Trial objective: adjunctive azetukalner in focal onset seizures

“The X-TOLE2 Phase 3 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive therapy in focal-onset seizures.” (opens the source at this quote in a new tab)

Sponsor description of the study

“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)

Summary: sponsor, identifiers, sites, and study dates

The registry record for NCT05614063 gives Xenon Pharmaceuticals Inc. as lead sponsor, Worldwide Clinical Trials as collaborator, and XPF-010-301 as the sponsor protocol number. The actual study start date was 18 November 2022, the actual primary completion date was 12 January 2026, and the actual study completion date was 3 February 2026. The record lists 125 study locations across 18 countries: the United States (56 sites), Spain (10), Australia (9), Argentina (8), Germany (8), the United Kingdom (7), Italy (4), Poland (4), Canada (3), Portugal (3), Chile (2), Georgia (2), Latvia (2), Mexico (2), New Zealand (2), Bulgaria (1), Czechia (1), and Ireland (1).

Announcement of topline results

“VANCOUVER, British Columbia and BOSTON, MA, March 09, 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 positive topline results from the Phase 3 X-TOLE2 study of azetukalner in focal onset seizures (FOS).” (opens the source at this quote in a new tab)

Randomization, baseline period, and double-blind period

“Approximately 360 subjects will be randomized in a blinded manner to one of two active treatment groups or placebo in a 1:1:1 fashion (XEN1101 25 mg : 15 mg : Placebo). Eligible subjects will have up to 9.5 weeks of baseline to assess frequency of seizures, followed by 12 weeks of blinded treatment. In order to be included in the study, subjects must be treated with a stable dose of 1 to 3 allowable antiseizure medications (ASMs) for at least one month prior to screening, during baseline, and throughout the double-blind treatment period (DBP) of the study. 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)
“Subjects who complete the 12-week DBP will have the opportunity to qualify and enroll in a separate open-label extension (OLE) study for continued treatment with XEN1101. Subjects who do not enroll in the OLE will enter a 8-week post treatment follow-up period.” (opens the source at this quote in a new tab)

Design as described by the sponsor at congress presentation

“X-TOLE2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the clinical efficacy, safety, and tolerability of AZK as adjunctive treatment in adults with FOS over a 12-week double-blind period (DBP).” (opens the source at this quote in a new tab)

Design shared with the second Phase 3 focal seizure study

“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)

Summary: age and sex eligibility

The registry record sets a minimum age of 18 years, accepts participants of all sexes, and does not accept healthy volunteers.

Inclusion criteria

“Diagnosis (≥2 years) of focal epilepsy according to the International League Against Epilepsy (ILAE) Classification of Epilepsy (2017). Subject must have had adequate trials of at least 2 ASMs, which were given (and tolerated) at adequate therapeutic doses, without achieving sustained seizure freedom.” (opens the source at this quote in a new tab)
“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)
“Able to keep accurate seizure diaries” (opens the source at this quote in a new tab)

Exclusion criteria

“Previously documented electroencephalogram which shows any pattern not consistent with focal etiology of seizures.” (opens the source at this quote in a new tab)
“History of focal aware non-motor seizures only, non-epileptic psychogenic seizure, primary generalized seizure, developmental and epileptic encephalopathy, including Lennox-Gastaut syndrome.” (opens the source at this quote in a new tab)
“Seizures secondary to drug or alcohol use, ongoing infection, neoplasia, demyelinating disease, degenerative neurological disease, metabolic illness, progressive structural lesion, encephalopathy, or progressive central nervous system (CNS) disease.” (opens the source at this quote in a new tab)
“History of status epilepticus or repetitive seizures within the 12-month period preceding Visit 1 where the individual seizures cannot be counted.” (opens the source at this quote in a new tab)

Summary: study arms and interventions

Participants were randomized in a 1:1:1 ratio to azetukalner 25 mg per day, azetukalner 15 mg per day, or placebo. The investigational product is recorded in the registry as XEN1101 capsules, with azetukalner given as the other name, and the comparator as placebo capsules.

Administration once daily with an evening meal

“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)

No titration required

“The data also continue to support a differentiated clinical profile for azetukalner relative to other antiseizure medications, including no need for titration, once-daily dosing, and no meaningful drug-drug interactions.” (opens the source at this quote in a new tab)

Summary: rationale for the primary endpoint

Median percent change in monthly seizure frequency from baseline through the 12-week double-blind period is the primary efficacy endpoint used across the Phase 3 epilepsy trials of azetukalner. The same measure was the primary endpoint of the Phase 2b X-TOLE trial, which allows the placebo-adjusted effect sizes of the two focal seizure trials supporting the New Drug Application to be compared directly.

Primary outcome measure

“Median percent change (MPC) 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)

Secondary outcome measures

“Proportion of subjects experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline through the DBP for XEN1101 versus placebo.” (opens the source at this quote in a new tab)
“MPC in weekly (7 days) focal seizure frequency from baseline to Week 1 for XEN1101 versus placebo.” (opens the source at this quote in a new tab)
“Proportion of subjects experiencing "at least much improved" (including "much" and "very much improved") in Patient Global Impression of Change (PGI-C).” (opens the source at this quote in a new tab)
“To assess adverse events as criteria for safety and tolerability of XEN1101” (opens the source at this quote in a new tab)

Outcome time frames

“From baseline through to the double blind period (week 12)” (opens the source at this quote in a new tab)
“From screening through to 56 days post-final dose.” (opens the source at this quote in a new tab)

Primary efficacy endpoint definition used across the Phase 3 epilepsy trials

“The primary efficacy endpoint is median percent change (MPC) in monthly seizure frequency from baseline through the 12-week double-blind period (DBP) of azetukalner compared to placebo.” (opens the source at this quote in a new tab)

Planned enrollment

“Approximately 360 subjects will be randomized in a blinded manner to one of two active treatment groups or placebo in a 1:1:1 fashion (XEN1101 25 mg : 15 mg : Placebo).” (opens the source at this quote in a new tab)

Participants randomized and analyzed

“The study randomized participants in a blinded manner to either azetukalner 25 mg, 15 mg, or placebo, and included a total of 380 randomized participants, with 374 participants in the safety and modified intent-to-treat (mITT) population for the safety and efficacy analyses.” (opens the source at this quote in a new tab)

Participants analyzed per treatment group

Treatment group	Quoted record
Azetukalner 25 mg	“Azetukalner 25 mg (n=124)”
Azetukalner 15 mg	“Azetukalner 15 mg (n=125)”
Placebo	“Placebo (n=125)”

Safety and modified intention-to-treat populations

“with 374 participants in the safety and modified intent-to-treat (mITT) population for the safety and efficacy analyses” (opens the source at this quote in a new tab)

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

“Of the 332 participants who completed the double-blind period, 322 entered the open-label extension study.” (opens the source at this quote in a new tab)

Discontinuation due to treatment-emergent adverse events

“14.5% of participants in the 25 mg group, 4.8% in the 15 mg group, and 3.2% in the placebo group had a TEAE leading to treatment discontinuation.” (opens the source at this quote in a new tab)

Treatment resistance, seizure burden, and concomitant antiseizure medications

“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)

Prior and concomitant cenobamate use

“Participants had highly treatment-resistant epilepsy, with a median baseline seizure frequency of 12.75 per month, a median of five prior anti-seizure medications (ASMs), and 51.3% using three concomitant ASMs. Approximately 40% of participants entering the study were taking concomitant cenobamate, while 19% had previously tried and discontinued cenobamate.” (opens the source at this quote in a new tab)
“These data are particularly striking considering nearly 60% of the patient population were taking or had already discontinued cenobamate and were experiencing a high seizure burden with a median of 13 seizures per month at baseline.” (opens the source at this quote in a new tab)

Primary endpoint: median percent change in monthly focal onset seizure frequency

“The study met its primary endpoint of MPC in monthly FOS frequency from baseline to week 12 in both the 25 mg and 15 mg azetukalner dose groups compared to placebo [MPC of -53.2% (p=0.000000000006), -34.5% (p=0.00007) and -10.4%, respectively].” (opens the source at this quote in a new tab)

Primary and key secondary endpoint results by treatment group

Endpoint	Azetukalner 25 mg (n=124)	Azetukalner 15 mg (n=125)	Placebo (n=125)
Median percent change in monthly focal onset seizure frequency, baseline to week 12	“-53.2% (p=0.000000000006)”	“-34.5% (p=0.00007)”	“-10.4%”
Proportion with at least a 50 percent reduction in monthly focal onset seizure frequency	“54.8%”	“37.6%”	“20.8%”

Placebo-adjusted effect compared with the Phase 2b trial

“The placebo-adjusted MPC in the 25 mg group was -42.7%, outperforming the previously completed Phase 2b X-TOLE study, which demonstrated a -34.6% placebo-adjusted MPC in the 25 mg dose group over 8 weeks (-52.8% in the 25 mg group and -18.2% in the placebo group).” (opens the source at this quote in a new tab)

Key secondary endpoint: 50 percent responder rate

“In addition to meeting the primary endpoint of MPC in monthly FOS frequency, the study also met the key secondary endpoint of Responder Rate 50 (RR50), with 54.8% in the 25 mg group and 37.6% in the 15 mg group experiencing at least a 50% reduction in monthly FOS frequency from baseline, compared with 20.8% in the placebo group (p=0.00000008 and p=0.003 for 25 mg and 15 mg groups, respectively).” (opens the source at this quote in a new tab)

Onset of effect at week 1 and dose-dependent responder rates

“Early and significant reductions in seizure frequency (Median Percent Change in FOS): Treatment with 25 mg or 15 mg AZK resulted in a statistically significant -53.2% or -34.5% Median Percent Change (MPC), respectively, from baseline through the DBP in monthly FOS, compared to a -10.4% MPC for placebo (p<0.0001 for both 25 and 15 mg vs. placebo). Dose-dependent MPC reductions in weekly FOS were observed from baseline to week 1, which were sustained through the DBP with both AZK doses.” (opens the source at this quote in a new tab)
“Dose-dependent increase in 50%, 75%, and 90% Responder Rates: There was a statistically significant, dose-dependent increase in the proportion of participants with a ≥50% reduction in monthly seizure frequency from baseline through the DBP. Dose-dependent increases in the proportion of participants with a ≥75% and a ≥90% reduction in monthly seizure frequency were also observed.” (opens the source at this quote in a new tab)

Seizure freedom over the double-blind period

“Improvements in 100% Responder Rate observed over time: A 100% reduction in monthly FOS frequency from baseline through the DBP was attained by a greater proportion of participants with AZK 25 mg than with placebo (6.5% vs. 0.8%, respectively; nominal p<0.05). A post hoc analysis showed that a greater proportion of participants achieved a 100% Responder Rate over time with AZK in the last eight, six and four weeks of the DBP (nominal p<0.05) as AZK reached steady-state levels.” (opens the source at this quote in a new tab)
“Last 8 weeks: 25 mg: 10.5%, 15 mg: 5.6%, placebo: 2.4%” (opens the source at this quote in a new tab)
“Last 6 weeks: 25 mg: 11.3%, 15 mg: 8.0%, placebo: 4.0%” (opens the source at this quote in a new tab)
“Last 4 weeks: 25 mg: 13.7%, 15 mg: 12.8%, placebo: 4.0%” (opens the source at this quote in a new tab)

Investigator characterization of the magnitude of effect

“In X-TOLE2, azetukalner demonstrated the best placebo-adjusted efficacy ever observed in a pivotal FOS study, to our knowledge.” (opens the source at this quote in a new tab)

Patient Global Impression of Change as a prespecified secondary endpoint

“Proportion of subjects experiencing "at least much improved" (including "much" and "very much improved") in Patient Global Impression of Change (PGI-C).” (opens the source at this quote in a new tab)

Reported patient-reported outcome results

No evidence found.

Most common treatment-emergent adverse events

“The most common treatment-emergent adverse events (TEAEs) across both azetukalner dose groups were dizziness (20.5%), headache (8.8%), somnolence (8.8%), and fatigue (7.6%) as compared to the placebo group, which reported dizziness (3.2%), headache (6.4%), somnolence (7.2%), and fatigue (6.4%).” (opens the source at this quote in a new tab)

Serious treatment-emergent adverse events

“The incidence of serious TEAEs was low and similar across treatment groups, with 5.6% in the 25 mg group, 3.2% in the 15 mg group, and 2.4% in the placebo group experiencing a serious TEAE.” (opens the source at this quote in a new tab)

Adverse events of special interest not observed during the double-blind period

“No notable weight gain, severe allergic rashes, retinal pigment epithelium or macular abnormalities, or notable cardiovascular adverse events occurred during the DBP. These results are consistent with the Phase 2b X-TOLE safety and tolerability results.” (opens the source at this quote in a new tab)

Consistency with the Phase 2b safety profile

“The safety and tolerability profile of azetukalner remains consistent with the previously disclosed data from the X-TOLE study.” (opens the source at this quote in a new tab)

Cumulative exposure across the epilepsy trials

“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)
“We remain very confident in the product profile of azetukalner as a potential new treatment option for patients with epilepsy based on strong efficacy and safety data and a consistent safety profile across over 1,500 patient-years of data,” (opens the source at this quote in a new tab)

Summary: limitations of the available X-TOLE2 evidence

As of September 2026, X-TOLE2 results are available only from company press releases and congress presentations. No peer-reviewed publication and no ClinicalTrials.gov results record have been posted, so treatment-group-level baseline characteristics, confidence intervals, the statistical testing hierarchy, and full adverse event tables are not publicly available. The double-blind period was 12 weeks, so durability of effect beyond that interval is inferred from a separate open-label extension rather than from randomized comparison. Enrollment was restricted to adults aged 18 years and older with focal epilepsy of at least 2 years duration who had failed at least 2 prior antiseizure medications and were taking 1 to 3 concomitant antiseizure medications, which limits generalizability to monotherapy use, to adolescents and children, and to newly diagnosed epilepsy. The reported analyses of the 100% responder rate over the last 8, 6, and 4 weeks of the double-blind period were post hoc and used nominal p-values. Patient Global Impression of Change was a prespecified secondary endpoint, but no results have been disclosed. Exact p-values differ between company statements, with the March 2026 topline release reporting p=0.000000000006 and p=0.00007 and the April 2026 congress release reporting p<0.0001 for both doses.