Phase 3 success for Xenon (NASDAQ: XENE) epilepsy candidate azetukalner
Rhea-AI Filing Summary
Xenon Pharmaceuticals reported positive Phase 3 results from its X-TOLE2 study of azetukalner in adults with focal onset seizures. The trial met its primary endpoint, with median percent change in monthly seizure frequency of -53.2% for the 25 mg dose and -34.5% for 15 mg, versus -10.4% for placebo, giving a placebo-adjusted effect of -42.7% for 25 mg. Key secondary goals were also achieved, including responder rates (≥50% seizure reduction) of 54.8% for 25 mg and 37.6% for 15 mg, versus 20.8% for placebo. Safety and tolerability were generally consistent with prior studies, though dizziness and other nervous system side effects were more frequent at higher doses. Xenon plans to submit a New Drug Application to the FDA for focal onset seizures in the third quarter of 2026 and is preparing for potential commercialization.
Positive
- Phase 3 efficacy exceeded prior data: Azetukalner 25 mg achieved a -42.7% placebo-adjusted median reduction in monthly focal onset seizure frequency, outperforming the earlier X-TOLE Phase 2b study’s -34.6% result and strengthening the overall efficacy package.
- Multiple clinically relevant endpoints met: The study hit its primary endpoint and key secondary measures, including ≥50% responder rates of 54.8% and 37.6% for 25 mg and 15 mg doses versus 20.8% for placebo, plus favorable patient and clinician global impression scores.
- Regulatory and commercialization path defined: Xenon plans to submit a New Drug Application for focal onset seizures in Q3 2026 and is advancing commercial readiness, positioning azetukalner as a potential first KV7 potassium channel opener for epilepsy if approved.
Negative
- None.
Insights
Phase 3 success with strong efficacy supports an NDA filing for azetukalner in focal onset seizures.
Xenon Pharmaceuticals delivered a clearly positive Phase 3 readout for azetukalner in focal onset seizures. The 25 mg dose achieved a
Key secondary outcomes aligned with the primary signal. Responder rates (≥50% seizure reduction) reached
Safety showed more nervous system adverse events such as dizziness, tremor, and balance issues, particularly at 25 mg, and higher discontinuation rates, but serious adverse events were infrequent and similar across arms, with no deaths or severe allergic rashes reported. Xenon explicitly plans a New Drug Application submission in
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| Item 7.01 | Regulation FD Disclosure. |
On March 9, 2026, Xenon Pharmaceuticals Inc. (the “Company”) issued a press release announcing topline data from the Company’s Phase 3 X-TOLE2 study of azetukalner in focal onset seizures, which is furnished as Exhibit 99.1 to this Current Report on Form 8-K (the “Press Release”). Additionally, the Company is furnishing as Exhibit 99.2 to this Current Report on Form 8-K an investor presentation about the topline data (the “Investor Presentation”), which may be used, in whole or in part, and subject to modification, on March 9, 2026 and at subsequent meetings with investors or analysts.
The information in this Item 7.01 (including Exhibits 99.1 and 99.2 attached hereto) is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Cautionary Note Regarding Forward-Looking Statements. The Press Release and Investor Presentation both contain forward-looking statements that involve certain risks and uncertainties that could cause actual results to differ materially from those expressed or implied by these statements. Please refer to the cautionary notes in the Press Release and Investor Presentation regarding these forward-looking statements.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit |
Description | |
| 99.1 | Press Release issued by Xenon Pharmaceuticals Inc. dated March 9, 2026 | |
| 99.2 | Investor Presentation, dated March 9, 2026 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| XENON PHARMACEUTICALS INC. | ||
| By: | /s/ Thomas P. Kelly | |
| Name: Thomas P. Kelly | ||
| Title: Chief Financial Officer | ||
Date: March 9, 2026
Exhibit 99.1
Xenon Announces Positive Topline Data from Phase 3 X-TOLE2 Study of Azetukalner in Focal Onset Seizures (FOS)
| • | X-TOLE2 met primary endpoint in both dose groups, including -53.2% median percent change (MPC) from baseline in monthly FOS frequency with 25 mg dose compared with -10.4% for placebo (p=0.000000000006) |
| • | X-TOLE2 outperformed Phase 2b X-TOLE study, with a placebo-adjusted MPC of -42.7% in 25 mg group in X-TOLE2 compared to -34.6% in 25 mg group in X-TOLE |
| • | Azetukalner was generally well-tolerated with a safety profile consistent with X-TOLE study |
| • | Xenon anticipates submitting New Drug Application for azetukalner in FOS to the U.S. FDA in Q3 2026 |
| • | X-TOLE2 data to be featured in Late Breaking Science oral presentation at AAN Annual Meeting in April |
| • | Company to host conference call and webcast today at 8:00 am ET |
VANCOUVER, British Columbia and BOSTON, MA, Mar. 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). Azetukalner is a novel, potent, KV7 potassium channel opener currently in clinical development for epilepsy and depression.
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]. 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). Azetukalner also demonstrated a safety and tolerability profile consistent with prior studies. 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. If approved, azetukalner would be the only KV7 potassium channel opener available for the treatment of epilepsy.
“We are very happy to announce these data for azetukalner, which exceeded expectations and, to our knowledge, show the highest placebo-adjusted efficacy ever observed in a pivotal epilepsy study. The magnitude of effect in X-TOLE2 and favorable safety profile, along with its differentiated KV7 mechanism of action and ease-of-use attributes, give us great confidence in azetukalner’s potential to become a preferred medication for patients living with uncontrolled seizures,” said Ian Mortimer, President and Chief Executive Officer of Xenon. “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.”
“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,” said Jacqueline A. French, MD, Professor in the Department of Neurology at NYU Langone Health, Co-director of Epilepsy Clinical Trials at NYU Langone’s Comprehensive Epilepsy Center, Founder/Director of the Epilepsy Study Consortium, and Chair of the Steering Committee for X-TOLE2. “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. I am pleased to see another successful pivotal trial for azetukalner that exceeds the strong X-TOLE data and look forward to this potential new medicine becoming available to more patients in the future.”
Study Design and Participant Disposition
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. 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. 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. Of the 332 participants who completed the double-blind period, 322 entered the open-label extension study.
Additional Study Results
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).
| Azetukalner 25 mg (n=124) |
Azetukalner 15 mg (n=125) |
Placebo (n=125) | ||||
| Primary Endpoint: Median percent change (MPC) in monthly (28 days) FOS frequency from baseline to Week 12 | -53.2% (p=0.000000000006) |
-34.5% (p=0.00007) |
-10.4% | |||
| Key Secondary Endpoint: Proportion of participants experiencing ≥50% reduction in monthly (28 days) FOS frequency from baseline to Week 12 (RR50) | 54.8% (p=0.00000008) |
37.6% (p=0.003) |
20.8% | |||
The safety and tolerability profile of azetukalner remains consistent with the previously disclosed data from the X-TOLE study. 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%). 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. 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.
“Epilepsy is one of the most common neurological diseases, and foundational antiseizure medications do not provide sufficient seizure control for up to 50% of patients, so we are very optimistic about the opportunity for azetukalner to meaningfully shift the epilepsy treatment paradigm,” said Chris Kenney, MD, Chief Medical Officer of Xenon. “We are grateful to the epilepsy community for their close partnership on azetukalner’s clinical development plan over the years. In particular, we wish to extend our appreciation to the patients, families, investigators, and clinical trial staff who participated in X-TOLE2. With their support, we believe we were able to execute a gold-standard clinical trial program for epilepsy and deliver a comprehensive and important dataset to support this potential new therapeutic option.”
Upcoming Congress Presentation
The X-TOLE2 efficacy and safety results will be featured as a Late Breaking Science oral presentation on Sunday, April 19th, at the American Academy of Neurology (AAN) Annual Meeting, taking place in Chicago, Illinois.
Conference Call Information
Xenon will host a conference call and webcast today at 8:00 am Eastern Time (5:00 am Pacific Time) to discuss the X-TOLE2 topline results. A listen-only webcast can be accessed on the Investors section of the Xenon website, with a replay available following the event. Participants can access the conference call by dialing (800) 715-9871 or (646) 307-1963 for international callers and referencing conference ID 7885306.
About Azetukalner
Azetukalner is a novel, potent KV7 potassium channel opener currently in Phase 3 clinical trials for the treatment of epilepsy, major depressive disorder (MDD) and bipolar depression (BPD). It represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development. 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. It is the only KV7 potassium channel opener in development for multiple indications that is backed by long-term efficacy and safety data in epilepsy patients and proof-of-concept data in MDD patients.
About Epilepsy and Focal Onset Seizures
Epilepsy is a neurological condition characterized by abnormal electrical activity in the brain that leads to spontaneous, recurrent and unprovoked seizures. It is the fourth most common neurological condition and affects approximately three million adults in the U.S. Focal epilepsy is the most common form of epilepsy. It is characterized by recurrent seizures that originate in a specific area of the brain (i.e. “focal onset seizures”), leading to various motor, sensory, autonomic, or cognitive symptoms depending on the affected region.
Epilepsy is often managed with polytherapy – or concurrent use of multiple antiseizure medications (ASMs) – in an attempt to improve seizure control. However, despite a large number of available epilepsy treatments, up to half of people with focal epilepsy still live with uncontrolled seizures. Epilepsy treatment is further complicated by often burdensome drug interactions and lengthy titration and dose-adjustment periods. These challenges highlight the critical need for a new therapeutic approach.
About Xenon Pharmaceuticals Inc.
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 Phase 3 clinical trials for the treatment of epilepsy, major depressive disorder (MDD) and bipolar depression (BPD). Xenon is also advancing an early-stage portfolio of multiple promising potassium and sodium channel modulators, including KV7 and NaV1.7 programs in Phase 1 development for the potential treatment of pain. Xenon has offices in Vancouver, British Columbia, and Boston, Massachusetts. For more information, visit www.xenon-pharma.com and follow us on LinkedIn and X.
Xenon and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in the US, Canada, and elsewhere. All other trademarks belong to their respective owner.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian securities laws. These forward-looking statements are not based on historical fact, and include statements regarding the timing of and potential results from clinical studies; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success, and commercial potential of our and our partners’ product candidates; the efficacy of our clinical study designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs, including the anticipated filing of investigational new drug applications and NDAs; the timing and results of our interactions with regulators, including the timing of any NDA submission; our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates; and anticipated timing of topline data readout from our clinical studies of azetukalner. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical studies may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical study results may not be replicated in later clinical studies; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation or completion of clinical studies; the impact of market, industry, and regulatory conditions on clinical study enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; the impact of unstable economic conditions in the general domestic and global economic markets; adverse conditions from geopolitical events; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward-looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements.
Contacts
For Investors:
Tucker Kelly
Chief Financial Officer
investors@xenon-pharma.com
For Media:
Colleen Alabiso
Senior Vice President, Corporate Affairs
media@xenon-pharma.com
Exhibit 99.2 Phase 3 X-TOLE2 Study: Topline Results MARCH 09, 2026 NASDAQ: XENE xenon-pharma.com
On Today’s Call Ian Mortimer Chris Kenney, MD Darren Cline Tucker Kelly President & Chief Medical Officer Chief Commercial Officer Chief Financial Officer Chief Executive Officer MARCH 2026 2
Forward Looking Statement/Safe Harbor This slide presentation and the accompanying oral commentary contain forward-looking statements (within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995 and Canadian Securities laws) that involve risks, uncertainties and assumptions. If the risks or uncertainties ever materialize or the assumptions prove incorrect, our results may differ materially from those expressed or implied by such forward- looking statements. All statements other than statements of historical fact could be deemed forward-looking and include statements regarding the timing of and potential results from clinical studies; the potential efficacy, safety profile, future development plans in current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partners’ product candidates; the efficacy of our clinical study designs; our ability to successfully develop and achieve milestones in our azetukalner and other pipeline and development programs, including the anticipated filing of INDs and NDAs; the timing and results of our interactions with regulators, including the timing of any NDA submission; our ability to successfully develop and obtain regulatory approval of azetukalner and our other product candidates; anticipated timing of topline data readout from our clinical studies of azetukalner; and our expectation that we will have sufficient cash to fund operations into the second half of 2027. These forward-looking statements are based on current assumptions that involve risks, uncertainties and other factors that may cause the actual results, events, or developments to be materially different from those expressed or implied by such forward-looking statements. These risks and uncertainties, many of which are beyond our control, include, but are not limited to: clinical studies may not demonstrate safety and efficacy of any of our or our collaborators’ product candidates; promising results from pre-clinical development activities or early clinical study results may not be replicated in later clinical studies; our assumptions regarding our planned expenditures and sufficiency of our cash to fund operations may be incorrect; our ongoing discovery and pre-clinical efforts may not yield additional product candidates; any of our or our collaborators’ product candidates, including azetukalner, may fail in development, may not receive required regulatory approvals, or may be delayed to a point where they are not commercially viable; we may not achieve additional milestones in our proprietary or partnered programs; regulatory agencies may impose additional requirements or delay the initiation or completion of clinical studies; the impact of market, industry, and regulatory conditions on clinical study enrollment; the impact of competition; the impact of expanded product development and clinical activities on operating expenses; the impact of new or changing laws and regulations; the impact of unstable economic conditions in the general domestic and global economic markets; adverse conditions from geopolitical events; as well as the other risks identified in our filings with the U.S. Securities and Exchange Commission and the securities commissions in British Columbia, Alberta, and Ontario. These forward- looking statements speak only as of the date hereof and we assume no obligation to update these forward-looking statements, and readers are cautioned not to place undue reliance on such forward-looking statements. Xenon and the Xenon logo are registered trademarks or trademarks of Xenon Pharmaceuticals Inc. in the US, Canada, and elsewhere. All other trademarks belong to their respective owner. MARCH 2026 3
Opening Remarks Ian Mortimer President & Chief Executive Officer
Thank you to our partners in the epilepsy community, including patient advocates, clinicians and study participants. Hadley, living with epilepsy
POSITIVE TOPLINE DATA Azetukalner in Focal Onset Seizures MARCH 2026 6
Azetukalner’s Differentiated Profile in FOS Robust Clinical Data Well-Documented Safety Profile Compelling double-blind efficacy data in FOS 800+ patient years of data in FOS patients, patients from two placebo-controlled studies with some dosed for more than 5 years Consistent safety profile between X-TOLE and Durable long-term seizure reduction and seizure freedom data in ongoing X-TOLE OLE X-TOLE2 studies Ease-of-Use Novel Mechanism Once-daily dosing Highly potent K 7.2/7.3 potassium channel V opener No titration needed Differentiated mechanism may allow for No meaningful DDIs with other ASMs or rational polytherapy anticipated monitoring requirements FOS, focal onset seizures; DDIs, drug-drug interactions; ASMs, anti-seizure medications Source: 1. “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 MARCH 2026 7 7 Ongoing 7-Year X-TOLE Open-Label Extension.” 2025 Annual Meeting of the American Epilepsy Society (AES). 2. French JA et al. JAMA Neurol.2023;80(11):1145-1154.
X-TOLE2 Results Summary Positive Phase 3 study results support an anticipated NDA submission in Q3 2026 PRIMARY ENDPOINT WAS MET: Highly statistically significant, dose-dependent reduction from baseline in median monthly FOS frequency (MPC) over the 12-week treatment period vs. placebo Responder rate 50: Statistically significant, dose-dependent (15 and 25 mg) increase in number of responders with >50% reduction in monthly FOS frequency Onset of efficacy: Rapid onset of response as assessed by statistically significant MPC achieved within one week for AZK 25 mg vs. placebo Overall health status: Significant improvements in PGI-C/CGI-C for both 15 and 25 mg treatment groups vs. placebo Safety and tolerability: AZK profile consistent with Phase 2b X-TOLE study AZK, azetukalner; PGI-C, Patient Global Impression of Change; CGI-C, Clinical Global Impression of Change; MPC, median percent change; FOS, focal onset seizure MARCH 2026 8
Topline Results from Phase 3 X-TOLE2 Study Chris Kenney, MD Chief Medical Officer
X-TOLE2 Study Design Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical study to evaluate the clinical efficacy, safety, and tolerability of azetukalner as adjunctive treatment in adults diagnosed with FOS Primary objective: Ø Evaluate effect of AZK vs. PBO on MPC from baseline in monthly FOS frequency during the DBP Secondary objectives include: Ø Assess the effect of AZK vs. PBO on RR50, treatment effect as measured at Week 1, and PGI-C score Safety and tolerability of AZK AZK, azetukalner; DBP, double-blind period; FOS, focal onset seizure; MPC, median percent change; OLE, open-label extension; PBO, placebo; PGI-C, Patient Global Impression of MARCH 2026 Change; QD, once daily; RR50, 50% responder rate. 10 X-TOLE2: NCT05614063; Open-Label Extension: NCT05718817
Baseline Demographic Characteristics: Safety Population PBO AZK 15 mg AZK 25 mg Overall (n=125) (n=125) (n=124) (n=374) 39.9 (12.4) 38.3 (11.9) 41.8 (14.3) 40.0 (12.9) Age, mean (SD), years Sex, n (%) 69 (55.2) 62 (49.6) 59 (47.6) 190 (50.8) Female 56 (44.8) 63 (50.4) 65 (52.4) 184 (49.2) Male Region, n (%) 54 (43.2) 52 (41.6) 52 (41.9) 158 (42.2) North America 71 (56.8) 73 (58.4) 72 (58.1) 216 (57.8) Ex-North America 26.1 (5.5) 27.0 (6.0) 27.3 (5.5) 26.8 (5.7) BMI, mean (SD) 14.9 (13.1) 16.2 (12.4) 16.6 (14.0) 15.9 (13.2) Age at disease onset, mean (SD), y All doses administered once daily with food and no titration. AZK, azetukalner; BMI, body mass index; PBO, placebo; SD, standard deviation. MARCH 2026 11
Baseline Characteristics: Disease History in Safety Population PBO AZK 15 mg AZK 25 mg Overall (n=125) (n=125) (n=124) (n=374) Duration of epilepsy (years) 25.96 (13.66) 23.12 (13.19) 26.18 (14.30) 25.09 (13.75) Mean (SD) Baseline seizure frequency (28-day FOS) 12.50 (7.21, 39.50) 12.50 (7.11, 28.47) 14.34 (8.13, 36.44) 12.75 (7.56, 32.97) Median [IQR] Participants taking concomitant ASM, n (%) 13 (10.4) 15 (12.0) 10 (8.1) 38 (10.2) 1 43 (34.4) 49 (39.2) 52 (41.9) 144 (38.5) 2 69 (55.2) 61 (48.8) 62 (50.0) 192 (51.3) 3 Number of ASMs tried and discontinued before study entry 5.0 (3.0, 9.0) 5.0 (3.0, 8.0) 6.0 (3.0, 8.0) 5.0 (3.0, 8.0) Median [IQR] Participants had highly treatment-resistant epilepsy, with a median of 5 prior ASMs, a baseline seizure frequency of 12.75 per month, and 51.3% using 3 concomitant ASMs All doses administered once daily with food and no titration. ASM, antiseizure medication; AZK, azetukalner; IQR, interquartile range; PBO, placebo MARCH 2026 12
Primary Endpoint: Median Percent Change (MPC) in Monthly FOS Change from baseline in seizure frequency AZK AZK PBO 15 mg 25 mg 0% -10% -10.4% -20% 42.7% placebo- -30% adjusted MPC in -34.5% -40% monthly FOS p=0.00007 -50% -53.2% p=0.000000000006 -60% Highly statistically significant reduction in monthly FOS frequency with placebo-adjusted MPC for 25 mg cohort outperforming Phase 2b X-TOLE study Ranked ANCOVA for MPC in monthly (28-day) focal seizure frequency during the DBP in the modified intent-to-treat population. ANCOVA, analysis of covariance; AZK, azetukalner; FOS, focal onset seizure; MPC, median percent change; PBO, placebo; DBP, double-blind period MARCH 2026 13 Phase 2b X-TOLE results: -34.6% placebo-adjusted MPC over 8 weeks in the 25 mg group (-52.8% from baseline in 25 mg group and -18.2% from baseline in placebo group) MPC (%)
Key Secondary Endpoint: Responder Rate 50 (RR50) in DBP Responder rate 50 (RR50) 60% 54.8% 50% 37.6% 40% 30% 20.8% 20% 10% 0% PBO AZK AZK Placebo AZK (15mg) AZK (25mg) 15 mg 25 mg p=0.003 p=0.00000008 Logistic regression for RR50 (28-day) in the DBP in the modified intent-to-treat population. MARCH 2026 14 AZK, azetukalner; DBP, double-blind period; PBO, placebo; RR50, 50% responder rate. Responders (%)
MPC from Baseline in Weekly FOS Frequency During Week 1 Change in Seizure Frequency at Week 1 PBO AZK AZK 15 mg 25 mg 0% -10% -20% -19.3% -30% -33.3% -40% (p=0.08) -45.2% -50% ** -60% **p<0.01 Dose-dependent reductions in weekly seizure frequency observed as early as week 1 and sustained through DBP MPC from baseline in weekly (7 days) focal seizure frequency for each week during the DBP in the modified intent-to-treat population. MARCH 2026 15 AZK, azetukalner; DBP, double-blind period; MPC, median percent change; PBO, placebo. MPC (%)
Patient and Clinical Global Impression of Change Patient Global Impression of Change (PGI-C) Clinical Global Impression of Change (CGI-C) PBO 23.1% PBO 26.4% (n=125) (n=121) AZK 15 mg AZK 15 mg 46.4% *** 37.7% * (n=122) (n=125) AZK 25 mg AZK 25 mg 38.5% * 45.2% ** (n=124) (n=122) 0% 10% 20% 30% 40% 50% 0% 10% 20% 30% 40% 50% Participants at least much improved (%) Participants at least much improved (%) *p<0.05 (nominal) **p<0.01 ***p<0.001 (nominal) Significant improvements in PGI-C/CGI-C for both AZK 15 mg and AZK 25 mg treatment groups vs. placebo PGI-C is a key secondary endpoint. PGI-C change is defined as participants experiencing at least much improved (i.e., ‘much improved’ or ‘very much improved’) at Week 12. CGI-C is an exploratory endpoint. CGI-C change is defined as at least much improved (i.e., ‘much improved’ or ‘very much improved’) reported by clinicians at Week 12. MARCH 2026 16 Logistic regression for PGI-C and CGI-C responders at week 12 in the modified intent-to-treat population. AZK, azetukalner; PGI-C, Patient Global Impression of Change; CGI-C, Clinical Global Impression of Change
Most Common TEAEs (≥5%) in Any Treatment Group PBO AZK 15 mg AZK 25 mg AZK Any Dose System Organ Class/Preferred Term, n (%) (n=125) (n=125) (n=124) (n=249) Any TEAE 78 (62.4) 84 (67.2) 102 (82.3) 186 (74.7) Any Serious TEAE 3 (2.4) 4 (3.2) 7 (5.6) 11 (4.4) Any TEAE Leading to Treatment Discontinuation 4 (3.2) 6 (4.8) 18 (14.5) 24 (9.6) Nervous system disorders 32 (25.6) 37 (29.6) 73 (58.9) 110 (44.2) Dizziness 4 (3.2) 12 (9.6) 39 (31.5) 51 (20.5) Headache 8 (6.4) 8 (6.4) 14 (11.3) 22 (8.8) Somnolence 9 (7.2) 10 (8.0) 12 (9.7) 22 (8.8) Tremor 2 (1.6) 2 (1.6) 15 (12.1) 17 (6.8) Aphasia 0 3 (2.4) 12 (9.7) 15 (6.0) Balance disorder 2 (1.6) 1 (0.8) 8 (6.5) 9 (3.6) Dysarthria 0 0 8 (6.5) 8 (3.2) Psychiatric disorders 15 (12.0) 16 (12.8) 31 (25.0) 47 (18.9) Confusional state 1 (0.8) 0 13 (10.5) 13 (5.2) General disorders and administration site conditions 13 (10.4) 11 (8.8) 27 (21.8) 38 (15.3) Fatigue 8 (6.4) 5 (4.0) 14 (11.3) 19 (7.6) Gait disturbance 0 2 (1.6) 12 (9.7) 14 (5.6) Gastrointestinal disorders 19 (15.2) 14 (11.2) 22 (17.7) 36 (14.5) Constipation 1 (0.8) 4 (3.2) 8 (6.5) 12 (4.8) Eye disorders 9 (7.2) 6 (4.8) 24 (19.4) 30 (12.0) Vision blurred 4 (3.2) 2 (1.6) 10 (8.1) 12 (4.8) Diplopia 1 (0.8) 0 8 (6.5) 8 (3.2) Injury, poisoning and procedural complications 18 (14.4) 13 (10.4) 11 (8.9) 24 (9.6) Fall 5 (4.0) 6 (4.8) 9 (7.3) 15 (6.0) Renal and urinary disorders 4 (3.2) 6 (4.8) 18 (14.5) 24 (9.6) Pollakiuria 1 (0.8) 0 7 (5.6) 7 (2.8) Most common TEAEs across all AZK groups included dizziness, somnolence , headache , and fague; consistent with those reported for X-TOLE MARCH 2026 17 AZK, azetukalner; PBO, placebo; TEAE, treatment-emergent adverse event.
Serious Adverse Events and Additional Safety Findings Serious Adverse Events Additional Safety Findings: No severe allergic rashes (SJS, DRESS) occurred Incidence of SAEs was low and similar across AZK groups: No signals of retinal pigment epithelium or macular abnormalities PBO (2.4%) No signals of cardiovascular events AZK 15 mg (3.2%) No meaningful weight gain occurred AZK 25 mg (5.6%) No deaths occurred Four non-serious TEAEs of urinary retention were reported SAEs reported in >1 participant: Dysarthria (2) – One participant in PBO and two in 25 mg with no dose reduction Tremor (2) – One participant in 15 mg was hospitalized for a psychiatric event, which Confusional state (2) included catheterization and discontinuation Fall (2) All reported from the AZK 25 mg group AZK, azetukalner; PBO, placebo; TEAE, treatment-emergent adverse event; SJS, Stevens-Johnson Syndrome; DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms. MARCH 2026 18
X-TOLE2 Summary of Safety and Tolerability Summary of Safety and Tolerability Treatment-Emergent Adverse Events Most common TEAEs across all TEAEs resulted in AZK groups included: discontinuation in: AZK was generally well tolerated with a dose-dependent incidence of TEAEs consistent with X-TOLE Dizziness (20.5%) 3.2% in PBO Somnolence (8.8%) 4.8% in AZK 15 mg Incidence of TEAEs for AZK 15 mg was similar to PBO Headache (8.8%) 14.5% in AZK 25 mg Fague (7.6%) Most common TEAEs across all AZK groups were consistent with those reported for X-TOLE Most common TEAEs leading to discontinuation across No individual TEAE led to discontinuation in all AZK groups: >5% of participants Dizziness (3.2%) Gait disturbance (1.2%) Incidence of SAEs was low and similar across AZK groups Headache (1.6%) Coordination abnormal (1.2%) Fatigue (1.6%) Speech disorder (1.2%) AZK, azetukalner; PBO, placebo; TEAE, treatment-emergent adverse event; SAE, serious adverse event. MARCH 2026 19
Keep content within provided margin guidelines: 12.5” width Please do not move or change the size of the Placebo-Adjusted MPCs for All AZK Doses in X-TOLE and X-TOLE2 Title box Use eyedropper tool to select colors from the expanded color palette: AZK (10 mg) AZK (15 mg) AZK (15 mg) AZK (20 mg) AZK (25 mg) AZK (25 mg) AZK (25 mg) XTOLE (8 wks) XTOLE2 (8 wks) XTOLE2 (12 wks) XTOLE (8 wks) XTOLE (8 wks) XTOLE2 (8 wks) XTOLE2 (12 wks) 0% -5% -10% -15% -15.0% -20% Keep content -21.8% -25% within provided -24.1% margin guidelines: -30% -28.2% 5.5” height -35% -34.6% -40% -39.6% -45% -42.7% -50% Placebo-adjusted MPC in monthly FOS frequency shows consistent dose-dependent efficacy for AZK at all doses tested AZK, azetukalner; MPC: median percent change. All doses administered once daily with food and no titration. Post-hoc week 8 values for X-TOLE2 AZK 25 mg: Focal Seizure Frequency During the first 8 weeks in the Modified MARCH 2026 20 Intent-to-Treat Population. Phase 2b X-TOLE Source: French et al., JAMA Neurol. 2023;80(11):1145-1154; Phase 2b X-TOLE results: -34.6% placebo-adjusted MPC over 8 weeks in the 25 mg group (-52.8% from baseline in 25 mg group and -18.2% from baseline in placebo group) Please try to avoid covering the logo Placebo-Adjusted MPC (%)
Summary of X-TOLE2 Topline Results Study met primary endpoint in both dose groups, including -53.2% MPC from baseline in monthly FOS frequency with 25 mg dose vs. 10.4% for placebo (p=0.000000000006) X-TOLE2 outperformed X-TOLE study with a placebo-adjusted MPC of -42.7% in the 25 mg group in X-TOLE2 compared to -34.6% in X-TOLE Azetukalner was generally well-tolerated with a safety profile consistent with X-TOLE X-TOLE results: -34.6% placebo-adjusted MPC at Week 8 in the 25 mg group (-52.8% from baseline in 25 mg group and -18.2% from baseline in placebo group) MARCH 2026 21
Moving Toward Commercialization Darren Cline Chief Commercial Officer
Significant Epilepsy Burden in the U.S. Estimated Diagnosed Adult Epilepsy Patient Population Epilepsy is the fourth most in the U.S. common neurological condition Despite the availability of multiple anti-seizure medications (ASMs), most share a limited and U.S. Adults with overlapping set of mechanisms of Generalized Seizures action Approximately 80% of 0.9M adult patients with U.S. Adults with generalized epilepsy Up to 50% of patients are in need Focal Onset Seizures 3M experience PGTCS FOS represent the of additional treatment options to 1.8M U.S. Adults largest segment of the improve seizure control with Epilepsy epilepsy population 0.3M U.S. Adults with Undefined/Combination Epilepsy FOS, focal onset seizures; PGTCS: Primary generalized tonic clonic seizures Sources: Milligan, TA. Epilepsy: A clinical overview. Am J Med. 2021; Barnard S, et al. Treatment outcomes in newly diagnosed focal epilepsy. AES. 2024.; Chen Z, et al. Long- term outcomes with ASMs. JAMA Neurol. 2018.; Ioannou P, et al. Burden and unmet need in focal seizures. Brain Behav. 2022; Keränen T, Sillanpää M, Riekkinen PJ. Distribution of seizure types in an epileptic population. Epilepsia. 1988.; Kobau R, et al. Active epilepsy prevalence in U.S. adults. Epilepsy Behav. 2023.; Kwan P, et al. Definition of drug- MARCH 2026 23 resistant epilepsy. Epilepsia. 2010.; Landmark CJ, et al. Pharmacology of antiseizure medications. Epileptic Disord. 2023. ScienceDirect. Genetic generalized epilepsy. ScienceDirect Topics. Accessed March 6, 2026.
Market Research Suggests Both Epilepsy Specialists and General Neurologists May Find Value in Potential Azetukalner Attributes 1 1 Epilepsy Specialists General Neurologists Perceptions of Unfavorable Favorable Unfavorable Favorable “Product X” 2 Novel Mechanism of Action Ease of Use “Product X” Dosing Flexibility to Balance Efficacy and Safety Manageable Safety Profile Value Drivers Branded ASM-like Efficacy Fast Onset of Action The MoA is interesting to me. I The side effect profile of Product X Product X is distinguished from Product X has strong efficacy, great onset and [manageable] side like to choose something that is is tolerable. I also don’t have to other brands from a safety effects, it would be a 2/3L agent. different than what my patients wait to get my patients to an perspective, along with the lack – General Neurologist have received. This product gives effective dose, but have some of titration and rapid onset. me more flexibility. flexibility in the dose I choose. – General Neurologist –Epilepsy Specialist –Epilepsy Specialist 1. Research sample includes 14 general neurologists and 4 epileptologists. 2. Lack of titration schedule and limited DDIs drove physician perceptions of Product X as an “easy to MARCH 2026 24 use” treatment option with simple onboarding. Source: Physician Interviews; ClearView Analysis. Market research referenced herein is preliminary and qualitative in nature.
Path to Commercialization of Azetukalner Clinical Evidence Target Attributes Xenon Approach Customer Universe Strong efficacy, HCP mix of epilepsy X-TOLE2 Phase 3 Early commercial well-tolerated specialists, investments neurologists, APPs X-TOLE Phase 2b Novel MOA Deep expertise in Patients with FOS epilepsy + drug launches X-TOLE OLE QD, no titration Payors Focus on innovating Rapid onset the patient & HCP experiences Mood neutral or positive OLE, open-label extension; MOA, mechanism of action; QD, once-daily dosing; HCP, healthcare professionals; APPs, advanced practice providers; FOS, focal onset seizures MARCH 2026 25
Looking Toward the Future Ian Mortimer President & Chief Executive Officer
X-TOLE2 Results Summary Positive Phase 3 study results support an anticipated NDA submission in Q3 2026 PRIMARY ENDPOINT WAS MET: Highly statistically significant, dose-dependent reduction from baseline in median monthly FOS frequency (MPC) over the 12-week treatment period vs. placebo Responder rate 50: Statistically significant, dose-dependent (15 and 25 mg) increase in number of responders with >50% reduction in monthly FOS frequency Onset of efficacy: Rapid onset of response as assessed by statistically significant MPC achieved within one week for AZK 25 mg vs. placebo Overall health status: Significant improvements in PGI-C/CGI-C for both 15 and 25 mg treatment groups vs. placebo Safety and tolerability: AZK profile consistent with Phase 2b X-TOLE study AZK, azetukalner; PGI-C, Patient Global Impression of Change; CGI-C, Clinical Global Impression of Change; MPC, median percent change; FOS, focal onset seizure MARCH 2026 27
Thank you to our partners in the epilepsy community, including patient advocates, clinicians and study participants. Hadley, living with epilepsy
POSITIVE TOPLINE DATA Azetukalner in Focal Onset Seizures
For more information INVESTORS@XENON-PHARMA.COM
FAQ
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