Long-Term Safety and Efficacy of Azetukalner, a Novel, Potent KV7 Potassium Channel Opener, in Adults With Focal Epilepsy: ≥48-Month Interim Analysis of the Ongoing 7-Year X-TOLE Open-Label Extension

Poster: P0332 | 16th European Epilepsy Congress | September 5-9, 2026 | Athens, Greece INTRODUCTION • Azetukalner (AZK) is a novel, potent KV7 channel opener in development for the treatment of focal seizures (FS), primary generalized tonic-clonic seizures, major depressive disorder, and bipolar depression1-7 – X-TOLE is a completed phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, multicenter study with an ongoing optional 7-year open-label extension (OLE) evaluating the efficacy, safety, and tolerability of AZK administered with food as adjunctive treatment in adults with FS8,9 – In the double-blind period (DBP) of X-TOLE, treatment with AZK yielded a statistically significant dose-dependent reduction from baseline in monthly FS in participants with difficult-to-treat disease9 – AZK was generally well tolerated with a low incidence of serious adverse events (SAEs)9 • We report interim efficacy and safety data (cutoff date October 6, 2025) from the ongoing OLE of X-TOLE in which participants enrolled at 20 mg of AZK once daily (QD) METHODS • The study design for the X-TOLE study (NCT03796962)1 is shown in Figure 1 • Select eligibility criteria for the DBP and OLE of X-TOLE are outlined in Table 1 • Dosing in the OLE: AZK 20 mg QD taken with food. AZK dose adjustments and changes in concomitant antiseizure medications (ASMs) were allowed during the OLE8 • Select efficacy endpoints in the OLE: – Median percent change (MPC) in monthly FS frequency from DBP baseline – Proportion of participants with ≥50%, ≥75%, ≥90%, and 100% reduction from the DBP baseline in monthly FS frequency for any consecutive ≥12-, ≥24-, ≥36-, and ≥48-month period during the OLE – Efficacy endpoints are reported for the overall group of participants who entered the OLE and for those treated for ≥48 months in the OLE • Safety endpoints in the OLE: – Severity and frequency of treatment-emergent adverse events (TEAEs) and SAEs – Clinically significant changes in laboratory findings – Other measures • Assessment schedule in the OLE: – First year: Week 3 in the OLE (study day 77, week 11 from randomization) and 3-month intervals thereafter – After the first year: On-site visits at 6-month intervals with teleconferences at 3-month intervals between each on-site visit Table 1. X-TOLE DPB and OLE Eligibility Criteria Select Inclusion Criteria DBP • Age 18-75 years (inclusive) • Diagnosis of focal epilepsy per International League Against Epilepsy criteria (≥2 years) • Receiving stable treatment with 1-3 ASMs • Countable seizure frequency (over the 8-week baseline period) of ≥4 focal seizures/month on average, recorded in an eDiary OLE • Successful completion of the DPB with ≥80% compliance with study medication ASM, antiseizure medication; DBP , double-blind period; OLE, open-label extension.

RESULTS Participants • 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) • Of the 285 participants who completed the DBP , 275 (96.5%) enrolled in the OLE • Demographics and baseline characteristics of participants in the OLE (Table 2) were consistent with those observed in the DBP • At the analysis cutoff (October 6, 2025), 122 participants (44.4%) continued with the OLE – The most common reasons for discontinuation were lack of efficacy (17.8%), study withdrawal by the participant (17.5%), and adverse events (AEs; 13.1%) • Retention rates with AZK at 1, 2, 3, and 4 years into the OLE study were 182 (66.2%), 165 (60.0%), 143 (52.0%), and 126 (45.8%) participants, respectively Long-Term Safety and Efficacy of Azetukalner, a Novel, Potent KV7 Potassium Channel Opener, in Adults With Focal Epilepsy: ≥48-Month Interim Analysis of the Ongoing 7-Year X-TOLE Open-Label Extension Jacqueline A. French, 1 Roger J. Porter,2 Emilio Perucca, 3 Martin J. Brodie, 4 Jenny Qian,5 Constanza Luzon Rosenblut, 5 Christopher Kenney,5 Gregory N. Beatch 5 1New York University Grossman School of Medicine and NYU Langone Health, New York, NY, USA; 2University of Pennsylvania, Philadelphia, PA, USA; 3Department of Medicine (Austin Health), The University of Melbourne and Department of Neuroscience, Monash University, Melbourne, VIC, Australia; 4University of Glasgow Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, UK; 5Xenon Pharmaceuticals Inc., Vancouver, BC, Canada Efficacy • For the overall group, MPC reductions in monthly FS frequency from DBP baseline ranged from 61.6% to 81.9% during months 1-24 of the OLE study (n=266 to n=165) and increased further to a 90.9% reduction at OLE month 48 (n=129; Figure 2) • Participants treated for ≥48 months in the OLE (n=131) had a MPC in monthly FS frequency of -69.8% at month 1 in the OLE, which further increased to -85.1% at month 12, and -90.9% at month 48 in the OLE (Figure 2) • At OLE month 48, higher monthly MPC reductions in FS frequency from the DBP baseline were observed for the overall group of 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%; data not shown) Table 2. Demographics and Baselinea Characteristics of the OLE Population8 Characteristics OLE Population (N=275) Age at study entry, mean (SD), y 41.1 (13.3) Sex, n (%) Male 137 (49.8) Female 138 (50.2) Race, n (%) White 250 (90.9) Black 11 (4.0) Other 14 (5.1) Region, n (%) North America 109 (39.6) Europe 166 (60.4) BMI, mean (SD), kg/m2 27.0 (5.2) Age at epilepsy onset, mean (SD), y 18.1 (13.8) Baseline seizure rate per month, median (IQR) 13.5 (7.9-30.3) Number of prestudy ASMs tried and discontinued before study entry, mean (SD) 6.5 (3.7) Background ASM use, n (%) 1 23 (8.4) 2 108 (39.3) 3 144 (52.4) CYP3A4 inducer use, n (%) 160 (58.2) aDBP baseline.

ASM, antiseizure medication; BMI, body mass index; CYP3A4, cytochrome P450 3A4; DBP , double-blind period; IQR, interquartile range; OLE, open-label extension; SD, standard deviation; y, year .

• For any consecutive ≥12, ≥24, ≥36, and ≥48 months during the OLE, responder rates for ≥50%, ≥75%, and ≥90% seizure frequency reduction are shown in Figure 3, and 100% seizure frequency reduction (seizure freedom) are shown in Figure 4 – Among all 275 participants who entered the OLE, responder rates for any consecutive ≥12 months in the OLE were 47.6%, 30.5%, and 24.0% for ≥50%, ≥75%, and ≥90% seizure frequency reduction, respectively; 17.1% had ≥48 consecutive months of ≥50% reduction in seizure frequency (Figure 3A) – Among the 131 participants treated for ≥48 months in the OLE, these rates were 83.2%, 57.3%, and 43.5% for ≥50%, ≥75%, and ≥90% seizure frequency reduction, respectively; 35.9% had ≥48 consecutive months of ≥50% reduction in seizure frequency (Figure 3B) – Any consecutive ≥12 months of seizure freedom were attained by 20.7% of the participants entering the OLE, and 38.2% of the participants treated for ≥48 months in the OLE; 5.1% and 10.7% had ≥48 consecutive months of seizure freedom, respectively (Figure 4) Figure 1. X-TOLE Study Design Up to 4 weeks 8 weeks AZK 25 mg QDa AZK 20 mg QDa 8-week double-blind period (DBP) Randomization 2:1:1:2 Screening Baseline AZK 10 mg QDa Placebo QDa Final 6-week follow-up (if not entering OLE) OLE (20 mg QDa) 7-year open-label extension (OLE) Phase 2b study and 7-year OLE Safety • As of October 6, 2025, the OLE has generated >775 patient-years of safety data exposure • Long-term safety of AZK in the OLE was comparable with the safety observed in the DBP • At the end of the fourth year of the OLE, participants recorded a mean (SD) weight increase of 0.91 (10.0) kg from the start of the OLE • TEAEs and treatment-related TEAEs occurred in 89.5% and 65.8% of the safety population, respectively (Table 3) • 4 participants reported urinary retention, 1 reported as mild and the other 3 as moderate; no dose changes were made in any case • Serious TEAEs were reported in 45 (16.4%) participants, and those occurring in >1 participant included seizure (n=12, 4.4%); deep vein thrombosis (n=3, 1.1%); and paresthesia, seizure cluster, influenza, pneumonia aspiration, rhabdomyolysis, and fall (n=2, 0.7% each) • 2 deaths considered unrelated to AZK treatment were reported (sudden unexplained death in epilepsy and viral pneumonia, n=1, 0.4% each) Figure 2. MPC in Monthly FS Frequency During DBP and OLE a for the Overall OLE Participant Population and Participants Treated for ≥48 Months in the OLE b 0 4 8 12 16 20 24 28 32 36 40 44 48 Months (OLE) −100 −90 −80 −70 −60 −50 −40 −30 −20 −10 0 MPC from baseline, % 50% reduction 75% reduction 90% reduction 8-wkDBP Overall (n=275) ≥48 mo (n=131) 2 6 10 14 18 22 26 30 34 38 42 46 275 232 196 187 170 167 165 161 156 147 142 135 129251 206 193 177 167 166 162 161 148 144 137 132 131 129 129 129 129 130 130 131 131 131 131 131 129129 129 129 129 130 131 128 131 131 131 131 131 Overall n= ≥48 moc n= aAfter the DBP , all participants received 20 mg azetukalner at start of OLE as a once-daily capsule with food and no titration period. bData cutoff: October 6, 2025. Monthly seizure rate was calculated for 28 days per month. cSample sizes for each month varied for the 131 participants treated for ≥48 months in the OLE due to non-compliance with daily seizure diary entries.

DBP , double-blind period; FS, focal seizure; mo, month; MPC, median percent change; OLE, open-label extension; wk, week.

Figure 3. Responder Rates for Any Consecutive ≥12, ≥24, ≥36, and ≥48 Months During the OLE Any consecutive months of seizure reduction in the OLE Participants (n=131) Treated for ≥48 MonthsA B Responders n= 131 84 66 95 61 44 47 32 2064 43 33 Responders n= 109 75 57 85 58 41 47 32 2062 42 32 Any consecutive months of seizure reduction in the OLE All Participants (N=275) Who Entered the OLE ≥12 mo ≥24 mo ≥36 mo ≥48 mo 17.1 11.67.3 0 20 40 60 80 100 ≥24 mo ≥36 mo ≥48 mo Participants reaching responder rate, % 47.6 ≥12 mo 30.5 24.0 34.5 22.2 16.0 23.3 15.612.0 0 20 40 60 80 100 Participants reaching responder rate, % 35.9 24.4 15.3 83.2 57.3 43.5 64.9 44.3 31.3 47.3 32.1 24.4 Seizure Reduction Responders ≥50% ≥75% ≥90% Seizure Reduction Responders ≥50% ≥75% ≥90% Data cutoff: October 6, 2025. Monthly seizure rate was calculated for 28 days per month. mo, month; OLE, open-label extension.

Figure 4. Seizure Freedom Rates for Any Consecutive ≥12, ≥24, and ≥48 Months During the OLE 0 10 20 30 40 50 0 10 20 30 40 50 20.7 ≥12 mo 12.7 ≥24 mo 9.8 ≥36 mo 5.1 ≥48 mo 38.2 ≥12 mo 25.2 ≥24 mo 19.8 ≥36 mo 10.7 ≥48 mo Participants with 100% seizure reduction, % Participants with 100% seizure reduction, % Any consecutive months of 100% seizure reduction Any consecutive months of 100% seizure reduction All Participants (N=275) Who Entered the OLE Participants (n=131) Treated for ≥48 Months A B Responders n= Responders n=57 35 14 50 33 1427 26 Data cutoff: October 6, 2025. Monthly seizure rate was calculated for 28 days per month. mo, month; OLE, open-label extension.

Table 3. TEAEs During the OLE Period Summary of TEAEs, n (%) AZK (N=275) At least 1 TEAE 246 (89.5) At least 1 serious TEAE 45 (16.4) At least 1 TEAE leading to permanent treatment discontinuation 35 (12.7) TEAE leading to death 2 (0.7)a Most common AEs (≥5% of overall OLE population), n (%) Dizziness 69 (25.1) Headache 52 (18.9) COVID-19 47 (17.1) Somnolence 47 (17.1) Fall 40 (14.5) Weight increased 31 (11.3) Memory impairment 30 (10.9) Gait disturbance 28 (10.2) Seizure 27 (9.8) Urinary tract infection 26 (9.5) Fatigue 25 (9.1) Aphasia 22 (8.0) Nasopharyngitis 22 (8.0) Tremor 19 (6.9) Arthralgia 17 (6.2) Balance disorder 17 (6.2) Confusional state 17 (6.2) Disturbance in attention 17 (6.2) Vertigo 16 (5.8) Back pain 15 (5.5) Nausea 15 (5.5) Diarrhea 14 (5.1) Insomnia 14 (5.1) Paresthesia 14 (5.1) Pyrexia 14 (5.1) aOne death from sudden unexplained death in epilepsy (SUDEP) and 1 death from viral pneumonia, both considered unrelated to AZK.

AE, adverse event; AZK, azetukalner; OLE, open-label extension; TEAE, treatment-emergent adverse event.

References: 1. ClinicalTrials.gov identifier: NCT03796962. Accessed September 29, 2025. https://clinicaltrials.gov/study/NCT03796962. 2. ClinicalTrials.gov identifier: NCT05614063. Accessed September 29, 2025. https://clinicaltrials.gov/study/NCT05614063. 3. ClinicalTrials.gov identifier: NCT05716100. Accessed September 29, 2025. https://clinicaltrials.gov/study/NCT05716100. 4. ClinicalTrials.gov identifier: NCT05667142. Accessed September 29, 2025. https://clinicaltrials.gov/study/NCT05667142. 5. ClinicalTrials.gov identifier: NCT06775379. Accessed October 10, 2025. https://clinicaltrials.gov/ study/NCT06775379. 6. ClinicalTrials.gov identifier: NCT07076407. Accessed October 10, 2025. https://clinicaltrials.gov/study/NCT07076407. 7. ClinicalTrials.gov identifier: NCT07172516. Accessed October 10, 2025. https://clinicaltrials.gov/study/NCT07172516. 8. French JA, et al. Epilepsia Open. 2025;10(2):539-548. 9. French JA, et al. JAMA Neurol. 2023;80(11):1145-1154.

ACKNOWLEDGMENTS: Medical writing support was provided by Oishika Panda, PhD, CMPP , from Citrus Health Group, Inc. (Chicago, Illinois), and editorial support was provided by Heidi Reinholdt, MS, MA, CMPP, of Helios Global Group; both were funded by Xenon Pharmaceuticals Inc. (Vancouver, BC, Canada).

DISCLOSURES: Jacqueline A. French has numerous relationships on behalf of the Epilepsy Study Consortium with various commercial and academic entities (consulting, salary support, research support, travel reimbursement, or served on the editorial board), including Xenon Pharmaceuticals Inc. She receives salary support from the Epilepsy Study Consortium and no other income from these relationships. Roger J. Porter is a consultant for Aeterna, Axonis, Bright Minds Bioscience, Cadent, Engrail, Longboard, Neurocrine, Otsuka, Passage Bio, and Xenon Pharmaceuticals Inc. Emilio Perucca has received speaker or consultancy fees from Eisai, GRIN Therapeutics, SK Life Science, Sun Pharma, Takeda, and Xenon Pharmaceuticals Inc. Martin J. Brodie has nothing to declare. Jenny Qian, Constanza Luzon Rosenblut, Christopher Kenney, and Gregory N. Beatch are employees of and own stock or stock options in Xenon Pharmaceuticals Inc.

FUNDING: This study was funded by Xenon Pharmaceuticals Inc.

These data were previously presented at the American Epilepsy Society Annual Meeting, December 5-9, 2025, Atlanta, GA, USA.

• AZK showed long-term efficacy and safety in this interim analysis of the X-TOLE OLE, with 45.8% participant retention at 4 years in the OLE • A sustained monthly reduction in FS frequency from DBP baseline was observed during OLE study months 12-48 for 131 participants who were treated for ≥48 months in the OLE (MPC, 82.2%-90.9%) • Seizure freedom in the OLE for any ≥12-, ≥24-, ≥36-, and ≥48-month consecutive durations was attained by 20.7%, 12.7%, 9.8%, and 5.1% of all 275 participants enrolled in the OLE, respectively CONCLUSIONS • Seizure freedom in the OLE for any ≥12-, ≥24-, ≥36-, and ≥48-month consecutive durations was attained by 38.2%, 25.2%, 19.8%, and 10.7% of the 131 participants with ≥48 months treatment in the OLE, respectively • Long-term safety of AZK in the OLE was comparable with the safety observed in the DBP • These promising data suggest long-term efficacy and tolerability of AZK in patients with difficult-to-treat disease aAdministered as a once-daily capsule with food with no titration period.

Azetukalner (AZK) is an investigational drug that has not been approved by any health authority and its safety and effectiveness have not been established.

AZK, azetukalner; OLE, open-label extension; QD, once daily.