Xenon Announces Positive Topline Data from Phase 3 X-TOLE2 Study of Azetukalner in Focal Onset Seizures (FOS)

Rhea-AI Summary

Xenon (Nasdaq: XENE) reported positive topline Phase 3 X-TOLE2 results for azetukalner in focal onset seizures (FOS) on March 9, 2026. The trial met its primary endpoint with a -53.2% median percent change (MPC) in monthly FOS frequency for 25 mg versus -10.4% for placebo (placebo-adjusted -42.7%, p=6e-12).

Key secondary RR50 was 54.8% (25 mg) versus 20.8% placebo. Safety was consistent with prior studies. Xenon plans to file an NDA in Q3 2026 and will present X-TOLE2 as a Late Breaking Science oral at AAN on April 19, 2026.

Positive

• Primary endpoint met: MPC -53.2% (25 mg) versus -10.4% placebo
• Placebo-adjusted efficacy of -42.7% in 25 mg group
• Responder rate (RR50) 54.8% for 25 mg versus 20.8% placebo
• Plans to submit NDA to FDA in Q3 2026
• 322 of 332 completers entered open-label extension

Negative

• TEAE discontinuations higher in 25 mg group at 14.5% versus 3.2% placebo
• Dizziness incidence 20.5% in azetukalner groups versus 3.2% placebo
• Serious TEAEs 5.6% in 25 mg group versus 2.4% placebo

Key Figures

MPC 25 mg dose: -53.2% MPC in monthly FOS frequency MPC 15 mg dose: -34.5% MPC in monthly FOS frequency MPC placebo: -10.4% MPC in monthly FOS frequency +5 more

8 metrics

MPC 25 mg dose -53.2% MPC in monthly FOS frequency Baseline to Week 12, azetukalner 25 mg vs baseline

MPC 15 mg dose -34.5% MPC in monthly FOS frequency Baseline to Week 12, azetukalner 15 mg vs baseline

MPC placebo -10.4% MPC in monthly FOS frequency Baseline to Week 12, placebo group

Placebo-adjusted MPC 25 mg -42.7% vs -34.6% in Phase 2b Placebo-adjusted MPC, X-TOLE2 vs X-TOLE 25 mg

RR50 25 mg 54.8% vs 20.8% placebo Responder Rate ≥50% reduction, Week 12

Participants randomized 380 participants Total randomized in X-TOLE2 Phase 3 study

mITT population 374 participants Safety and modified intent-to-treat analyses

Primary endpoint p-value p=0.000000000006 25 mg dose primary endpoint MPC vs placebo

Market Reality Check

Price: $41.94 Vol: Volume 1,076,785 is 1.16x...

normal vol

$41.94 Last Close

Volume Volume 1,076,785 is 1.16x the 20-day average of 932,038 shares ahead of the data release. normal

Technical Price at 41.94 trades above the 200-day MA of 38.34 and 10.75% below the 52-week high of 46.99.

Peers on Argus

Momentum scanner did not flag a sector-wide move. Among high-affinity biotech pe...

Momentum scanner did not flag a sector-wide move. Among high-affinity biotech peers, same-day changes were mixed, with VKTX, IMVT, SLNO and SRRK up and RARE slightly down, suggesting this clinical update is more stock-specific than sector-driven.

Previous Clinical trial Reports

1 past event · Latest: May 28 (Positive)

Same Type Pattern 1 events

Date	Event	Sentiment	Move	Catalyst
May 28	Phase 2 MDD data	Positive	+0.6%	Presented Phase 2 X-NOVA MDD data showing symptom reduction and good tolerability.

Pattern Detected

Prior clinical-trial news for azetukalner in MDD saw a modestly positive price reaction, indicating past clinical updates were absorbed without outsized volatility.

Recent Company History

Over the last several quarters, Xenon has highlighted azetukalner as its lead asset across epilepsy and mood disorders, supported by Phase 2 and long-term open-label data. A prior May 28, 2024 Phase 2 MDD readout showed meaningful symptom reductions with generally good tolerability and a modest 0.63% share-price gain. Subsequent disclosures emphasized progressing to Phase 3 and broad late-stage development. Today’s Phase 3 focal onset seizure topline results extend that trajectory by adding pivotal epilepsy efficacy and safety data ahead of a planned NDA in Q3 2026.

Historical Comparison

+0.6% avg move · Past 12 months saw one azetukalner clinical-trial update, a Phase 2 MDD readout, with an average mov...

clinical trial

+0.6%

Average Historical Move clinical trial

Past 12 months saw one azetukalner clinical-trial update, a Phase 2 MDD readout, with an average move of +0.63%. Today’s Phase 3 epilepsy topline expands on that clinical story with pivotal seizure data.

The clinical program has progressed from Phase 2 MDD data toward multiple Phase 3 programs, now including positive Phase 3 focal onset seizure topline results supporting an NDA planned for Q3 2026.

Market Pulse Summary

This announcement details robust Phase 3 X-TOLE2 results, including a -53.2% median seizure reductio...

Analysis

This announcement details robust Phase 3 X-TOLE2 results, including a -53.2% median seizure reduction and strong responder rates, with a safety profile consistent with prior studies. It builds on earlier Phase 2 and long-term extension data and supports an NDA submission planned for Q3 2026 in focal onset seizures. Historically, clinical updates produced only modest share moves, so investors may focus on upcoming detailed presentations, regulatory interactions, and progress across the broader Phase 3 azetukalner program.

Key Terms

focal onset seizures, median percent change, placebo-adjusted, treatment-emergent adverse events, +2 more

6 terms

focal onset seizures medical

"Phase 3 X-TOLE2 study of azetukalner in focal onset seizures (FOS)."

Focal onset seizures are seizures that begin in a specific part of the brain and can cause localized symptoms such as brief changes in awareness, unusual sensations, or jerking in one limb; they can sometimes spread to affect the whole brain. Investors care because these seizures define patient groups, influence how drugs and devices are tested and approved, and shape market size, pricing and risk — like a localized outage that requires a targeted fix rather than a whole-system replacement.

median percent change medical

"primary endpoint of MPC in monthly FOS frequency from baseline to week 12"

Median percent change is the middle value of a list of individual percentage changes, found by ordering those percent changes and picking the one in the center; if there are an even number of values, it’s the average of the two middle values. For investors, it shows the typical or “middle” move across a group of stocks or time periods without being pulled by extreme winners or losers — like reporting the height of the person in the middle of a line rather than the average height.

placebo-adjusted medical

"The placebo-adjusted MPC in the 25 mg group was -42.7%, outperforming..."

The placebo-adjusted effect is the measured benefit of a treatment after subtracting any improvement seen in people who received a dummy or inactive treatment (placebo). Think of it like checking how much louder a new speaker is by comparing it to a broken speaker playing the same track; it isolates the true contribution of the product itself. Investors watch this because it shows the real clinical benefit that regulators, doctors, and payers will use to judge a therapy’s approval, demand, and pricing potential.

treatment-emergent adverse events medical

"The most common treatment-emergent adverse events (TEAEs) across both azetukalner dose groups..."

Events or symptoms that either appear for the first time or get worse after a patient starts a treatment; think of new or intensified side effects that show up once medicine or a medical device is used. Investors watch these closely because they affect whether a therapy can gain regulatory approval, be prescribed widely, or face legal and commercial setbacks—similar to how early customer complaints can sink a new product’s prospects.

open-label extension medical

"322 entered the open-label extension study."

An open-label extension is a continuation of a clinical trial where all participants and researchers know which treatment is being given, often after an initial blinded phase. It allows further study of a drug's long-term safety and effectiveness. For investors, it can indicate ongoing interest and confidence in a product's potential, influencing perceptions of its future value.

KV7 potassium channel opener medical

"Azetukalner is a novel, potent, KV7 potassium channel opener currently in clinical development..."

A Kv7 potassium channel opener is a drug that helps certain cellular ‘gates’ called Kv7 channels stay open so potassium can flow out of cells, calming electrical activity in nerves and muscle. For investors, these compounds matter because they can form the basis of treatments for conditions driven by excessive electrical firing—like some seizures, pain, or heart rhythm disorders—so successful candidates can create new medical markets or reduce risks in drug pipelines.

AI-generated analysis. Not financial advice.

• 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, 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). Azetukalner is a novel, potent, K_V7 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 K_V7 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 K_V7 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 K_V7 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 19^th, 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 K_V7 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 K_V7 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 K_V7 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 K_V7 and Na_V1.7 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

FAQ

What were the X-TOLE2 Phase 3 efficacy results for azetukalner (XENE) on March 9, 2026?

Azetukalner 25 mg reduced median monthly focal seizure frequency by 53.2% versus 10.4% for placebo. According to Xenon, the placebo-adjusted MPC was -42.7% with highly significant p-values, meeting the study primary endpoint.

What was the responder rate (RR50) in X-TOLE2 for azetukalner (XENE) and placebo?

The RR50 was 54.8% for azetukalner 25 mg versus 20.8% for placebo. According to Xenon, the 25 mg result was statistically significant and the 15 mg group also showed improved RR50 compared with placebo.

What safety signals did X-TOLE2 report for azetukalner (XENE) in focal onset seizures?

Azetukalner showed a safety profile consistent with prior trials but higher discontinuations at 14.5% (25 mg). According to Xenon, common TEAEs included dizziness, headache, somnolence, and fatigue versus lower rates in placebo.

When will Xenon (XENE) submit an NDA for azetukalner for focal onset seizures?

Xenon expects to submit a New Drug Application to the FDA in Q3 2026. According to Xenon, NDA submission follows the positive X-TOLE2 topline results and builds on prior Phase 2b data and long-term exposure data.

Will X-TOLE2 data for azetukalner (XENE) be presented at a medical congress?

Yes. X-TOLE2 results will be a Late Breaking Science oral presentation at the American Academy of Neurology on April 19, 2026. According to Xenon, the presentation will feature efficacy and safety topline data from the trial.