a significantly higher preference-based HRQoL than those in any other seizure frequency group.” (opens the source at this quote in a new tab)
“Further differentiation of QoL at higher response levels has been reported, with people achieving high response rates (particularly ≥90%) exhibiting higher QoL than people with ≤50% response rates” (opens the source at this quote in a new tab)
“This suggests that for a significant QoL improvement, seizure freedom must be attained and maintained” (opens the source at this quote in a new tab)

Determinants of reduced quality of life

“Some risk factors for reduced QoL have been identified, including frequent seizures, longer seizure duration, convulsions, and earlier age of onset” (opens the source at this quote in a new tab)
“Other factors affecting QoL include ASM side effects, depression or anxiety, lack of social support, stigma, and employment concerns” (opens the source at this quote in a new tab)
“Adults with epilepsy are likely to report more mentally and physically unhealthy days per month than those without epilepsy, with the highest rates in those with seizures in the past 3 months” (opens the source at this quote in a new tab)

Health utilities by seizure frequency in United States adults with focal epilepsy

Seizure frequency group, United States, unadjusted	Quoted mean SF-6D health utility with standard deviation
Total sample (n = 345)	“0.67 ± 0.14”
At least once a week (n = 55)	“0.63 ± 0.14”
One to three times a month (n = 68)	“0.65 ± 0.15”
One to four times a year (n = 71)	“0.67 ± 0.13”
Less than once a year (n = 151)	“0.70 ± 0.14”
p value for relationship to seizure frequency	“0.006”

United States aggregate spending attributable to epilepsy and seizures

“The difference in annual spending for cases compared to controls was $4580 (95% CI = $3362–$5798) for epilepsy, $7935 (95% CI, $6237–$9634) for seizure, and $6853 (95% CI = $5623–$8084) for epilepsy or seizure, translating into aggregate costs of $5.4 billion, $19.0 billion, and $24.5 billion.” (opens the source at this quote in a new tab)
“From 2010 to 2018, the annual growth rate in total spending incurred for seizures and/or epilepsies was 7.6% compared to 3.6% among controls.” (opens the source at this quote in a new tab)
“US economic burden of seizures and/or epilepsies is substantial and warrants interventions focused on their unique and overlapping causes.” (opens the source at this quote in a new tab)

United States spending for adults with epilepsy, 2016 to 2022

“An estimated 6.6 million adults had unclassified seizures, with annual healthcare spending totaling $38.9 billion, substantially more than $21.3 billion for 4.5 million adults with epilepsy.” (opens the source at this quote in a new tab)
“Adults with unclassified seizures and epilepsy represent a high-need population with great healthcare use and costs.” (opens the source at this quote in a new tab)

Cost of discrete epilepsy-related health care encounters in the United States

“More than 160,000 epilepsy-related emergency transportations, 225,000 emergency department (ED) visits, 49,000 hospitalizations, 700 urgent care visits, and ~2.5 million office visits were analyzed.” (opens the source at this quote in a new tab)
“37.4% of epilepsy-related hospitalizations included care in the intensive care unit (ICU).” (opens the source at this quote in a new tab)
“In commercially insured patients, epilepsy-related health care encounters had median health plan-paid costs of $22,305 (Q1-Q3 = $14,336–$36,096, hospitalization); $3,375 ($565–$9,095, ICU visit); $1,913 ($417–$4,163, ED visit); $687 ($415–$1,083, emergency transportation); $95 ($23–$232, office visit); and $57 ($0–$171, urgent care visit).” (opens the source at this quote in a new tab)

Direct costs by seizure frequency in United States adults with focal epilepsy

Seizure frequency group, United States, adjusted least-squares means	Quoted total direct costs in dollars with confidence interval
At least one seizure per week	“43,708 (28,420, 67,219)”
One to three seizures per month	“28,978 (19,665, 42,701)”
One to four seizures per year	“20,943 (14,497, 30,257)”
Less than one seizure per year	“18,600 (14,319, 24,162)”
Overall p value	“0.0008”

Association of seizure frequency with resource utilization in the United States

“In the United States, seizure frequency was associated with hospitalizations, indirect costs (ages 18–60), and total direct costs.” (opens the source at this quote in a new tab)
“The results support the hypothesis that reducing seizures can improve productivity and reduce resource utilization and associated costs.” (opens the source at this quote in a new tab)

Incremental utilization and cost of uncontrolled and drug-resistant epilepsy

“a US-based study estimated the odds of epilepsy-related hospitalization (OR: 2.2) and epilepsy-related emergency department visits (OR: 1.9) to be more significant for people with uncontrolled epilepsy; epilepsy-related costs were found to be ∼$6890/case/year higher for DRE” (opens the source at this quote in a new tab)
“The cost of epilepsy depends on seizure severity, frequency, and drug refractoriness (20% to 40% of people with drug-refractory epilepsy account for 80% of the costs).” (opens the source at this quote in a new tab)
“DRE incurs significantly higher resource utilization and costs than controlled epilepsy” (opens the source at this quote in a new tab)

Overall direct cost of epilepsy in the United States

“The direct costs of epilepsy have been estimated to be high (approximately $28 billion per year).” (opens the source at this quote in a new tab)

Caregiver health care costs and absenteeism in focal onset seizures

“Sick days were significantly lower in the monotherapy cohort (2.4 days vs 4.4 days annually; P <.0001), with an associated cost difference of $541.” (opens the source at this quote in a new tab)
“Caregivers of patients with partial-onset seizures in the adjunctive therapy cohort had significantly greater medical and sick day costs than caregivers in the monotherapy cohort.” (opens the source at this quote in a new tab)
“These findings suggest that higher treatment burden among patients with epilepsy is associated with greater direct and indirect healthcare costs for their caregivers.” (opens the source at this quote in a new tab)

Caregiver work loss by treatment regimen

“A 2018 study found that caregivers of people on monotherapy had an average of 2.7 days of work lost annually due to sick leave and short-term disability. In contrast, the caregivers to those on adjunctive therapy had an average of 5.1 days of work lost annually due to the same reasons” (opens the source at this quote in a new tab)
“Sick leave in caregivers of those on monotherapy was associated with average costs of $582; whereas, in the adjunctive therapy caregivers group, this increased to $1123.” (opens the source at this quote in a new tab)

Caregiving time and caregiver distress

“In a 2014 study in which 92% of people had focal seizures, a higher caregiver burden was associated with the individuals taking a higher number of ASMs, lower neuropsychological performance, lower QoL score, and lower caregiver education level.” (opens the source at this quote in a new tab)
“On average, 11.4 (±21.2) h were spent on care per week, with the majority (58.3%) of caregivers being a spouse/partner” (opens the source at this quote in a new tab)
“Caregivers of adults with epilepsy experience extreme psychological distress and poor QoL” (opens the source at this quote in a new tab)
“The results suggest that 72% of caregivers strongly agree that they fear another seizure, irrespective of when the last episode was.” (opens the source at this quote in a new tab)

Caregiver productivity loss and health-related quality of life

“Caregivers similarly reported high productivity loss and absenteeism related to caregiving duties.” (opens the source at this quote in a new tab)
“In another international cross-sectional study of caregivers of adults with uncontrolled drug-resistant focal-onset seizures, caregivers reported the greatest problems (moderate, severe, or extreme problems) in anxiety/depression (44% of caregivers) and pain/discomfort (40%).” (opens the source at this quote in a new tab)

Comparative cost of ambulatory electroencephalography and inpatient video-electroencephalography monitoring

“In a large retrospective cohort study of 13,958 patients, outpatient AEEG cost was significantly lower compared to inpatient VEM monitoring.” (opens the source at this quote in a new tab)
“These findings were similar to original economic models which indicated that AEEG was up to 66% cheaper than inpatient VEM” (opens the source at this quote in a new tab)
“Since January 1, 2020, in the United States, reimbursement for long-term inpatient EEG monitoring modified the fee structure for VEM and AEEG reimbursement for professional and technical components” (opens the source at this quote in a new tab)

Health care utilization before and after seizure monitoring unit admission, Canadian cohort

“A total of 315 of 600 (53%) patients met eligibility criteria. Mean age was 40 years (SD = 17.4), 176 (56%) were female, 220 (70%) had focal epilepsy, and 60 (19%) had functional seizures or physiologic seizure mimics without epilepsy as adjudicated by the attending physician at the point of discharge.” (opens the source at this quote in a new tab)
“Admission to an SMU is associated with significant and enduring declines in HCU.” (opens the source at this quote in a new tab)

Diagnostic uncertainty as a cost driver

“These findings highlight the impact of diagnostic uncertainty and care fragmentation, suggesting that improved identification and healthcare coordination could enhance outcomes and reduce inefficiencies.” (opens the source at this quote in a new tab)

First-line monotherapy for focal seizures

“Consider lamotrigine or levetiracetam as first-line monotherapy for people with focal seizures. If the first choice is unsuccessful, consider the other of these options.” (opens the source at this quote in a new tab)

Second-line and third-line monotherapy

“They agreed that if these treatments were unsuccessful, carbamazepine, oxcarbazepine or zonisamide could be considered for second-line monotherapy. The evidence was weaker for lacosamide, so this was included as a third-line option.” (opens the source at this quote in a new tab)
“If second-line monotherapies tried are unsuccessful in people with focal seizures, consider lacosamide as third-line monotherapy.” (opens the source at this quote in a new tab)

Comparative retention and tolerability evidence

“The evidence showed that lamotrigine and levetiracetam were continued for longer than other drugs for treating focal epilepsy, suggesting that they may be more effective and better tolerated. However, the evidence also suggested they were not more effective than other drugs in terms of remission at 6 and 12 months, and the evidence for time to first seizure suggested they were less effective than carbamazepine.” (opens the source at this quote in a new tab)

Initial monotherapy in new-onset adult focal epilepsy

“Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy.” (opens the source at this quote in a new tab)
“LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years with new-onset focal epilepsy.” (opens the source at this quote in a new tab)

Adjunctive sodium channel blockers in treatment-resistant focal epilepsy

“Lacosamide, eslicarbazepine, and extended-release topiramate use should also be considered to decrease seizure frequency in this population (Level B).” (opens the source at this quote in a new tab)
“Eslicarbazepine use may be considered to decrease seizure frequency as monotherapy for TRAFE (Level C).” (opens the source at this quote in a new tab)

Evidence levels for initial monotherapy for adult focal seizures

“Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures.” (opens the source at this quote in a new tab)
“Selection of the initial AED therapy for a person with newly diagnosed or untreated seizures requires integration of evidence and expert opinion for the patient-specific, AED-specific, and nation-specific variables that can impact overall response to therapy.” (opens the source at this quote in a new tab)

Lamotrigine compared with levetiracetam and zonisamide in newly diagnosed focal epilepsy

“Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47)” (opens the source at this quote in a new tab)
“These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy.” (opens the source at this quote in a new tab)
“Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials.” (opens the source at this quote in a new tab)
“Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide.” (opens the source at this quote in a new tab)

Mechanistic basis of the sodium channel blocking class

“Classical ASMs such as phenytoin, carbamazepine, oxcarbazepine (OXC), and lamotrigine preferentially bind to sodium channels in the inactivated state.” (opens the source at this quote in a new tab)
“Enhancement of slow inactivation of sodium channels by newer ASMs, such as lacosamide (LCM) and eslicarbazepine acetate (ESL), represents an innovative mechanism distinguishing them from classical VGSC blockers” (opens the source at this quote in a new tab)

Adjunctive lacosamide: pooled efficacy and withdrawal

“The RR for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.79 (95% CI 1.55 to 2.08; 5 studies; 2199 participants; high-certainty evidence).” (opens the source at this quote in a new tab)
“The RR for seizure freedom for all doses of lacosamide compared with placebo was 2.27 (95% CI 1.35 to 3.83; 5 studies; 2199 participants; low-certainty evidence).” (opens the source at this quote in a new tab)
“The RR for treatment withdrawal for all doses of lacosamide compared with placebo was 1.57 (95% CI 1.24 to 1.98; 5 studies; 2199 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)

Adjunctive lacosamide: pivotal trial

“Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention-to-treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT).” (opens the source at this quote in a new tab)

Adjunctive lacosamide: seizure freedom in pooled trials

“A total of 2.7%, 3.3% and 4.8% of patients completing the Maintenance Phase in the lacosamide 200, 400 and 600 mg/day groups, respectively, experienced no seizures throughout the entire Maintenance Phase (placebo group = 0.9%).” (opens the source at this quote in a new tab)

Adjunctive eslicarbazepine acetate: pooled efficacy

“For adults, the RR was 1.71 (95% CI 1.42 to 2.05; 5 studies, 1799 participants; moderate-certainty evidence)” (opens the source at this quote in a new tab)
“ESL was associated with seizure freedom (RR 3.16, 95% CI 1.73 to 5.78; 6 studies, 1922 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“ESL reduces seizure frequency when used as an add-on treatment for adults with drug-resistant focal epilepsy.” (opens the source at this quote in a new tab)

Adjunctive eslicarbazepine acetate: pivotal trial responder rate

“Responder rate (≥50% reduction in SSF) was significantly higher with ESL 1,200 mg (42.6%, p < 0.001) but not ESL 800 mg (30.5%, p = 0.07) than placebo (23.1%).” (opens the source at this quote in a new tab)
“The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia.” (opens the source at this quote in a new tab)

Adjunctive oxcarbazepine: pooled efficacy

“Oxcarbazepine may increase the responder rate for 50% or greater reduction in seizure frequency compared to control treatment (RR 1.80, 95% CI 1.27 to 2.56; random-effects model; 6 studies; low-certainty evidence).” (opens the source at this quote in a new tab)
“Treatment with oxcarbazepine was associated with an increased treatment withdrawal rate compared to control (RR 1.75, 95% CI 1.44 to 2.13; fixed-effect model; 6 studies; moderate-certainty evidence).” (opens the source at this quote in a new tab)

Adjunctive lamotrigine: pooled efficacy

“The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 trials, 1322 participants (adults and children); moderate-certainty evidence)” (opens the source at this quote in a new tab)
“Lamotrigine as an add-on treatment for drug-resistant focal seizures appears to be effective in reducing seizure frequency, and seems to be fairly well-tolerated.” (opens the source at this quote in a new tab)

Levetiracetam as a first-line monotherapy option

“The committee agreed that lamotrigine and levetiracetam should be considered as first-line monotherapy options, and this was supported by economic modelling.” (opens the source at this quote in a new tab)

Mechanistic basis of the SV2A ligand class

“Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), whereas pregabalin and gabapentin are selective ligands for the α2δ1 subunits of the voltage-gated calcium channels.” (opens the source at this quote in a new tab)

Adjunctive levetiracetam: pooled efficacy and dose response

“RR was significantly in favour of levetiracetam compared to placebo when results were pooled across all doses (RR 2.37, 95% CI 2.02 to 2.78; 14 studies, 2455 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“Dose–response analysis demonstrated that the odds of achieving response (50% or greater reduction in seizure frequency) were increased by nearly 40% (odds ratio (OR) 1.39, 95% CI 1.23 to 1.58) for each 1000 mg increase in dose of levetiracetam.” (opens the source at this quote in a new tab)

Adjunctive levetiracetam: pivotal placebo-controlled trial

“Of 199 patients receiving levetiracetam, 11 became seizure free; no patient became seizure free in the placebo group.” (opens the source at this quote in a new tab)

Adjunctive levetiracetam: European multicentre trial

“A reduction in seizure frequency of > or =50% occurred in 22.8% of patients in the 1,000-mg group and 31.6% of patients in the 2,000-mg group, compared with 10.4% of patients in the placebo group.” (opens the source at this quote in a new tab)

Adjunctive brivaracetam: pooled efficacy and withdrawal

“Participants receiving brivaracetam add-on were more likely to experience a 50% or greater reduction in seizure frequency than those receiving placebo (RR 1.81, 95% CI 1.53 to 2.14; 6 studies; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“Participants receiving brivaracetam were more likely to attain seizure freedom; however, the evidence is of low certainty (RR 5.89, 95% CI 2.30 to 15.13; 6 studies).” (opens the source at this quote in a new tab)
“However, participants receiving brivaracetam did appear to be more likely to withdraw from treatment due to adverse events compared with those receiving placebo (RR 1.54, 95% CI 1.02 to 2.33; 6 studies; low-certainty evidence).” (opens the source at this quote in a new tab)

Adjunctive brivaracetam: phase 3 trial

“Percent reduction over PBO in 28-day adjusted seizure frequency (95% confidence interval [CI]) was 22.8% for BRV 100 mg/day (13.3-31.2%; p < 0.001) and 23.2% for BRV 200 mg/day (13.8-31.6%; p < 0.001).” (opens the source at this quote in a new tab)
“The ≥ 50% responder rate (odds ratio vs. PBO; 95% CI) was 21.6% for PBO, 38.9% for BRV 100 mg/day (2.39; 1.6-3.6; p < 0.001), and 37.8% for BRV 200 mg/day (2.19; 1.5-3.3; p < 0.001).” (opens the source at this quote in a new tab)

Adjunctive brivaracetam: pooled phase 3 analysis

“The ≥50% responder rate was 34.2% (50 mg/d, p = 0.0015), 39.5% (100 mg/d, p < 0.00001), and 37.8% (200 mg/d, p = 0.00003) vs 20.3% for placebo (p < 0.01).” (opens the source at this quote in a new tab)
“TEAEs in ≥5% patients taking BRV (vs placebo) were somnolence (15.2% vs 8.5%), dizziness (11.2% vs 7.2%), headache (9.6% vs 10.2%), and fatigue (8.7% vs 3.7%).” (opens the source at this quote in a new tab)

Position of valproate in the treatment sequence

“Sodium valproate was moved to a third-line add-on treatment option for focal seizures.” (opens the source at this quote in a new tab)

Pregnancy prevention conditions for valproate and topiramate

“These antiseizure medications should not be used in women and girls of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled.” (opens the source at this quote in a new tab)

Efficacy levels of older broad-spectrum agents as initial monotherapy

“CBZ, LEV, PHT, and ZNS are established (level A); VPA is probably (level B); GBP, LTG, OXC, phenobarbital (PB), TPM, and vigabatrin (VGB) are possibly (level C); whereas clonazepam (CZP) and primidone (PRM) are potentially (level D) efficacious/effective as initial monotherapy for adults with newly diagnosed or untreated partial-onset seizures.” (opens the source at this quote in a new tab)

Adjunctive topiramate: pooled efficacy and withdrawal

“The RR for a 50% or greater reduction in seizure frequency with add-on topiramate compared to placebo was 2.71 (95% CI 2.05 to 3.59; 12 studies; high-certainty evidence).” (opens the source at this quote in a new tab)
“The proportion of participants achieving seizure freedom was also significantly increased with add-on topiramate compared to placebo (RR 3.67, 95% CI 1.79 to 7.54; 8 studies; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“Treatment withdrawal was significantly higher for add-on topiramate compared to placebo (RR 2.37, 95% CI 1.66 to 3.37; 12 studies; high-certainty evidence).” (opens the source at this quote in a new tab)

Adjunctive zonisamide: pooled efficacy and withdrawal

“The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8).” (opens the source at this quote in a new tab)
“The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-certainty evidence)” (opens the source at this quote in a new tab)

Teratogenic risk restricting use

“Valproate, phenobarbital, and topiramate increase the risk of major congenital malformations in babies born to people with epilepsy and should therefore be avoided in those planning to conceive or who are pregnant” (opens the source at this quote in a new tab)

Perampanel in treatment-resistant adult focal epilepsy

“For TRAFE, immediate-release PGB and PER are established as effective to reduce seizure frequency (Level A).” (opens the source at this quote in a new tab)

Mechanism and approved role of perampanel

“Perampanel is a highly selective, non-competitive AMPA receptor antagonist that may exert its antiepileptic effect through selective inhibition of AMPA receptors” (opens the source at this quote in a new tab)
“as add-on treatment for people with focal epilepsy who are 12 years of age and older” (opens the source at this quote in a new tab)

Adjunctive perampanel: pooled efficacy and withdrawal

“Compared with placebo, participants receiving perampanel were more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.67, 95% CI 1.43 to 1.95; 7 trials, 2524 participants; high-certainty evidence).” (opens the source at this quote in a new tab)
“Compared to placebo, perampanel increased seizure freedom (RR 2.50, 95% CI 1.38 to 4.54; 5 trials, 2323 participants; low-certainty evidence)” (opens the source at this quote in a new tab)
“Participants treated with perampanel were more likely to withdraw from treatment due to adverse effects compared to those receiving placebo (RR 2.36, 95% CI 1.59 to 3.51; 7 trials, 2524 participants; low-certainty evidence).” (opens the source at this quote in a new tab)
“Add-on perampanel is effective at reducing seizure frequency and may be effective at maintaining seizure freedom for people with drug-resistant focal epilepsy.” (opens the source at this quote in a new tab)

Adjunctive perampanel: pivotal study 304

“Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively).” (opens the source at this quote in a new tab)
“Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914).” (opens the source at this quote in a new tab)

Adjunctive perampanel: pivotal study 305

“The 50% responder rates (intent-to-treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001).” (opens the source at this quote in a new tab)

Adjunctive perampanel: dose-ranging study 306

“Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively.” (opens the source at this quote in a new tab)
“The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%.” (opens the source at this quote in a new tab)

Position in the second-line add-on tier

“If first-line add-on treatments tried are unsuccessful in people with focal seizures, consider 1 of the following second-line add-on treatment options:” (opens the source at this quote in a new tab)
“If the first choice is unsuccessful, consider the other second-line add-on options.” (opens the source at this quote in a new tab)

Recommendation for use in drug-resistant focal onset seizures

“Cenobamate is recommended as an option as an add-on treatment for focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2 antiseizure medicines.” (opens the source at this quote in a new tab)

Adjunctive cenobamate: pooled efficacy

“The overall RR for at least a 50% reduction in seizure frequency for add-on cenobamate at any dose compared to placebo was 2.17 (52% versus 24%, 95% CI 1.66 to 2.84; 2 studies, 605 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“The RR for seizure freedom for add-on cenobamate at any dose compared to placebo was 4.45 (16% versus 5%, 95% CI 2.25 to 8.78; 2 studies, 605 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“Add-on cenobamate is probably better than placebo in reducing the frequency of seizures by at least 50% and in achieving seizure freedom in adults with focal epilepsy uncontrolled by one or more concomitant ASMs (moderate level of certainty).” (opens the source at this quote in a new tab)

Adjunctive cenobamate: pivotal placebo-controlled trial

“Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001)” (opens the source at this quote in a new tab)
“The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001).” (opens the source at this quote in a new tab)
“During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free.” (opens the source at this quote in a new tab)

Adjunctive cenobamate: dose-response trial

“Responder rates during the maintenance phase were 25% (26 of 102 patients) for the placebo group compared with 40% (41 of 102; odds ratio 1·97, 95% CI 1·08-3·56; p=0·0365) for the 100 mg dose group, 56% (55 of 98; 3·74, 2·06-6·80; p<0·0001) for the 200 mg dose group, and 64% (61 of 95; 5·24, 2·84-9·67; p<0·0001) for the 400 mg dose group.” (opens the source at this quote in a new tab)
“Treatment-emergent adverse events led to discontinuation in five (5%) patients in the placebo group, 11 (10%) in the 100 mg dose group, 15 (14%) in the 200 mg dose group, and 22 (20%) in the 400 mg dose group.” (opens the source at this quote in a new tab)
“One serious case of drug reaction with eosinophilia and systemic symptoms occurred in the 200 mg cenobamate group.” (opens the source at this quote in a new tab)

Adjunctive cenobamate: long-term open-label safety study

“The ≥50% responder rate for the total treatment duration was 71.7% (172/240).” (opens the source at this quote in a new tab)
“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).” (opens the source at this quote in a new tab)
“Common treatment-emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).” (opens the source at this quote in a new tab)

Network meta-analysis of third-generation adjunctive antiseizure medications

“Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments” (opens the source at this quote in a new tab)
“Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11–3.66], ESL (OR 1.93, 95% CI 1.07–3.48), LCM (OR 1.86, 95% CI 1.04–3.32), and PER (OR 2.07, 95% CI 1.16–3.70).” (opens the source at this quote in a new tab)
“Adjunctive cenobamate had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction. Adjunctive brivaracetam and lacosamide had the highest probabilities of being the best-tolerated treatments.” (opens the source at this quote in a new tab)

Network meta-analysis of approved add-on antiseizure medications for focal epilepsy

“All ASMs showed significantly higher ≥50% responder rate compared with placebo.” (opens the source at this quote in a new tab)
“Among treatments, significantly higher 100% responder rate was observed with cenobamate compared to eslicarbazepine (10.71; 95% CI: 1.56–323.9) and zonisamide (10.63; 95% CI: 1.37–261.2).” (opens the source at this quote in a new tab)
“Of the ASMs included, cenobamate had the greatest likelihood of allowing patients to attain seizure freedom.” (opens the source at this quote in a new tab)

Network meta-analysis ranking by seizure response and seizure freedom

“For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB.” (opens the source at this quote in a new tab)
“For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100 mg/d leading, followed by CNB 400 mg/d.” (opens the source at this quote in a new tab)

Expert consensus on position in the treatment sequence

“Cenobamate can be used after the failure of two antiseizure medications, rather than being reserved for later stages of treatment” (opens the source at this quote in a new tab)
“This manuscript aims to synthesize available clinical trial data, real-world studies, and expert opinions regarding the use of cenobamate, and to provide practical recommendations for its early introduction in patients with drug-resistant focal epilepsy, particularly following the failure of two adequately dosed ASMs.” (opens the source at this quote in a new tab)

Pregabalin in treatment-resistant adult focal epilepsy

“For TRAFE, immediate-release PGB and PER are established as effective to reduce seizure frequency (Level A).” (opens the source at this quote in a new tab)

Mechanistic basis of the alpha-2-delta ligand class

“Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), whereas pregabalin and gabapentin are selective ligands for the α2δ1 subunits of the voltage-gated calcium channels.” (opens the source at this quote in a new tab)

Adjunctive pregabalin: pooled efficacy

“For the primary outcome, participants randomised to pregabalin were significantly more likely to attain a 50% or greater reduction in seizure frequency compared to placebo (RR 1.95, 95% CI 1.40 to 2.72, 9 trials, 2663 participants, low-certainty evidence).” (opens the source at this quote in a new tab)
“Pregabalin was significantly associated with seizure freedom (RR 3.94, 95% CI 1.50 to 10.37, 4 trials, 1125 participants, moderate-certainty evidence).” (opens the source at this quote in a new tab)
“For people with drug-resistant focal epilepsy, pregabalin when used as an add-on treatment was significantly more effective than placebo at producing a 50% or greater seizure reduction and seizure freedom.” (opens the source at this quote in a new tab)

Comparative tolerability of gabapentin

“The evidence suggested that lamotrigine, levetiracetam and gabapentin may have more tolerable adverse events than other drugs.” (opens the source at this quote in a new tab)

Position in the third-line add-on tier

“If second-line add-on treatments tried are unsuccessful in people with focal seizures, consider 1 of the following third-line add-on treatment options:” (opens the source at this quote in a new tab)
“If the first choice is unsuccessful, consider the other third-line add-on options.” (opens the source at this quote in a new tab)

Vigabatrin and rufinamide in treatment-resistant focal epilepsy

“VGB and RFN should be considered established as effective for decreasing seizure frequency in TRAFE (Level A) but are not first-line agents (retinopathy risk with VGB and modest benefit with RFN).” (opens the source at this quote in a new tab)
“Clobazam and OXC-XR use may be considered to decrease seizure frequency in TRAFE (Level C).” (opens the source at this quote in a new tab)

Vigabatrin is not first-line in new-onset focal epilepsy

“VGB use appears to be less efficacious than CBZ-IR use and may not be offered (Level C); furthermore, toxicity profile precludes VGB use as first-line therapy” (opens the source at this quote in a new tab)

Adjunctive tiagabine: pooled efficacy and withdrawal

“The overall risk ratio (RR) with 95% confidence intervals (CIs) for a 50% or greater reduction in seizure frequency (tiagabine versus placebo) was 3.16 (95% CI 1.97 to 5.07; 3 trials; 769 participants; high-certainty evidence).” (opens the source at this quote in a new tab)
“The RR for treatment withdrawal (tiagabine versus placebo) was 1.81 (95% CI 1.25 to 2.62; 3 trials, 769 participants; moderate-certainty evidence).” (opens the source at this quote in a new tab)
“Tiagabine reduced seizure frequency but was associated with some adverse effects when used as an add-on treatment in people with drug-resistant focal epilepsy.” (opens the source at this quote in a new tab)

Vigabatrin: mechanism, vision loss, and restricted distribution

“Vigabatrin is an irreversible inhibitor of gamma-amino-butyric acid transaminase (GABA-T), an enzyme that degrades GABA, an inhibitory neurotransmitter.” (opens the source at this quote in a new tab)
“Vigabatrin can cause permanent bilateral concentric visual field constriction (ie, tunnel vision), which may lead to disability and reduced visual acuity.” (opens the source at this quote in a new tab)
“Vigabatrin is available only through a restricted program called the Risk Evaluation and Mitigation Strategy (REMS).” (opens the source at this quote in a new tab)

Referral for resective epilepsy surgery

“Refer people with drug-resistant epilepsy, including those without identified MRI abnormalities, for consideration of assessment for resective epilepsy surgery:” (opens the source at this quote in a new tab)
“For adults, this should be to a tertiary epilepsy service.” (opens the source at this quote in a new tab)

Role and outcomes of resective surgery

“Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures.” (opens the source at this quote in a new tab)
“Resective surgery can improve quality-of-life and cognitive outcomes and is the only treatment demonstrated to improve survival and reverse excess mortality attributed to drug-resistant epilepsy (DRE)” (opens the source at this quote in a new tab)
“Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy.” (opens the source at this quote in a new tab)

Timing of referral for surgical evaluation

“Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug-resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities” (opens the source at this quote in a new tab)
“A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1–2 anti-seizure medications (ASM)s but have a brain lesion in non-eloquent cortex” (opens the source at this quote in a new tab)

Randomized trial of surgery for temporal lobe epilepsy

“At one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58 percent in the surgical group and 8 percent in the medical group (P<0.001).” (opens the source at this quote in a new tab)
“In temporal-lobe epilepsy, surgery is superior to prolonged medical therapy.” (opens the source at this quote in a new tab)
“Four patients (10 percent) had adverse effects of surgery. One patient in the medical group died.” (opens the source at this quote in a new tab)

Randomized trial of early surgery in newly intractable temporal lobe epilepsy

“Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up” (opens the source at this quote in a new tab)
“Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone.” (opens the source at this quote in a new tab)
“Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.” (opens the source at this quote in a new tab)

Practice parameter on temporal lobe resection

“A single Class I study and 24 Class IV studies indicate that the benefits of anteromesial temporal lobe resection for disabling complex partial seizures is greater than continued treatment with antiepileptic drugs, and the risks are at least comparable.” (opens the source at this quote in a new tab)
“For patients who are compromised by such seizures, referral to an epilepsy surgery center should be strongly considered.” (opens the source at this quote in a new tab)

Laser interstitial thermal therapy for mesial temporal lobe epilepsy

“At both 1- and 2-years after LITT, 58.0% achieved Engel I outcomes.” (opens the source at this quote in a new tab)
“LITT is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center.” (opens the source at this quote in a new tab)

Vagus nerve stimulation when surgery is not suitable

“If resective epilepsy surgery is not suitable for a person with drug-resistant seizures, consider vagus nerve stimulation as an add-on treatment to antiseizure medication.” (opens the source at this quote in a new tab)

Vagus nerve stimulation: guideline update on efficacy over time

“A ≥50% seizure reduction occurred in 36.8% of patients at 1 year, 43.2% at 2 years, and 42.7% at 3 years.” (opens the source at this quote in a new tab)
“Median seizure reductions relative to baseline were 35% at 1 year, 44.3% at 2 years, and 44.1% at 3 years.” (opens the source at this quote in a new tab)
“VNS may be considered progressively effective in patients over multiple years of exposure (Level C).” (opens the source at this quote in a new tab)
“In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).” (opens the source at this quote in a new tab)

Vagus nerve stimulation: pivotal randomized trial

“Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group” (opens the source at this quote in a new tab)
“Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures.” (opens the source at this quote in a new tab)

Responsive neurostimulation: pivotal randomized trial

“Seizures were significantly reduced in the treatment (-37.9%, n = 97) compared to the sham group (-17.3%, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events.” (opens the source at this quote in a new tab)
“This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.” (opens the source at this quote in a new tab)

Responsive neurostimulation: nine-year prospective outcomes

“responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency.” (opens the source at this quote in a new tab)
“We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years” (opens the source at this quote in a new tab)
“There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators” (opens the source at this quote in a new tab)

Deep brain stimulation of the anterior nucleus of the thalamus: pivotal trial

“In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002).” (opens the source at this quote in a new tab)
“By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months.” (opens the source at this quote in a new tab)

Deep brain stimulation of the anterior nucleus of the thalamus: five-year follow-up

“The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years.” (opens the source at this quote in a new tab)
“The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years.” (opens the source at this quote in a new tab)
“In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months.” (opens the source at this quote in a new tab)
“anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.” (opens the source at this quote in a new tab)

Deep brain stimulation of the anterior nucleus of the thalamus: seven-year follow-up

“At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery.” (opens the source at this quote in a new tab)
“The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%.” (opens the source at this quote in a new tab)

Ketogenic diet in drug-resistant epilepsy

“Consider a ketogenic diet under the guidance of a tertiary epilepsy specialist, in people with:” (opens the source at this quote in a new tab)
“drug-resistant epilepsy if other treatment options have been unsuccessful or are not appropriate.” (opens the source at this quote in a new tab)

Ketogenic diet in adults with intractable epilepsy: meta-analysis

“We identified 402 articles, of which, 16 studies including 338 patients met the inclusion criteria.” (opens the source at this quote in a new tab)
“The results of the meta-analysis showed that the combined efficacy rates of all the symptoms of seizure freedom, seizure reduction by 50% or more, and seizure reduction below 50% in adults with intractable epilepsy were 13%, 53%, and 27%, respectively.” (opens the source at this quote in a new tab)

Recommendations for ketogenic dietary therapy in adults

“Surveys were obtained from 20 medical institutions with >2,000 adult patients treated with KDTs for epilepsy or other neurologic disorders.” (opens the source at this quote in a new tab)
“KDTs may be safe and effective in treating adults with drug-resistant epilepsy, and there is emerging evidence supporting the use in other adult neurologic disorders and general medical conditions as well.” (opens the source at this quote in a new tab)

Summary

Roughly one third of adults with epilepsy continue to have seizures despite available antiseizure medications. In a 30-year longitudinal cohort of participants with newly diagnosed epilepsy, 1,144 participants (63.7%) had been seizure free for the previous year or longer at the end of the study period, and the authors concluded that overall outcomes in newly diagnosed epilepsy have not improved despite the availability of many new medications with differing mechanisms of action. The yield of each successive medication falls steeply. Expressed as model-predicted probabilities, the first regimen gave a probability of seizure freedom of 50.5%, the second added 11.6%, the third added 4.1%, and from the fourth regimen onward each additional medication added approximately 1% or less. An earlier cohort in the same clinical setting reported that 222 of 470 previously untreated participants (47%) became seizure free on their first medication and 67 (14%) on a second or third, and that among participants with no response to the first medication only 11% subsequently became seizure free when the first failure was due to lack of efficacy, compared with 41% when it was due to intolerable side effects. A 2025 update reported that 64% of participants were seizure free, a proportion identical to that reported in the smaller 2000 study from the same setting.

Tolerability and interaction burden compound this efficacy ceiling. In up to a quarter of people, tolerability issues may lead to treatment discontinuation and harm adherence, and polypharmacotherapy further increases the risk of drug interactions and adverse events. Carbamazepine, phenobarbital, phenytoin, and primidone induce cytochrome P450 enzymes while valproic acid inhibits them, changing the serum concentrations of other antiseizure medications and of anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobial drugs, antineoplastic drugs, and immunosuppressants. Enzyme-inducing medications also affect sex hormone metabolism, vitamin D homeostasis, bone metabolism, and cholesterol synthesis, and reduce the effectiveness of hormonal contraceptives. Valproate, phenobarbital, and topiramate increase the risk of major congenital malformations, and in the United Kingdom valproate must not be prescribed to any woman or girl able to have children unless the conditions of the Pregnancy Prevention Programme are followed, because around 1 in 9 babies (11%) exposed in pregnancy will have a birth defect.

The only previously marketed potassium channel opener, ezogabine, also known as retigabine, is no longer available. Its United States label carried a warning that the product can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, restricted use to adults who had responded inadequately to several alternative treatments, and required baseline and six-monthly visual monitoring by an ophthalmic professional. Approximately 10% of participants in long-term clinical trials developed skin discoloration, generally after two or more years of treatment and at doses of 900 mg or greater, and retinal pigmentary abnormalities occurred in about one third of participants examined after approximately four years of treatment. The product was withdrawn from the United States market in 2017 after use declined, and the European Commission withdrew the marketing authorisation for Trobalt on 19 July 2018 at the request of the marketing authorisation holder, for commercial reasons.

Proportion of adults who remain uncontrolled on antiseizure medications

“At the end of the study period, 1144 patients (63.7%) had been seizure free for the previous year or longer.” (opens the source at this quote in a new tab)
“More than one-third of patients experience epilepsy that remains uncontrolled.” (opens the source at this quote in a new tab)
“Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved.” (opens the source at this quote in a new tab)
“Despite the introduction of more than a dozen new AEDs in the past 2 decades, there remain no robust data to suggest improvement in treatment outcomes.” (opens the source at this quote in a new tab)

Diminishing probability of seizure freedom with successive medication regimens

“There were 820 patients who were seizure free 1 year or longer with the initial AED, so the predicted probability was 50.5% (95% CI, 47.9%-53.1%).” (opens the source at this quote in a new tab)
“If the first treatment failed, the second AED regimen only provided an additional 11.6% probability of seizure freedom (n = 208; 95% CI, 10.1%-13.1%; P < .001).” (opens the source at this quote in a new tab)
“If the first 2 drugs failed to control all seizures, the third AED regimen offered only a 4.1% additional probability of seizure freedom.” (opens the source at this quote in a new tab)
“From the fourth AED regimen onwards, each additional AED only added an approximate 1% or less probability of seizure freedom.” (opens the source at this quote in a new tab)
“As a result, our findings lend support to the definition of drug-resistant epilepsy as failure of 2 appropriately selected and tolerated AED regimens.” (opens the source at this quote in a new tab)

Early identification of refractory epilepsy

“More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown.” (opens the source at this quote in a new tab)
“Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug.” (opens the source at this quote in a new tab)
“Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent).” (opens the source at this quote in a new tab)

Patterns of treatment response in newly diagnosed epilepsy

“The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.” (opens the source at this quote in a new tab)
“A total of 543 (49%) patients remained seizure-free on their first AED; 398 were treated with a second regimen (as monotherapy in 254, in combination with the first drug in 144), 146 (37%) of whom became seizure-free.” (opens the source at this quote in a new tab)
“Less than 2% of patients became seizure-free on subsequent regimens but a few did so on their sixth or seventh regimen.” (opens the source at this quote in a new tab)

Seizure freedom unchanged across three decades of new antiseizure medications

“In this latest update, 64% of patients were seizure-free, a proportion identical to that reported in the earlier, smaller study undertaken in the same clinical setting and published in 2000.” (opens the source at this quote in a new tab)
“This lack of fundamental progress in treatment outcomes has underpinned the relentless search for the "magic bullet" that will result in long-term seizure freedom for the majority of people designated as having drug-resistant epilepsy.” (opens the source at this quote in a new tab)

Goal of therapy and the proportion not achieving it

“The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients.” (opens the source at this quote in a new tab)
“Patient tolerability of adverse drug effects is integral to successful treatment” (opens the source at this quote in a new tab)

Tolerability burden and polypharmacotherapy in focal seizures

“In up to a quarter of people, tolerability issues may lead to treatment discontinuation, as well as harming adherence” (opens the source at this quote in a new tab)
“People with epilepsy are frequently treated with polypharmacotherapy, which further increases the risk of drug to drug interactions and, thus, adverse events.” (opens the source at this quote in a new tab)

Enzyme induction and inhibition among antiseizure medications

“The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants).” (opens the source at this quote in a new tab)
“It should also be noted that enzyme-inducing AEDs affect endogenous biochemical pathways, as metabolism of sex hormones, vitamin D homeostasis and bone metabolism and cholesterol synthesis” (opens the source at this quote in a new tab)

Contraceptive interactions and long-term adverse effects

“Be aware that some antiseizure medications, for example, carbamazepine, oxcarbazepine, phenytoin and topiramate, can impair the effectiveness of hormonal contraceptives.” (opens the source at this quote in a new tab)
“Enzyme-inducing medications in particular are associated with reduced bone density.” (opens the source at this quote in a new tab)
“Long-term side effects may include adverse effects on blood parameters or bone health, or changes in lipid metabolism.” (opens the source at this quote in a new tab)

Regulatory restrictions on valproate in people who can become pregnant

“Valproate must not be prescribed to any woman or girl able to have children unless the conditions of the Pregnancy Prevention Programme (PPP) are followed.” (opens the source at this quote in a new tab)
“In women who take valproate while pregnant, around 1 in 9 babies (11%) will have a birth defect.” (opens the source at this quote in a new tab)

Ezogabine: warning, restricted indication, and monitoring requirement

“POTIGA can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss.” (opens the source at this quote in a new tab)
“POTIGA is a potassium channel opener indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity.” (opens the source at this quote in a new tab)
“All patients taking POTIGA should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional.” (opens the source at this quote in a new tab)
“Approximately 10% of patients in long-term clinical trials developed skin discoloration, generally after 2 or more years of treatment and at higher doses (900 mg or greater) of POTIGA.” (opens the source at this quote in a new tab)

Withdrawal of the only previously marketed potassium channel opener

“Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae.” (opens the source at this quote in a new tab)
“Overall, retinal pigmentary abnormalities occurred in about one-third of patients who had eye examinations after approximately 4 years of treatment, but they may be seen earlier” (opens the source at this quote in a new tab)

European withdrawal of the retigabine marketing authorisation

“On 19 July 2018, the European Commission withdrew the marketing authorisation for Trobalt (retigabine) in the European Union (EU).” (opens the source at this quote in a new tab)
“The withdrawal was at the request of the marketing authorisation holder, Glaxo Group Ltd, which notified the European Commission of its decision to permanently discontinue the marketing of the product for commercial reasons.” (opens the source at this quote in a new tab)
“Trobalt was granted marketing authorisation in the EU on 28 March 2011 for adjunctive treatment of partial onset seizures.” (opens the source at this quote in a new tab)

Summary

The treatment position addressed by an adjunctive potassium channel opener is add-on therapy for adults whose focal onset seizures persist on existing antiseizure medications. Clinical practice guidance defines that position by the number of failed medications rather than by mechanism. The International League Against Epilepsy defines drug-resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used medication schedules, whether as monotherapy or in combination, to achieve sustained seizure freedom, and NICE adopts that definition. Approximately 30% of people with focal epilepsy have seizures that are not controlled by antiseizure medications. NICE directs that a single medication be used whenever possible, that an add-on treatment be considered when monotherapy is unsuccessful, and that when trials of add-on treatment do not reduce seizures the regimen chosen should be the one providing the best balance between effectiveness and tolerability.

Mechanistic diversity supports adding a new mechanism rather than a further agent from a class already used, since combining medications with various mechanisms of action appears more efficacious than combining medications sharing the same or comparable mechanisms. Expert consensus on the most recently approved adjunctive agent argues against reserving new mechanisms for late-stage use, recommending introduction after the failure of two adequately dosed antiseizure medications rather than at later stages of treatment. Azetukalner was studied in exactly this position: participants in X-TOLE2 had a median of five prior antiseizure medications, 51.3% were taking three concomitant medications, and approximately 40% were taking concomitant cenobamate.

The care setting is specialist outpatient neurology care with access to a tertiary or comprehensive epilepsy centre. NICE requires that all people with suspected or confirmed epilepsy have access to a tertiary epilepsy service via their specialist, and sets a four-week referral target when seizures are drug resistant or treatment causes intolerable side effects. The National Association of Epilepsy Centers recommends that all epilepsy centres regularly assess medication adherence and side effects as part of routine outpatient care, and regularly screen for drug-resistant epilepsy. Once-daily oral dosing with food, without titration and without dose adjustment of concomitant antiseizure medications, would place administration in the same setting as other oral adjunctive antiseizure medications.

Principles of monotherapy and add-on treatment

“Use a single antiseizure medication (monotherapy) to treat epilepsy whenever possible.” (opens the source at this quote in a new tab)
“If monotherapy is unsuccessful, consider trying an add-on treatment.” (opens the source at this quote in a new tab)
“If trials of add-on treatment do not result in a reduction in seizures, use the regimen that provides the best balance between effectiveness and tolerability of side effects.” (opens the source at this quote in a new tab)

Rationale for combining medications with different mechanisms of action

“It appears that combining ASMs with various mechanisms of action is more efficacious than using combinations of ASMs sharing the same or comparable mechanisms” (opens the source at this quote in a new tab)

Proportion of the focal epilepsy population that is drug resistant

“Drug-resistant focal epilepsy, as defined by the International League Against Epilepsy (ILAE), is characterized by the failure to achieve seizure control despite the use of at least two appropriately chosen and adequately dosed antiseizure medications (ASMs).” (opens the source at this quote in a new tab)
“This condition affects approximately 30% of patients and represents a significant clinical challenge.” (opens the source at this quote in a new tab)

Definition of drug-resistant epilepsy used in guidance

“Epilepsy in which seizures persist and seizure freedom is very unlikely to be attained with further manipulation of antiseizure medication. Defined by the International League Against Epilepsy as 'failure of adequate trials of 2 tolerated and appropriately chosen and used antiseizure medication schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom'.” (opens the source at this quote in a new tab)

Care setting: comprehensive epilepsy centres and outpatient monitoring

“As such, national and international professional organizations advocate for comprehensive epilepsy centers to provide both routine and highly specialized care for people with epilepsy (PWE).” (opens the source at this quote in a new tab)
“All epilepsy centers should regularly assess patient medication adherence and side effects as part of routine outpatient care.” (opens the source at this quote in a new tab)

Access to a tertiary epilepsy service

“Ensure that all children, young people and adults with suspected or confirmed epilepsy have access to a tertiary epilepsy service, if needed, via their specialist.” (opens the source at this quote in a new tab)
“Refer people with epilepsy to a tertiary epilepsy service, to be seen within 4 weeks, if any of the following apply: uncertainty about the diagnosis or cause of epilepsy, the seizure type or epilepsy syndrome” (opens the source at this quote in a new tab)

Pretreatment seizure burden and early response as predictors

“Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.” (opens the source at this quote in a new tab)
“The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001).” (opens the source at this quote in a new tab)

Quantified effect of baseline seizure frequency and prior treatment failure

“For each increase in the numbers of seizures in the year prior to treatment, there was a 6% decrease in likelihood of being seizure free at the last clinic visit.” (opens the source at this quote in a new tab)
“Epilepsy that was not successfully controlled with the first AED had 1.73 times greater odds of not responding to treatment for each subsequent medication regimen” (opens the source at this quote in a new tab)

Course patterns and their predictability in newly diagnosed epilepsy

“Most patients with newly diagnosed epilepsy had a constant course which could usually be predicted early. The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.” (opens the source at this quote in a new tab)
“Outcome pattern A was observed in 408 (37%), pattern B in 246 (22%), pattern C in 172 (16%), and pattern D in 272 (25%) patients.” (opens the source at this quote in a new tab)
“This pattern of response was particularly impressive in patients with localization-related epilepsies, who should, therefore, be evaluated early for resective surgery.” (opens the source at this quote in a new tab)

Clinical predictors of pharmacoresistance

“Those reporting more than 10 seizures prior to initiation of therapy were more than twice as likely to develop refractory epilepsy.” (opens the source at this quote in a new tab)
“Univariate and multivariate logistic regression analyses demonstrated that pharmacoresistance was also associated with family history of epilepsy, previous febrile seizures, traumatic brain injury as the cause of the epilepsy, intermittent recreational drug use, and prior or current psychiatric comorbidity, particularly depression.” (opens the source at this quote in a new tab)
“Factors not predicting poorer outcome included gender, neurological deficit and mental retardation.” (opens the source at this quote in a new tab)

Structural etiology as a determinant of seizure control

“Seizure control (>1 year without seizure) was achieved in 82% of patients who had idiopathic generalized epilepsy, 35% of those with symptomatic partial epilepsy, 45% of those with cryptogenic partial epilepsy, and 11% of those with partial epilepsy associated with hippocampal sclerosis (HS).” (opens the source at this quote in a new tab)
“In partial epilepsy, HS, cerebral dysgenesis, and dual pathology (HS and another lesion) were associated with a low rate of seizure-free patients (11%, 24%, and 3%, respectively).” (opens the source at this quote in a new tab)

Pharmacogenomic predictor of carbamazepine hypersensitivity

“HLA-B*15:02 is specific for carbamazepine- and oxcarbazepine-induced SJS and TEN, though the data are strongest for carbamazepine.” (opens the source at this quote in a new tab)
“The FDA label for carbamazepine carries a boxed warning about the risk of SJS/TEN with the presence of the HLA-B*15:02 allele” (opens the source at this quote in a new tab)

Adjunctive efficacy by number of previously used antiseizure medications

“Adjunctive BRV showed efficacy and was generally well tolerated in adults with focal seizures independent of the number of previous ASMs.” (opens the source at this quote in a new tab)
“The 50% responder rate was 26.9%, 29.9%, 30.0%, and 29.7% for BRV 50, 100, 200, and 50-200 mg/day, respectively (placebo: 13.2%); odds ratios versus placebo were statistically significant (p < 0.05) for BRV 100, 200, and 50-200 mg/day.” (opens the source at this quote in a new tab)

Real-world seizure freedom by timing of adjunctive treatment

“Sustained seizure freedom was achieved by 22.4% (n = 17) of early users and 8.7% (95% CI: 5.8–12.3, n = 27) of late users” (opens the source at this quote in a new tab)

Azetukalner response by baseline disease severity

“Overall, 14.9% (n=114) in the placebo group and 54.5% (n=112) in the XEN1101 25-mg group achieved RR50. With XEN1101 treatment, RR50 was achieved by 65.5% of patients with ≤8.5 seizures per month at baseline (n=29) and 50.6% with >8.5 seizures per month (n=83), 64.2% of patients with ≤6 prior ASMs (n=67) and 40.0% with >6 ASMs (n=45), and 56.9% of patients with one to two concomitant ASMs (n=58) and 51.9% with three concomitant ASMs (n=54).” (opens the source at this quote in a new tab)
“XEN1101 was relatively more effective in patients with indicators of less-severe disease in the trial population. These findings suggest that XEN1101 may be appropriate for use in patients with focal epilepsy across the spectrum of disease severity.” (opens the source at this quote in a new tab)

Adherence to antiseizure medications and interventions to improve it

“Poor adherence to antiepileptic medication is associated with increased mortality, morbidity and healthcare costs.” (opens the source at this quote in a new tab)
“We included 20 studies reporting data on 2832 participants.” (opens the source at this quote in a new tab)
“Behavioural interventions such as intensive reminders and the use of mixed interventions demonstrate some positive results, however, we need more reliable evidence on their efficacy, derived from carefully-designed RCTs before we can draw a firm conclusion.” (opens the source at this quote in a new tab)

Consequences of nonadherence to antiseizure medications

“Nonadherence was associated with an over threefold increased risk of mortality compared to adherence (hazard ratio = 3.32, 95% CI = 3.11-3.54) after multivariate adjustments.” (opens the source at this quote in a new tab)
“Time periods of nonadherence were also associated with a significantly higher incidence of ED visits (IRR = 1.50, 95% CI = 1.49-1.52), hospital admissions (IRR = 1.86, 95% CI = 1.84-1.88), MVA injuries (IRR = 2.08, 95% CI = 1.81-2.39), and fractures (IRR = 1.21, 95% CI = 1.18-1.23) than periods of adherence.” (opens the source at this quote in a new tab)
“These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.” (opens the source at this quote in a new tab)

Service models: specialist epilepsy nurses and self-management education

“Two intervention types, the specialist epilepsy nurse and self management education, have some evidence of benefit.” (opens the source at this quote in a new tab)
“At present it is not possible to advocate any single model of service provision.” (opens the source at this quote in a new tab)

Recommendations for specialized epilepsy centers

“The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings” (opens the source at this quote in a new tab)
“All epilepsy centers should regularly screen patients for drug-resistant epilepsy and refer such patients to multidisciplinary surgical conference for consideration of epilepsy surgery.” (opens the source at this quote in a new tab)
“Telemedicine is an important resource, providing earlier access to specialized care and improving patient satisfaction, especially in resource-limited areas.” (opens the source at this quote in a new tab)

Goal of antiseizure therapy

“The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients.” (opens the source at this quote in a new tab)

Operational definition of seizure freedom

“seizure freedom (Category 1 outcome) is defined as freedom from seizures for a minimum of three times the longest preintervention interseizure interval (determined from seizures occurring within the past 12 months) or 12 months, whichever is longer.” (opens the source at this quote in a new tab)
“It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.” (opens the source at this quote in a new tab)

Clinically accepted benchmark used by the manufacturer

“The clinically accepted definition of seizure freedom is no seizures for at least 12 months.” (opens the source at this quote in a new tab)

What constitutes unsuccessful treatment

“Treatment is unsuccessful if it does not reduce or stop seizures, or if side effects are intolerable for the person with epilepsy.” (opens the source at this quote in a new tab)

The responder endpoint used in adjunctive trials

“Another widely used efficacy endpoint for evaluating ASM efficacy is the percentage of patients with a ≥50% reduction in seizure frequency during a given treatment period compared with baseline, known as the RR50.” (opens the source at this quote in a new tab)

Seizure freedom rather than seizure reduction drives quality of life

“In this study, HRQOL improvement occurred primarily among patients who achieved complete seizure freedom.” (opens the source at this quote in a new tab)
“Many AED trials use a 50% seizure-frequency reduction criterion as a trial end point, but measurable impacts of this degree of reduction in seizure frequency on HRQOL in this sample were not observed.” (opens the source at this quote in a new tab)
“No significant change in QOLIE-31 and QOLIE-89 overall scores was observed for subjects who did not achieve seizure freedom.” (opens the source at this quote in a new tab)
“These results further support striving for seizure freedom as an epilepsy care goal.” (opens the source at this quote in a new tab)

Statistical limitations of the 50 percent responder criterion

“We showed that individual variance in monthly seizure rates can lead to an unacceptably high false-positive rate in the detection of individual treatment responders.” (opens the source at this quote in a new tab)
“This finding suggests that some drugs may be incorrectly evaluated as effective; or, conversely, that helpful drugs could be rejected based on 50% response rates.” (opens the source at this quote in a new tab)

Seizure control and sudden unexpected death in epilepsy

“Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.” (opens the source at this quote in a new tab)