Small Molecule · XEN1101

Azetukalner (XEN1101)

Phase 3Xenon Pharmaceuticals Inc. (XENE)

Potent, selective oral opener of Kv7.2/Kv7.3 (KCNQ2/3) potassium channels (a second-generation successor to ezogabine), from Xenon Pharmaceuticals. In Phase 3 for major depressive disorder (X-NOVA program), with parallel Phase 3 programs in focal epilepsy (X-TOLE2) and bipolar depression (X-CEED).

Also known as: XEN1101, Azetukalner

Data current as of

Modality
Small molecule
Chemical class
Tetrahydroisoquinoline, Butyramide, fluoroarene
Chemistry
Achiral
Mechanism
Kv7.2 activator
Highest phase
Phase 3
Lead indication
Epilepsy
Developer
Xenon Pharmaceuticals Inc. (XENE)
Trials
8 tracked · 4 recruiting · 468 sites
Next catalyst
Q3 2026 — Regulatory (Epilepsy)

Mechanism of action

Selective opener of neuronal Kv7.2/Kv7.3 (KCNQ2/3) channels; increases K+ flux, hyperpolarizes the membrane and dampens hyperexcitability. EC50 ~27 nM at the Kv7.2/7.3 heteromer.

TargetActionAffinity
Kv7.2primaryKCNQ2ActivatorEC50 27 nMⓘ
Kv7.3KCNQ3Activator—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
Azetukalner oral once-dailypowder-in-capsule
10-25 mg once daily with food, no titration; effective half-life >24 h supports once-daily dosing. Phase 1 used a powder-in-capsule formulation; Phase 2b/3 (X-TOLE, X-TOLE2) used 10/15/20/25 mg once daily with food.
OralOnce daily—

Development timeline

Phase 3Nov 2022 – Jun 2028
  1. UpcomingX-CEED Phase 3 topline in bipolar I/II depression (MADRS at Week 6) anticipatedBipolar depression
  2. UpcomingX-TOLE3 Phase 3 topline (second pivotal focal-onset-seizure trial) anticipated; primary completion ~Oct 2026.Epilepsy
  3. UpcomingFDA NDA submission for azetukalner in focal onset seizures planned for Q3 2026.Epilepsy↗
  4. metX-TOLE2 Phase 3 POSITIVE: azetukalner cut monthly focal-onset seizure frequency -53.2% at 25 mg (placebo-adjusted -42.7%, p=6e-12) vs -10.4% placebo; supports Q3 2026 NDA.Epilepsy↗
  5. Phase 3 bipolar depression program initiated; X-CEED (NCT07172516) began enrolling (actual study start 2025-08-08). X-CEED is the first of two planned Phase 3 BPD efficacy trials.Bipolar depression
  6. Phase 3 MDD program initiated (X-NOVA2, then X-NOVA3).Major depressive disorder
  7. Pivotal Phase 3 focal-epilepsy program initiated: X-TOLE2 (NCT05614063) first-patient-in 2022-11-18, followed by X-TOLE3 (NCT05716100, start 2023-05-09).Epilepsy
Phase 2Oct 2021 – Sept 2023
  1. Phase 2 X-NOVA completed; MADRS 20 mg vs placebo difference 3.04 (p=0.135), significant week-1 separation + anhedonia benefit.Major depressive disorder↗
  2. Phase 2b X-TOLE (NCT03796962) positive topline: met primary endpoint with statistically significant, dose-dependent reduction in monthly focal seizure frequency (52.8% at 25 mg, p<0.001) vs placebo. Primary completion 2021-09-02.Epilepsy↗

Azetukalner (XEN1101) for Epilepsy

Phase 3ActiveEpilepsy indication →

Azetukalner (XEN1101) for focal onset seizures (FOS) as adjunctive therapy in adults with treatment-resistant focal epilepsy. This is azetukalner's lead and most advanced indication. Phase 2b X-TOLE (NCT03796962) met its primary endpoint with a dose-dependent reduction in monthly focal seizure frequency (52.8% at 25 mg, p<0.001). The pivotal Phase 3 program comprises X-TOLE2 (NCT05614063, completed) and X-TOLE3 (NCT05716100, recruiting). X-TOLE2 reported POSITIVE topline on 2026-03-09: median percent reduction in monthly FOS frequency of -53.2% (25 mg, p=6e-12) and -34.5% (15 mg, p=0.00007) vs -10.4% placebo (placebo-adjusted -42.7% at 25 mg). Xenon guided to an FDA NDA submission for FOS in Q3 2026; as of this record the NDA has not been confirmed submitted.

Readouts

  • 2H 2026AnticipatedTopline dataNCT05716100

    X-TOLE3 Phase 3 topline (second pivotal focal-onset-seizure trial) anticipated; primary completion ~Oct 2026.

  • Q3 2026AnticipatedRegulatory

    FDA NDA submission for azetukalner in focal onset seizures planned for Q3 2026. ↗

  • 2026-03-09ReportedTopline datametNCT05614063

    X-TOLE2 Phase 3 POSITIVE: azetukalner cut monthly focal-onset seizure frequency -53.2% at 25 mg (placebo-adjusted -42.7%, p=6e-12) vs -10.4% placebo; supports Q3 2026 NDA. ↗

Azetukalner (XEN1101) for Major depressive disorder

Phase 3RecruitingMajor depressive disorder indication →

Azetukalner for moderate-to-severe MDD. Phase 2 X-NOVA (NCT05376150) showed a 3.04-point MADRS difference (20 mg vs placebo, p=0.135 — not significant, but clinically meaningful with significant week-1 separation and anhedonia benefit). Phase 3 X-NOVA program: X-NOVA2 (NCT06775379, started Dec 2024) + X-NOVA3 (NCT07076407, Jul 2025) + open-label long-term (NCT06922110); X-NOVA2 topline expected H1 2027.

Azetukalner (XEN1101) for Bipolar depression

Phase 3RecruitingBipolar depression indication →

Azetukalner for depressive episodes associated with bipolar I or II disorder (X-CEED Phase 3 program). 20 mg azetukalner administered orally with food as monotherapy over a 6-week double-blind period; primary efficacy endpoint is change from baseline in MADRS total score at Week 6. The Phase 3 BPD program comprises two planned randomized, double-blind, placebo-controlled trials (~400 patients each); the first, X-CEED (NCT07172516), began enrolling August 2025 (primary completion estimated June 2028). A long-term open-label extension, X-CEED-OLE (NCT07217860), opened October 2025 (enrolling by invitation). The second pivotal efficacy trial is planned but not yet registered. No direct Phase 2 study in bipolar depression preceded X-CEED; the program leverages the MDD/X-NOVA and epilepsy clinical experience.

Readouts

  • 2028AnticipatedTopline dataNCT07172516

    X-CEED Phase 3 topline in bipolar I/II depression (MADRS at Week 6) anticipated

Clinical trials

NCT07217860X-CEED-OLEPhase 3Activen=400

A Multicenter, Long-term, Open-Label, Safety, Tolerability, and Efficacy Study of Azetukalner in Bipolar I or II Depression (X-CEED-OLE)

Started Oct 2025· 📍 15 sites across 1 country (United States)

NCT07172516X-CEEDPhase 3Recruitingn=400

A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Azetukalner in Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) (X-CEED)

Started Aug 2025· 📍 28 sites across 1 country (United States)

NCT07076407X-NOVA3Phase 3Recruitingn=450

Phase 3 Study of Azetukalner in Moderate-to-Severe Major Depressive Disorder (X-NOVA3)

Started Jul 2025· Primary completion May 2027· 📍 44 sites across 6 countries (United States, Poland, Finland, Romania)

NCT06775379X-NOVA2Phase 3Recruitingn=450

Phase 3 Study of Azetukalner in Moderate-to-Severe Major Depressive Disorder (X-NOVA2)

Started Dec 2024· Primary completion Aug 2026· 📍 46 sites across 1 country (United States)

NCT05716100X-TOLE3Phase 3Recruitingn=360

A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE3)

Started May 2023· Primary completion Oct 2026· 📍 95 sites across 20 countries (United States, Argentina, Portugal, France)

NCT05614063X-TOLE2Phase 3Completedn=380

A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE2)

Started Nov 2022· Primary completion Jan 2026· 📍 125 sites across 18 countries (United States, Spain, Australia, Germany)

metprimaryMedian percent change in monthly focal onset seizure frequency from baseline (Week 12), 25 mg vs placebo — -53.2% (25 mg) vs -10.4% placebo; placebo-adjusted -42.7% (6e-12)

POSITIVE topline (2026-03-09). Median percent reduction in monthly FOS frequency: -53.2% (25 mg, p=0.000000000006) and -34.5% (15 mg, p=0.00007) vs -10.4% placebo; placebo-adjusted effect -42.7% at 25 mg. 50% responder rate: 54.8% (25 mg, p=8e-8) and 37.6% (15 mg, p=0.003) vs 20.8% placebo. Highly treatment-resistant population (median 5 prior ASMs; baseline 12.75 seizures/month). 380 randomized, 374 in safety/mITT. Most common TEAEs (azetukalner): dizziness 20.5%, headache 8.8%, somnolence 8.8%, fatigue 7.6%; AE discontinuations 14.5% (25 mg) / 4.8% (15 mg) / 3.2% (placebo). Data support an FDA NDA submission planned for Q3 2026.

NCT05376150X-NOVAPhase 2Completedn=168

Phase 2 Proof-of-Concept Study of XEN1101 in Major Depressive Disorder (X-NOVA)

Started May 2022· Primary completion Sept 2023· 📍 20 sites across 1 country (United States)

missedprimaryMADRS change at Week 6 (20 mg vs placebo) — -3.04 points (16.94 vs 13.90) (0.135)

Primary not statistically significant; significant week-1 separation (p=0.047) and significant anhedonia reduction; advanced to Phase 3.

NCT03796962X-TOLEPhase 2Activen=325

A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (X-TOLE)

Started Jan 2019· Primary completion Sept 2021· 📍 95 sites across 9 countries (United States, Spain, Germany, Italy)

metprimaryMedian percent change in monthly focal seizure frequency, 25 mg vs placebo (double-blind period) — -52.8% (25 mg) vs placebo (<0.001)

Met primary endpoint: statistically significant, dose-dependent reduction in monthly focal seizure frequency vs placebo (52.8% reduction at 25 mg [n=112, p<0.001]; 46.4% at 20 mg [n=51, p<0.001]; 33.2% at 10 mg [n=46, p=0.035]). Open-label extension showed sustained ~80-90% median reduction and 68% one-year retention at 20 mg.

Conference coverage

XEN1101 appears in 1 CNS Pulse conference abstract:

Related compounds

Other Kv7.2 compounds

Identifiers

Sources

  1. clinicaltrials.gov — ClinicalTrials.gov
  2. medchemexpress.com — Reference
  3. X-CEED — Phase 3 Azetukalner in Bipolar I/II Depression (NCT07172516) — ClinicalTrials.gov
  4. X-CEED-OLE — Open-label Azetukalner in Bipolar I/II Depression (NCT07217860) — ClinicalTrials.gov
  5. X-NOVA (NCT05376150) — ClinicalTrials.gov
  6. X-NOVA2 (NCT06775379) — ClinicalTrials.gov
  7. X-TOLE Phase 2b (NCT03796962) — ClinicalTrials.gov
  8. X-TOLE2 Phase 3 (NCT05614063) — ClinicalTrials.gov
  9. X-TOLE3 Phase 3 (NCT05716100) — ClinicalTrials.gov
  10. Xenon Announces Final Results of XEN1101 Phase 1 Clinical Trial (powder-in-capsule formulation, effective half-life >24 h, once-per-day dosing) — Xenon Pharmaceuticals / GlobeNewswire
  11. Xenon X-NOVA Phase 2 MDD data (ASCP 2024) — Xenon Pharmaceuticals
  12. Xenon X-TOLE Phase 2b positive topline (focal epilepsy) — Xenon Pharmaceuticals
  13. Xenon X-TOLE2 Phase 3 positive topline; Q3 2026 NDA guidance — Xenon Pharmaceuticals