Trial objective: efficacy and safety of a KV7.2 and KV7.3 opener in focal onset seizures

“To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).” (opens the source at this quote in a new tab)

Primary and secondary objectives stated by the investigators

“The primary objectives of X-TOLE were to assess the efficacy, safety, and tolerability of 3 doses of XEN1101 in comparison with placebo on FOS frequency in adults with focal epilepsy. Secondary objectives included an assessment of 50% responder rates and a characterization of the effects of each XEN1101 dose on seizure frequency in weekly intervals during the double-blind phase (DBP) to allow a determination of the speed of onset and durability of response.” (opens the source at this quote in a new tab)
“Additional exploratory analyses reported herein include a time-to-event analysis (time for seizure count to reach the baseline monthly count) and an assessment of the effects of XEN1101 on overall health status as reported by the patients and their caregivers.” (opens the source at this quote in a new tab)

Registry statement of purpose

“The XEN1101 Phase 2 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the clinical efficacy, safety and tolerability of increasing doses of XEN1101 administered as adjunctive treatment in adult patients diagnosed with focal epilepsy, followed by an optional open-label extension (OLE).” (opens the source at this quote in a new tab)

Summary: sites, countries, and enrollment period

The registry record for NCT03796962 lists 95 investigative sites in 9 countries: the United States (54 sites), Spain (15), Germany (9), Italy (7), the United Kingdom (4), Canada (3), Georgia (1), Moldova (1), and Ukraine (1). The registry gives an actual study start date of January 30, 2019, an actual primary completion date of September 2, 2021, and an estimated completion date of October 2028 for the continuing open-label extension. The primary publication reports 97 trial sites in North America and Europe, while the open-label extension publication reports 95 sites. The sponsor is Xenon Pharmaceuticals Inc., and the protocol identifier is XPF-008-201.

Number of sites and regions

“Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.” (opens the source at this quote in a new tab)
“Patients were enrolled in North America (39.1%) or Europe (60.9%).” (opens the source at this quote in a new tab)

Site count reported in the open-label extension publication

“The X-TOLE study was conducted at 95 sites across North America and Europe (NCT03796962; EudraCT, 2018–003221-29).” (opens the source at this quote in a new tab)

Study dates

“This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up.” (opens the source at this quote in a new tab)
“The present article reports findings from the completed DBP of the study, including the first patient randomized in June 2019 through the last patient treated in August 2021.” (opens the source at this quote in a new tab)

Randomized, double-blind, placebo-controlled, dose-ranging adjunctive design

“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)
“Patients meeting eligibility criteria were randomized for an 8-week DBP to 1 of 3 active treatment groups or placebo in a 2:1:1:2 ratio: 25, 20, or 10 mg of XEN1101 or placebo.” (opens the source at this quote in a new tab)

Registry description of design, masking, and phases

“The XEN1101 Phase 2 clinical trial is designed as a randomized, double-blind, placebo-controlled, multicenter study with an optional open-label extension (OLE) to evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive treatment in adult patients aged 18 to 75 years diagnosed with focal epilepsy. Approximately 300 patients will be randomized in a blinded manner to one of three active treatment groups or placebo in a 2:1:1:2 fashion (XEN1101 25 mg : 20 mg : 10 mg : Placebo). After screening, patients will have 8 weeks of baseline to assess frequency of seizures, followed by 8 weeks of treatment and a 6-week post treatment follow-up period.” (opens the source at this quote in a new tab)

Baseline period and electronic seizure diary

“Key eligibility criteria included experiencing 4 or more countable FOSs on average per month, recorded from home in an e-diary during a prospective 8-week baseline period, while receiving stable treatment of between 1 and 3 ASMs. The e-diary stored daily seizure and treatment adherence information that was electronically transmitted to the database. Central surveillance of e-diary functionality and patient adherence, as well as clinical status, was used in addition to patient monitoring by participating sites.” (opens the source at this quote in a new tab)
“Extensions of the baseline period up to 20 weeks were allowed if COVID-19 pandemic-related site access restrictions prevented patients from attending site visits.” (opens the source at this quote in a new tab)

Randomization method and stratification

“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). Randomization was implemented centrally in the Medidata Rave Randomization and Trial Supply Management system, using a dynamic allocation randomization algorithm (nondeterministic).” (opens the source at this quote in a new tab)

Follow-up and total study duration for participants not entering the extension

“Patients who did not participate in the open-label extension (OLE) had a follow-up visit 1 week posttreatment and a final follow-up visit 6 weeks following the last dose. The total study duration per randomized patient (for those not entering the OLE) was approximately 26 weeks (6 months) from screening to follow-up.” (opens the source at this quote in a new tab)

Open-label extension design

“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. Assessments occurred at week 3 in the OLE (study day 77, week 11 from randomization) and at 3-month intervals thereafter for the first year. After the first year, on-site visits occurred at 6-month intervals, with teleconferences at 3 months between each on-site visit. The OLE phase is scheduled for completion after 378 weeks (7 years) of treatment, and no participant has yet completed the study.” (opens the source at this quote in a new tab)

Extension dose stated in the registry record

“An OLE will be available to eligible patients who complete the DBP. All patients will receive a 20 mg daily dose of XEN1101 during this extension period.” (opens the source at this quote in a new tab)

Reporting guideline and ethics oversight

“This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.” (opens the source at this quote in a new tab)

Age range and countable seizure types

“Adults aged 18 to 75 years with FOSs provided written informed consent and were enrolled; participants did not receive financial compensation.” (opens the source at this quote in a new tab)
“The types of countable focal seizures assessed included focal aware seizures with motor signs, focal seizures with impaired awareness, and focal seizures evolving to bilateral tonic-clonic seizures.” (opens the source at this quote in a new tab)

Seizure frequency and background antiseizure medication requirements

“Participants needed to be 18–75 years old with a diagnosis of focal epilepsy per International League Against Epilepsy criteria” (opens the source at this quote in a new tab)
“for ≥2 years, experience ≥4 countable FOS per month during an 8-week minimum baseline period, and receive stable treatment with 1–3 ASMs.” (opens the source at this quote in a new tab)

Key inclusion criteria as registered

“Diagnosis (≥2 years) of focal epilepsy according to the International League Against Epilepsy [ILAE] Classification of Epilepsy (2017)” (opens the source at this quote in a new tab)
“Treatment with a stable dose of 1 to 3 allowable current AEDs 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)
“Able to keep accurate seizure diaries” (opens the source at this quote in a new tab)
“Prior neuroimaging within the last 10 years and documentation is available” (opens the source at this quote in a new tab)

Key exclusion criteria: seizure type and epilepsy syndrome

“History of pseudoseizures, psychogenic seizures, primary generalized seizure, or focal aware non-motor seizures only” (opens the source at this quote in a new tab)
“Presence or previous history of Lennox-Gastaut syndrome” (opens the source at this quote in a new tab)
“Seizures secondary to other diseases or conditions” (opens the source at this quote in a new tab)
“History of repetitive seizures within the last 12 months where the individual seizures cannot be counted” (opens the source at this quote in a new tab)

Key exclusion criteria: prior ezogabine, vigabatrin, and felbamate exposure

“History of skin or retinal pigment epithelium abnormalities caused by ezogabine” (opens the source at this quote in a new tab)
“Past use of vigabatrin without stable visual fields tested twice over the 12 months after the last dose of vigabatrin (concomitant use of vigabatrin is not allowed)” (opens the source at this quote in a new tab)

Key exclusion criteria: psychiatric, cardiac, and other medical conditions

“Schizophrenia and other psychotic disorders, or active suicidal plan/intent in the past 6 months, or a history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt” (opens the source at this quote in a new tab)
“Have had multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (e.g., Stevens-Johnson syndrome), hematological, or organ toxicity reactions” (opens the source at this quote in a new tab)
“Current use of a ketogenic diet” (opens the source at this quote in a new tab)

Dose groups, formulation, and administration with food

“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)
“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)

Pharmacokinetic rationale for 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)

Concomitant antiseizure medications during the double-blind phase

“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)

Requirement for stable background medication

“In order to be included in the study, patients must already be treated with a stable dose of 1 to 3 allowable current anti-epileptic drugs for at least one month prior to screening, during baseline, and throughout the double-blind portion (DBP) of the study.” (opens the source at this quote in a new tab)

Primary endpoint and safety measures

“The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.” (opens the source at this quote in a new tab)

Registered primary outcome measure

“Median percent change in monthly (28 days) focal seizure frequency from baseline to DBP for XEN1101 versus placebo” (opens the source at this quote in a new tab)

Registered secondary outcome measures

“Responders are defined as patients experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline to DBP” (opens the source at this quote in a new tab)
“Percent change from baseline in focal seizure frequency at Month 1 and Month 2 in the DBP” (opens the source at this quote in a new tab)

Safety assessments

“Safety was assessed as severity and frequency of treatment-emergent adverse events (TEAEs) and serious AEs, clinically significant changes in laboratory findings, and other measures including electrocardiography.” (opens the source at this quote in a new tab)

Long-term outcome measures assessed in the open-label extension

“Long-term seizure outcomes included median percentage change (MPC) in monthly (28 days) FOS frequency from the double-blind phase (DBP) baseline and achievement of ≥50%, ≥75%, ≥90%, and 100% seizure reductions.” (opens the source at this quote in a new tab)
“Long-term safety was assessed by frequency and severity of TEAEs and serious adverse events (SAEs). Additional safety outcomes included findings from physical, neurologic, and ophthalmoscopy examinations, clinically significant laboratory findings, vital signs, 12-lead electrocardiograph, and urological symptoms, as well as an increase in suicide risk via the Columbia-Suicide Severity Rating Scale.” (opens the source at this quote in a new tab)

Dose-response objective and analysis model

“The primary study objective was to assess the dose-response activity of XEN1101 in reducing monthly (28-day) FOS frequency, and the primary end point assessed the monotonic dose-response relationship between the XEN1101 active dose groups compared with placebo, based on a ranked analysis of covariance model.” (opens the source at this quote in a new tab)
“The analysis of percent change from baseline was calculated based on monthly (28 days) FOS frequency.” (opens the source at this quote in a new tab)

Unmet need that the endpoint is intended to capture

“Many individuals with epilepsy continue to experience seizures despite treatment with available antiseizure medications (ASMs). There is therefore a need for more efficacious ASMs, and particularly for ones that confer greater seizure reduction or seizure freedom.” (opens the source at this quote in a new tab)

Responder rate as the accompanying secondary efficacy criterion

“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)

Planned sample size and power

“The sample size of 300 participants in the DBP was chosen to provide at least 80% power at a 2-sided .05-level for detecting a monotonic dose response.” (opens the source at this quote in a new tab)

Planned randomization ratio

“Approximately 300 patients will be randomized in a blinded manner to one of three active treatment groups or placebo in a 2:1:1:2 fashion (XEN1101 25 mg : 20 mg : 10 mg : Placebo).” (opens the source at this quote in a new tab)

Participants randomized and analyzed

“A total of 325 patients who were randomized and treated were included in the safety population (Figure 1B) and 323 patients in the modified intention-to-treat population were included in the efficacy analyses.” (opens the source at this quote in a new tab)
“A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase.” (opens the source at this quote in a new tab)

Participants by treatment group

“A total of 325 participants were randomized in the X-TOLE study (placebo, n = 114; 10 mg group, n = 46; 20 mg group, n = 51; 25 mg group, n = 114).” (opens the source at this quote in a new tab)

Participants screened and randomized

“A total of 530 patients were screened and 325 patients randomized and treated.” (opens the source at this quote in a new tab)

Modified intention-to-treat population used for efficacy

“All efficacy analyses were performed using the modified intention-to-treat population (randomized and treated patients with at least 1 seizure diary entry recorded post treatment).” (opens the source at this quote in a new tab)

Statistical testing and estimation

“Both 1-sided and 2-sided tests are reported, with significance threshold set at P < .05. The Hodges-Lehmann estimate for each dose vs placebo was calculated accompanied by the associated 2-sided 90% and 95% CIs. Statistical analysis was conducted with SAS, version 9.4 or higher (SAS Institute Inc).” (opens the source at this quote in a new tab)

Open-label extension analysis populations

“The MPC analysis was conducted for the overall group, for a numerically constant cohort group, which consisted of participants who were treated for at least 24 months in the OLE and for those who were continuing in the study at data cutoff.” (opens the source at this quote in a new tab)

Completion of the double-blind phase and entry into the open-label extension

“A total of 285 patients completed the DBP of the trial. Of these, 275 individuals (96.5%) entered the OLE to evaluate the long-term safety, tolerability, and effectiveness of XEN1101.” (opens the source at this quote in a new tab)

Overall dropout during the double-blind phase

“The overall dropout was 12.3%; 96.5% of study completers rolled over into the OLE.” (opens the source at this quote in a new tab)

Discontinuation due to treatment-emergent adverse events by dose group

“Discontinuation associated with TEAEs occurred in 3.5% of patients receiving placebo, 2.2% of patients receiving 10 mg, 13.7% of patients receiving 20 mg, and 15.8% of patients receiving 25 mg.” (opens the source at this quote in a new tab)

Open-label extension disposition at the 24-month interim analysis

“As of September 5, 2023 (cutoff date for the current interim analysis), 152 (55.3%) remained in the study, 182 (66%) had been treated in the OLE for ≥12 months, and 165 (60%) had been treated for ≥24 months. The mean and median duration of treatment were 662 days (21.8 months) and 799 days (26.3 months), respectively (range, 0.1–46.6 months). Of all participants who entered the OLE (N = 275), 67 participants (24.4%) had dose reductions. The most common reasons given for discontinuation were lack of efficacy (n = 38, 13.8%), AEs (n = 33, 12.0%), and study withdrawal by the participant (n = 33, 12.0%).” (opens the source at this quote in a new tab)

Open-label extension disposition at the April 2025 data cut

“As of the current data cut (April 1, 2025), 182 participants had received treatment for ≥12 months, 165 for ≥24 months, and 135 for ≥42 months; 123 (44.7%) are ongoing. As of the cutoff date, the OLE has generated >700 participant-years of safety data. The most common reasons for discontinuation were lack of efficacy (n=50 participants, 18.2%), withdrawal by participant (n=46, 16.7%), and AEs (n=36, 13.1%).” (opens the source at this quote in a new tab)

Demographic characteristics of the randomized population

“Patient baseline demographic and other characteristics are presented in Table 1 and were generally comparable across groups at study entry. Mean (SD) patient age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White.” (opens the source at this quote in a new tab)
“The mean (SD) body mass index was 26.8 (5.2) (calculated as weight in kilograms divided by height in meters squared). Patient mean (SD) age at the time of disease onset was 17.1 (13.6) years, with a range from 0 to 61 years.” (opens the source at this quote in a new tab)

Baseline seizure frequency and treatment history

“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. The median baseline FOS frequency was 13.5 (IQR, 7.9-30.3) per month.” (opens the source at this quote in a new tab)

Baseline characteristics by treatment group

Characteristic	Placebo (n = 114)	XEN1101, 10 mg (n = 46)	XEN1101, 20 mg (n = 51)	XEN1101, 25 mg (n = 114)	Total (N = 325)
Age, mean (SD), y	“42.9 (13.7)”	“40.0 (12.1)”	“41.7 (13.6)”	“38.7 (13.1)”	“40.8 (13.3)”
Female	“61 (53.5)”	“27 (58.7)”	“26 (51.0)”	“54 (47.4)”	“168 (51.7)”
Male	“53 (46.5)”	“19 (41.3)”	“25 (49.0)”	“60 (52.6)”	“157 (48.3)”
Europe	“67 (58.8)”	“31 (67.4)”	“32 (62.7)”	“68 (59.6)”	“198 (60.9)”
North America	“47 (41.2)”	“15 (32.6)”	“19 (37.3)”	“46 (40.4)”	“127 (39.1)”
BMI, mean (SD)	“27.3 (5.4)”	“26.6 (5.1)”	“26.7 (5.0)”	“26.5 (5.1)”	“26.8 (5.2)”
Age at disease onset, mean (SD), y	“19.2 (14.7)”	“19.8 (14.8)”	“14.1 (12.1)”	“15.3 (12.1)”	“17.1 (13.6)”
CYP3A4 inducer use: Yes	“69 (60.5)”	“25 (54.3)”	“29 (56.9)”	“65 (57.0)”	“188 (57.8)”
Background ASM use: 1	“12 (10.5)”	“4 (8.7)”	“2 (3.9)”	“11 (9.6)”	“29 (8.9)”
Background ASM use: 2	“46 (40.4)”	“18 (39.1)”	“20 (39.2)”	“48 (42.1)”	“132 (40.6)”
Background ASM use: 3	“56 (49.1)”	“24 (52.2)”	“29 (56.9)”	“55 (48.2)”	“164 (50.5)”
No. of prestudy ASMs failed, median (IQR)	“6.0 (4.0-8.0)”	“5.0 (4.0-9.0)”	“6.0 (4.0-9.0)”	“6.0 (3.0-9.0)”	“6.0 (4.0-9.0)”

Baseline characteristics of the open-label extension population

Characteristic	Open-label extension population (n = 275)
Age at study entry, mean (SD), years	“41.1 (13.3)”
Female	“138 (50.2)”
White	“250 (90.9)”
Black	“11 (4.0)”
Europe	“166 (60.4)”
North America	“109 (39.6)”
Age at epilepsy onset, mean (SD), years	“18.1 (13.8)”
Baseline seizure rate per month, median (IQR)	“13.5 (7.9, 30.3)”
Number of ASMs tried and discontinued before study entry, mean (SD)	“6.5 (3.7)”
Background ASM use: 3	“144 (52.4)”
CYP3A4 inducer use, n (%)	“160 (58.2)”

Primary endpoint: dose response and median percent reduction in monthly focal onset seizure frequency

“A robust dose response for seizure reduction was present (primary dose-response test: P < .001) (Table 2). There was a greater reduction in monthly FOS frequency from baseline during the treatment period for patients receiving XEN1101 compared with those receiving placebo, and the effect was statistically significant for each dose. The median percent reduction and associated 2-sided P values from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, −80.4% to −16.9%) in the 25-mg group, 46.4% (P < .001 vs placebo; IQR, −76.7% to −14.0%) in the 20-mg group, and 33.2% (P = .04 vs placebo; IQR, −61.8% to 0.0%) in the 10-mg group, compared with 18.2% (IQR, −37.3% to 7.0%) in the placebo group (Table 2 and Figure 2A).” (opens the source at this quote in a new tab)

Efficacy of azetukalner in the double-blind phase

Variable	Placebo (n = 114)	XEN1101, 10 mg (n = 46)	XEN1101, 20 mg (n = 51)	XEN1101, 25 mg (n = 112)
Monthly seizure frequency in baseline, median (IQR)	“13.4 (8.0 to 30.1)”	“17.4 (8.0 to 55.6)”	“14.5 (7.5 to 36.4)”	“12.8 (8.4 to 24.6)”
Monthly seizure frequency in the double-blind phase, median (IQR)	“10.5 (5.4 to 25.1)”	“10.9 (3.5 to 41.2)”	“5.2 (3.0 to 24.9)”	“5.3 (2.5 to 13.6)”
Percent change from baseline to the double-blind phase, median (IQR)	“−18.2 (−37.3 to 7.0)”	“−33.2 (−61.8 to 0.0)”	“−46.4 (−76.7 to −14.0)”	“−52.8 (−80.4 to −16.9)”
P value for pairwise comparison vs placebo (2-sided)	“NA”	“.04”	“<.001”	“<.001”
P value for primary dose response (2-sided)	“<.001”	“NA”	“NA”	“NA”
Responder rates, OR vs placebo (95% CI)	“NA”	“2.48 (1.05 to 5.84)”	“4.78 (2.18 to 10.52)”	“7.30 (3.77 to 14.10)”
CGI-C at least much improved, % of patients	“22.8”	“23.9”	“33.3”	“46.4”
PGI-C at least much improved, % of patients	“21.9”	“34.8”	“37.3”	“42.9”

Responder rates and seizure freedom during the double-blind phase

“Responders were defined as those who achieved a 50% or greater reduction from baseline in monthly FOS frequency. There was a dose-dependent increase in the number of responders (Figure 2B). The percentage and associated 2-sided P values vs placebo of patients who were responders was 54.5% (P < .001 vs placebo) in the 25-mg group, 43.1% (P < .001 vs placebo) in the 20-mg group, and 28.3% (P = .04 vs placebo) in the 10-mg group, compared with 14.9% in the placebo group (Figure 2B). Seizure freedom rates, derived from the median percent change at 100% reduction during the 8-week treatment period, in all observed patients were 6.3% in the 25-mg group, 7.8% in the 20-mg group, 2.2% in the 10-mg group, and 1.8% in the placebo group. In the completers, the rates of seizure freedom were 4.5% in the 25-mg group, 3.9% in the 20-mg group, 2.2% in the 10-mg group, and 1.8% in the placebo group (Figure 2C).” (opens the source at this quote in a new tab)

Sponsor-reported primary and responder analyses

“The median percent reduction in monthly focal seizure frequency was 52.8% in the XEN1101 25 mg group, 46.4% in the XEN1101 20 mg group, and 33.2% in the XEN1101 10 mg group compared to 18.2% in the placebo group. Statistical significance was achieved for all dose groups compared to placebo with 2-sided p-values of p<0.001 for 25 mg vs. placebo, p<0.001 for 20 mg vs. placebo, and p=0.035 for 10 mg vs. placebo.” (opens the source at this quote in a new tab)
“The percentage of subjects who achieved a >50% reduction in monthly focal seizures was 54.5% in the XEN1101 25 mg group, 43.1% in the XEN1101 20 mg group, and 28.3% in the XEN1101 10 mg group compared to 14.9% in the placebo group. Statistical significance was achieved for all dose groups compared to placebo with 2-sided p-values of p<0.001 for 25 mg vs. placebo, p<0.001 for 20 mg vs. placebo, and p=0.037 for 10 mg vs placebo.” (opens the source at this quote in a new tab)

Onset of response at week 1

“The onset of response was rapid as assessed by post hoc analysis of the percentage of patients who were responders at the end of the first week. The percentages were 53.6% (P < .001 vs placebo) in the 25-mg group, 47.1% (P < .05 vs placebo) in the 20-mg group, and 43.5% (P < .05 vs placebo) in the 10-mg group, compared with 28.1% of patients receiving placebo. Analysis of the reductions in median weekly FOS frequencies at the end of the first week also demonstrated rapid onset: there was a reduction of 55.4% (P < .001 vs placebo) in the 25-mg group, 41.5% (P = .04 vs placebo) in the 20-mg group, and 39.1% (P < .01 vs placebo) in the 10-mg group, compared with 20.2% in the placebo group. The response in the 20- and 25-mg groups was sustained throughout the study (Figure 2D).” (opens the source at this quote in a new tab)

Post hoc week 1 analysis presented at a congress

“At week 1, XEN1101 demonstrated a reduction of 39.1% (p=0.002), 41.5% (p=0.039) and 55.4% (p< 0.001) in the 10, 20, and 25 mg groups, respectively, from baseline in median weekly FOS compared to placebo (20.2%). At week 1, RR50 was 43.5% (p=0.034), 47.1% (p=0.015) and 53.6% (p< 0.001) for 10, 20 and 25 mg, respectively, compared to placebo (28.1%).” (opens the source at this quote in a new tab)

Exploratory endpoint: time to reach baseline monthly seizure count

“The exploratory end point of time to reach baseline monthly FOS count was also assessed (Figure 2E). Patients in the placebo group reached their baseline monthly FOS count by a median of 4.7 weeks, whereas patients in the 10-mg XEN1101 group did not reach their monthly baseline FOS count until approximately week 6, and those in the 20-mg group until a median of 7.4 weeks. The median time to baseline FOS count was more than 8 weeks in the 25-mg group, because most patients did not reach this end point at the end of the 8-week treatment period.” (opens the source at this quote in a new tab)

Open-label extension: median percent change in monthly focal onset seizure frequency

“For ongoing OLE participants, monthly MPC reductions from the DBP baseline in FOS frequency improved over time from 61% (n = 266) at month 1, with MPC reductions (lower, upper quartile) from baseline of 68.5% (95.4, 37.0) at 3 months and 73.1% (100, 40.7) at 6 months (Figure 2A). At months 12, 18, and 24, the MPC reductions were 80.2% (100.0, 60.0), 83.0% (100, 50.9), and 83.2% (100, 53.2), respectively. For the constant cohort (treatment ≥24 months), the reductions in monthly MPC from baseline were 73.8% (100.0, 47.1) at 3 months and 78.8% (100.0, 49.2) at 6 months (Figure 2B). At months 12, 18, and 24, the constant cohort reductions were 82.1% (100.0, 62.8), 83.0% (100, 51.4) and 83.3% (100.0, 53.6), respectively.” (opens the source at this quote in a new tab)

Open-label extension: responder rates and seizure freedom at 24 months

“In the OLE, 155 (56.4%) and 122 (44.4%) participants achieved a ≥50% seizure reduction for any consecutive ≥6-and ≥12-month period, respectively” (opens the source at this quote in a new tab)
“Seizure reductions of ≥90% were achieved by 78 (28.4%) participants for any consecutive ≥6-month period and 54 (19.6%) participants for any consecutive ≥12-month period.” (opens the source at this quote in a new tab)
“a ≥50% seizure reduction was achieved by 138 participants (83.6%) for any consecutive ≥6-month period and 115 (69.7%) participants for any consecutive ≥12-month period” (opens the source at this quote in a new tab)
“Seizure reductions of ≥90% for this population were achieved by 72 (43.6%) participants for any consecutive ≥6-month period and 52 (31.5%) participants for any consecutive ≥12-month period.” (opens the source at this quote in a new tab)
“Seizure freedom (100% reduction in monthly FOS frequency) in the overall population was achieved by 61 (22.2%) and 41 (14.9%) participants for any consecutive ≥6-month period and ≥12-month period, respectively (Figure 3C). For participants who had been treated for ≥24 months in the OLE, seizure freedom was achieved by 57 (34.5%) participants for any consecutive ≥6-month period and 39 (23.6%) participants for any consecutive ≥12-month period. In ongoing participants (n = 152), 19.1% (29/152) experienced seizure freedom for ≥12 months since the last visit.” (opens the source at this quote in a new tab)

Open-label extension: summary of long-term efficacy

“Azetukalner 20 mg once-daily with food yielded long-term efficacy in this open-label extension (OLE) study with 60% retention at 24 months.” (opens the source at this quote in a new tab)
“Sustained monthly reduction in seizure frequency (median percentage change 80.2%–83.2%) from baseline was observed during OLE months 12–24.” (opens the source at this quote in a new tab)
“Seizure freedom for ≥6- and ≥12-month consecutive durations was achieved in 22.2% and 14.9% of OLE participants, respectively.” (opens the source at this quote in a new tab)
“Seizure freedom for ≥6- and ≥12-month consecutive durations was achieved in 34.5% and 23.6% of those treated for ≥24 months, respectively.” (opens the source at this quote in a new tab)

Open-label extension: 36-month interim results

“Sustained reductions in seizure frequency: For ongoing OLE patients, monthly median percent change (MPC) reductions in FOS frequency ranged from 61%‑82% during month 1 to OLE study month 24 and were maintained at 85% at OLE study month 36. Patients who were receiving 1 to 2 anti-seizure medications (ASMs) at baseline experienced higher monthly MPC reductions in FOS frequency from baseline at OLE study month 36 (100% seizure reduction, n=67), compared to those receiving 3 ASMs (80.6% seizure reduction, n=80).” (opens the source at this quote in a new tab)
“Achieving seizure freedom: For those participants who were treated for >36 months in the OLE, 32.7% (48/147) achieved seizure freedom for a period of at least 12 months.” (opens the source at this quote in a new tab)
“Long-term retention: A total of 182 participants were treated in the OLE for ≥12 months, 165 participants were treated for ≥24 months, and 143 participants were treated for ≥36 months at the time of the analysis cutoff (October 7, 2024). Retention rates with azetukalner at 12, 24, and 36 months into the OLE study period were 66%, 60%, and 52%, respectively.” (opens the source at this quote in a new tab)

Open-label extension: 42-month interim analysis

“The MPC in seizure frequency was −87% for those remaining in OLE at 42 months.” (opens the source at this quote in a new tab)

Open-label extension: 48-month interim analysis

“Sustained reductions in seizure frequency: Among participants treated for ≥48 months in the OLE (n=131), monthly median percent change (MPC) in FOS frequency increased from a 69.8% reduction in the first month of the OLE to a 90.9% reduction at OLE study month 48. At OLE month 48, higher monthly MPC reductions in FOS frequency from the double-blind period (DBP) baseline were observed for participants in the OLE who were receiving 1-2 ASMs at DBP baseline (n=60, 100%) compared with those receiving 3 ASMs (n=69, 81.8%).” (opens the source at this quote in a new tab)
“Attained seizure freedom: Among the participants treated for ≥48 months in the OLE (n=131), seizure freedom for any ≥12-, ≥24-, ≥36-, and ≥48-month consecutive durations was attained by 38.2%, 25.2%, 19.8% and 10.7% of the participants respectively.” (opens the source at this quote in a new tab)

Open-label extension: regaining seizure freedom after a breakthrough seizure

“Of the 131 participants who were treated in the OLE for ≥48 months who had a breakthrough seizure after one interval, or epoch, of ≥6 consecutive months of seizure freedom in the OLE (n=33), 69.7% (n=23) and 57.6% (n=19) regained ≥6 and ≥12 months of subsequent seizure freedom, respectively, with continued azetukalner treatment. Of the participants who had a breakthrough seizure (n=33), there was a mean duration of regained seizure freedom of 18.9 months.” (opens the source at this quote in a new tab)

Open-label extension: characterization of seizure-freedom intervals

“Of all OLE participants, 137 (49.8%) were treated for ≥42 months as of April 1, 2025. Among them, 26.3% (36/137) had achieved ≥12 months of seizure freedom; of these participants 77.8% (28/36) had ≥24 months and 58.3% (21/36) had ≥36 months seizure freedom from last study visit. 46.7% (64/137) achieved one interval of seizure freedom for any ≥6 consecutive months. Of those participants, 48.4% (31/64) had a subsequent seizure, 71.0% (22/31) regained ≥6 months, and 58.1% (18/31) regained ≥12 months of subsequent seizure freedom. The mean duration of the regained consecutive period of seizure freedom in these 31 participants was 17.5 months (median, 13 months).” (opens the source at this quote in a new tab)

Clinical and patient global impression of change during the double-blind phase

“The significant reductions in FOS frequency in patients receiving XEN1101 were associated with improvement in overall health status as assessed by both investigators, using the Clinical Global Impression–Change (CGI-C) scale, and by patients, using the Patient Global Impression–Change (PGI-C) scale. The difference in the percentage of patients who were much improved or very much improved between the placebo vs the 25-mg XEN1101 treatment groups was statistically significant for both the CGI-C (46.4% vs 22.8%; P < .001) and PGI-C (42.9% vs 21.9%; P = .001) (Table 2). In addition, the PGI-C results for the 20-mg dose, although underpowered, were statistically significant (37.3% vs 21.9%; P = .04), and numeric improvements over placebo were noted in the CGI-C for the 20-mg dose and the CGI-C and PGI-C for the 10-mg dose.” (opens the source at this quote in a new tab)

Quality of Life in Epilepsy Inventory outcomes in the open-label extension at 1.5 years

“On completion of the double-blind period (DBP), eligible patients transitioned to the OLE at 20 mg QD in the fed state. Beginning at week 15 in the OLE, the QOLIE-31 was completed at three month intervals for the first year, then every six months thereafter. Results are reported for the OLE at 1.5 years compared to the double-blind baseline assessment. Minimally important change (MIC) thresholds in QOLIE-31 scores (Borghs et al. Epilepsy Behav 2012;23:230-4) were applied to the overall group and seizure-free group.” (opens the source at this quote in a new tab)
“In the interim analysis (data cut April 12, 2023), 170 patients were treated for ≥18 months in the ongoing X-TOLE OLE, and monthly (28-day) FOS median reduction at 18 months was 83.4%. Of these patients, 33 (19.4%) were seizure-free for ≥12 consecutive months. At 1.5 years, QOLIE-31 subscale scores met the MIC threshold for improvement in the overall and seizure-free groups, as follows: overall QoL of 6.4 and 13.2 points, respectively, seizure worry of 12.8 and 23.7 points, and social functioning of 8.3 and 22.3 points. Additionally, for the seizure-free group only, QOLIE-31 subscale scores met the MIC threshold for improvement for energy/fatigue (6.4 points), cognitive functioning (10.6 points), medication effects (15.2), and QOLIE-31 total score (13.1).” (opens the source at this quote in a new tab)

Quality of life domains improving in the open-label extension at 2 years

“Clinically important improvements in the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) subscales of Seizure Worry, Social Functioning, and Medication Effects were seen across all patients, with even greater improvements in the seizure-free group (SFG).” (opens the source at this quote in a new tab)
“The SFG achieved clinically important improvements in all quality-of-life domains assessed by the QOLIE-31 except for Energy/Fatigue.” (opens the source at this quote in a new tab)
“Quality-of-life improvements, as measured by the QOLIE-31, originally reported at year 1 were maintained or improved at year 2 of the X-TOLE OLE.” (opens the source at this quote in a new tab)

Overall tolerability and most common treatment-emergent adverse events

“The TEAEs are summarized in Table 3. XEN1101 was generally well tolerated in this study, with TEAEs being consistent with other commonly prescribed ASMs. The most common (>10%) TEAEs across all XEN1101 dose groups were dizziness (24.6%), somnolence (15.6%), and fatigue (10.9%). The incidence of TEAEs appeared to be dose related (Table 3). Weight increase as a TEAE was reported in 1 patient (0.9%) receiving placebo, 1 patient (2.2%) at 10 mg, 2 patients (3.9%) at 20 mg, and 3 patients (2.6%) at 25 mg. 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. 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)

Summary of adverse events in the double-blind phase

Variable	Placebo (n = 114)	XEN1101, 10 mg (n = 46)	XEN1101, 20 mg (n = 51)	XEN1101, 25 mg (n = 114)	XEN1101, any dose (n = 211)
At least 1 TEAE, No. (%)	“71 (62.3)”	“31 (67.4)”	“35 (68.6)”	“97 (85.1)”	“163 (77.3)”
At least 1 serious TEAE, No. (%)	“3 (2.6)”	“2 (4.3)”	“2 (3.9)”	“3 (2.6)”	“7 (3.3)”
At least 1 TEAE leading to permanent treatment discontinuation, No. (%)	“4 (3.5)”	“1 (2.2)”	“7 (13.7)”	“18 (15.8)”	“26 (12.3)”
At least 1 serious TEAE leading to death, No. (%)	“0”	“0”	“0”	“0”	“0”
Nervous system disorders	“35 (30.7)”	“20 (43.5)”	“28 (54.9)”	“83 (72.8)”	“131 (62.1)”
Dizziness	“8 (7.0)”	“3 (6.5)”	“13 (25.5)”	“36 (31.6)”	“52 (24.6)”
Somnolence	“8 (7.0)”	“5 (10.9)”	“11 (21.6)”	“17 (14.9)”	“33 (15.6)”
Headache	“9 (7.9)”	“6 (13.0)”	“6 (11.8)”	“9 (7.9)”	“21 (10.0)”
Balance disorder	“2 (1.8)”	“2 (4.3)”	“4 (7.8)”	“13 (11.4)”	“19 (9.0)”
Tremor	“2 (1.8)”	“3 (6.5)”	“3 (5.9)”	“12 (10.5)”	“18 (8.5)”
Aphasia	“1 (0.9)”	“1 (2.2)”	“1 (2.0)”	“8 (7.0)”	“10 (4.7)”
Ataxia	“1 (0.9)”	“3 (6.5)”	“1 (2.0)”	“5 (4.4)”	“9 (4.3)”
Dysarthria	“0”	“1 (2.2)”	“0”	“8 (7.0)”	“9 (4.3)”
Memory impairment	“1 (0.9)”	“1 (2.2)”	“2 (3.9)”	“6 (5.3)”	“9 (4.3)”
Psychiatric disorders	“18 (15.8)”	“7 (15.2)”	“13 (25.5)”	“31 (27.2)”	“51 (24.4)”
Confusional state	“1 (0.9)”	“1 (2.2)”	“3 (5.9)”	“6 (5.3)”	“10 (4.7)”
Fatigue	“6 (5.3)”	“5 (10.9)”	“4 (7.8)”	“14 (12.3)”	“23 (10.9)”
Gait disturbance	“1 (0.9)”	“2 (4.3)”	“2 (3.9)”	“8 (7.0)”	“12 (5.7)”
Eye disorders	“6 (5.3)”	“3 (6.5)”	“5 (9.8)”	“18 (15.8)”	“26 (12.3)”
Vision blurred	“1 (0.9)”	“0”	“1 (2.0)”	“7 (6.1)”	“8 (3.8)”

Discontinuations, serious adverse events, and deaths

“Discontinuation associated with TEAEs occurred in 3.5% of patients receiving placebo, 2.2% of patients receiving 10 mg, 13.7% of patients receiving 20 mg, and 15.8% of patients receiving 25 mg. The most common TEAEs leading to discontinuation across XEN1101 groups were dizziness (4.7%), balance disorder (2.4%), dysarthria (1.9%), and gait disturbance (1.9%). The incidence of serious AEs was low and balanced across treatment groups, occurring in 4.3% of patients receiving 10 mg, 3.9% of patients receiving 20 mg, and 2.6% of patients receiving 25 mg. The incidence of serious AEs in patients receiving placebo (2.6%) was the same as that recorded at the highest dose of XEN1101. There were no deaths in the study.” (opens the source at this quote in a new tab)

Cardiovascular, laboratory, and body weight findings

“There were no cardiovascular signals of concern based on vital signs including orthostatic tests, and no safety signals of concern from physical or neurologic examinations. Mean (SD) body weight changes from baseline were 0.2 (2.4) kg in patients receiving placebo, 0.6 (2.3) kg in patients receiving 10 mg, 1.6 (2.2) kg in patients receiving 20 mg, and 1.9 (2.9) kg in patients receiving 25 mg. There were no signals of concern from electrocardiograms, laboratory tests evaluating safety, or urinalysis.” (opens the source at this quote in a new tab)

Absence of pigmentary abnormalities reported by the sponsor

“There have been no TEAEs of pigmentary abnormalities reported during the double-blind phase of the study or in preliminary analysis during the ongoing open-label extension to date with approximately 70 subjects now treated more than 12 months.” (opens the source at this quote in a new tab)

Structural basis for the absence of pigmented dimers

“XEN1101 demonstrates higher in vitro and in vivo potency compared to the first generation Kv7.2-7.5 opener, ezogabine, and lacks the chemical properties that could form pigmented dimers.” (opens the source at this quote in a new tab)

Open-label extension: treatment-emergent adverse events at the 24-month interim analysis

“During the OLE, TEAEs were reported in 240 of 275 participants (87.3%) of the safety population (Table 2). Those reported most commonly (>10% of participants) were dizziness (21.8%), headache (15.3%), coronavirus infection (15.3%), somnolence (12.7%), fall (12.7%), and memory impairment (10.9%). Three participants reported urinary retention, 1 reported it as mild and 2 as moderate; no dose changes were made in any case. TEAEs that led to permanent treatment discontinuation (>2 participants) were dizziness (6 participants, 2.2%), somnolence (4 participants, 1.5%), and amnesia (3 participants, 1.1%). SAEs were reported in 35 participants (12.7%); SAEs reported in >1 participant were change in seizure presentation, reported in 6 participants (2.2%), and paresthesia, seizure, pneumonia aspiration, deep vein thrombosis, and fall, each reported in 2 participants (0.7%). There was 1 sudden unexpected death in epilepsy (SUDEP) reported, which was determined not to be related to the study drug. No signals of cardiovascular safety were identified as of the Sept 5, 2023, cutoff date. Overall, TEAEs were similar to those reported in the DBP, and no new safety signals were identified. At the end of the second year, participants recorded a mean (SD) weight change of −0.2 (8.8) kg.” (opens the source at this quote in a new tab)

Treatment-emergent adverse events during the open-label extension

Summary of TEAEs, n (%)	Azetukalner 20 mg (n = 275)
At least 1 TEAE	“240 (87.3)”
At least 1 serious TEAE	“35 (12.7)”
At least 1 TEAE leading to permanent discontinuation of study drug	“30 (10.9)”
At least 1 serious TEAE leading to death	“1 (0.4)”
Dizziness	“60 (21.8)”
Coronavirus infection	“42 (15.3)”
Headache	“42 (15.3)”
Fall	“35 (12.7)”
Somnolence	“35 (12.7)”
Memory impairment	“30 (10.9)”
Weight increased	“26 (9.5)”
Gait disturbance	“23 (8.4)”
Fatigue	“22 (8.0)”
Urinary tract infection	“22 (8.0)”
Aphasia	“21 (7.6)”
Change in seizure presentation	“20 (7.3)”
Nasopharyngitis	“17 (6.2)”
Confusional state	“16 (5.8)”
Disturbance in attention	“15 (5.5)”
Balance disorder	“14 (5.1)”
Paresthesia	“14 (5.1)”
Tremor	“14 (5.1)”

Long-term tolerability conclusions from the extension

“Safety results from the OLE demonstrate that azetukalner is generally well tolerated during long-term treatment, with a tolerability profile consistent with that reported during the DBP. Besides coronavirus infection and falls, the most commonly reported TEAEs were related to the central nervous system (dizziness, headache, somnolence, and memory impairment). One case of SUDEP has been reported, which was not attributed to treatment.” (opens the source at this quote in a new tab)
“In total, 10.9% of participants discontinued the OLE due to a TEAE. No new safety signals were observed, and no signals of cardiovascular safety were identified.” (opens the source at this quote in a new tab)

Open-label extension safety at the April 2025 data cut

“TEAEs were reported in 246 (89.5%) participants; 178 (64.7%) reported a treatment-related TEAE. Most TEAEs were mild or moderate; 49 participants (17.8%) reported severe TEAEs. The most common TEAEs (≥10% of participants) were dizziness (n=64, 23.3%), headache (n=50, 18.2%), COVID-19 infection (n=47, 17.1%), somnolence (n=45, 16.4%), fall (n=39, 14.2%), weight increased (n=31, 11.3%), and memory impairment (n=29, 10.5%). The mean (SD) weight change was 0.78 (9.96) kg and the median (Q1, Q3) was 0 (−3, 4) kg at 3.5 years in the OLE. In total, 43 (15.6%) participants reported ≥1 SAE, of which 7 (2.5%) were considered related to the study drug. Across the entire DBP and OLE study duration, 2 deaths have been reported, 1 due to sudden unexpected death in epilepsy and 1 from viral pneumonia, neither considered treatment related.” (opens the source at this quote in a new tab)

Cumulative exposure accrued in the open-label extension

“Consistent safety and tolerability: As of data cut-off, the OLE has generated more than 775 patient-years of safety and exposure data. Long-term safety of AZK in the OLE was comparable with the safety observed in the X-TOLE DBP.” (opens the source at this quote in a new tab)

Summary: limitations of the double-blind phase

The double-blind phase lasted 8 weeks, which the investigators identify as a limitation for assessing long-term safety and efficacy. Group sizes were unequal by design under the 2:1:1:2 randomization ratio, so the 10 mg group (n = 46) and 20 mg group (n = 51) were smaller than the placebo and 25 mg groups (n = 114 each), and the investigators note that the 20 mg analysis of global impression of change was underpowered. The investigators state that the effect of the COVID-19 pandemic on study outcomes is unknown and that pandemic restrictions on site access may have contributed to enrollment of a more refractory population, characterized by a median of 13.5 seizures per month and a median of 6 previously stopped antiseizure medications. Race was recorded but 298 of 325 participants (91.7%) identified as White, with less than 4% representation in any other category, so the investigators state that analysis by race would not contribute to a meaningful analysis in this single study. Seizure freedom rates derived from the 8-week treatment period were low in absolute terms, at 6.3% for 25 mg, 7.8% for 20 mg, 2.2% for 10 mg, and 1.8% for placebo among all observed participants.

Summary: limitations of the open-label extension

The open-label extension has no control group and no blinding, and the investigators note potential selection bias because not all participants who enrolled in the double-blind phase entered the extension, although 275 of 285 completers (96.5%) did so. Long-term efficacy estimates can be biased by dropout, because participants who perceive benefit may preferentially remain on treatment; retention was 60% at 24 months, with 13.8% discontinuing for lack of efficacy and 12.0% for adverse events. The investigators report that a constant-cohort analysis restricted to participants treated for at least 24 months produced comparable improvements, indicating that the improvement is not solely attributable to attrition bias. Comparisons against extension studies of other antiseizure medications are limited by differing methods and treatment durations. The data are interim: the extension is scheduled to run 378 weeks, or 7 years, and no participant had completed it at the time of the publication.

Limitations stated by the investigators for the double-blind phase

“Study limitations include the relatively short 8-week treatment duration; however, analysis of participants in the ongoing open-label extension phase is expected to provide insight into the long-term safety and efficacy of XEN1101. There were fewer individuals in the 10- and 20-mg groups compared with the placebo and 25-mg groups; nevertheless, a clear dose response was demonstrated. It is unknown what the impact of COVID-19 was on study outcomes. It is possible that general pandemic restrictions on site access may have contributed to enrollment of a more refractory population (ie, medians of 13.5 seizures/month and 6 previously stopped ASMs).” (opens the source at this quote in a new tab)

Limitation on analysis by race

“The US Food and Drug Administration expects race to be collected as a covariate across the development program. With less than 4% representation in any other race category, analysis by race would not contribute to a meaningful analysis in this single study.” (opens the source at this quote in a new tab)

Limitations stated by the investigators for the open-label extension

“OLE trials, such as this study, have inherent limitations that must be considered when interpreting the results. Key limitations are the open-label design and lack of a control group. In addition, there could also be selection biases since not all participants who enrolled in the DBP entered the OLE phase. This limitation is mitigated in the present situation by the fact that nearly all eligible subjects chose to receive double-blind treatment, and almost all (96%) of those completing the DBP continued into the OLE.” (opens the source at this quote in a new tab)
“As in all OLE studies, long-term assessment can be biased by participant dropout during the course of the OLE. Participants who perceive that they are doing well may preferentially remain on treatment. Moreover, at 24 months in the OLE, retention on azetukalner remained high at 60%, with only 13.8% and 12.0% of participants discontinuing the study due to lack of efficacy and due to AEs, respectively. In addition, our analysis of efficacy outcomes in a constant cohort group shows comparable improvements, indicating that the improvement is not solely due to attrition bias.” (opens the source at this quote in a new tab)

Limitation of cross-study comparison of seizure freedom rates

“While it is difficult to compare seizure freedom rates across studies due to different methodologies and study durations, other OLE studies have reported on seizure freedom rates.” (opens the source at this quote in a new tab)