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

Key facts

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#

201820202022202420262028TodayPhase 330 Jun 2028 — upcoming — X-CEED Phase 3 topline in bipolar I/II depression (MADRS at Week 6) anticipated1 Jan 2027 — upcoming — Phase 3 X-NOVA2 topline in major depressive disorder expected H1 2027.1 Oct 2026 — upcoming — X-TOLE3 Phase 3 topline (second pivotal focal-onset-seizure trial) anticipated; primary completion ~Oct 2026.1 Jul 2026 — upcoming — FDA NDA submission for azetukalner in focal onset seizures remains on track for Q3 2026; pre-NDA meeting with FDA completed.18 Jun 2026 — Conference presentation — Phase 3 X-TOLE2 topline efficacy and safety results presented at the Epilepsy Foundation Pipeline Conference9 Mar 2026 — readout (met) — 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.8 Aug 2025 — phase change — 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.20 Dec 2024 — phase change — Phase 3 MDD program initiated (X-NOVA2, then X-NOVA3).18 Nov 2022 — phase change — 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).10 Sept 2018 — Option exercise — Xenon buys out XEN1101 milestones and royalties from Valeant/Bausch Health subsidiaries25 Apr 2017 — Licensing deal — Xenon acquires worldwide rights to XEN1101 from 1st Order PharmaceuticalsPhase 218 Sept 2023 — phase change — Phase 2 X-NOVA completed; MADRS 20 mg vs placebo difference 3.04 (p=0.135), significant week-1 separation + anhedonia benefit.4 Oct 2021 — phase change — 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.
Phase change Readout Event UpcomingHover a marker for details.
Phase 3Apr 2017 – Jun 2028
  1. UpcomingX-CEED Phase 3 topline in bipolar I/II depression (MADRS at Week 6) anticipatedBipolar depression
  2. UpcomingPhase 3 X-NOVA2 topline in major depressive disorder expected H1 2027.Major depressive disorder↗
  3. UpcomingX-TOLE3 Phase 3 topline (second pivotal focal-onset-seizure trial) anticipated; primary completion ~Oct 2026.Epilepsy
  4. UpcomingFDA NDA submission for azetukalner in focal onset seizures remains on track for Q3 2026; pre-NDA meeting with FDA completed.Epilepsy↗
  5. Conference presentationPhase 3 X-TOLE2 topline efficacy and safety results presented at the Epilepsy Foundation Pipeline ConferenceEpilepsy↗
  6. 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↗
  7. 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
  8. Phase 3 MDD program initiated (X-NOVA2, then X-NOVA3).Major depressive disorder
  9. 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
  10. Option exerciseXenon buys out XEN1101 milestones and royalties from Valeant/Bausch Health subsidiaries↗
  11. Licensing dealXenon acquires worldwide rights to XEN1101 from 1st Order Pharmaceuticals↗
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 remains on track for Q3 2026; pre-NDA meeting with FDA completed. ↗

  • 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.

Readouts

  • H1 2027AnticipatedTopline data

    Phase 3 X-NOVA2 topline in major depressive disorder 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 StatesPolandFinlandRomania

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 StatesArgentinaPortugalFrance

Show all 8 trials

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 StatesSpainAustraliaGermany

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 StatesSpainGermanyItaly

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:

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
Show all 16 sources
  1. Xenon Enters into Agreement to Buy Out Milestones and Royalties Related to its XEN1101 Program — GlobeNewswire (Xenon Pharmaceuticals Inc.)
  2. Xenon Pharmaceuticals Announces Acquisition of XEN1101 (Form 8-K exhibit 99.1, April 2017) — U.S. Securities and Exchange Commission (EDGAR)
  3. Xenon Reports Q2 2026 Financial Results and Provides Business Update (8-K Exhibit 99.1) — Xenon Pharmaceuticals
  4. Xenon X-NOVA Phase 2 MDD data (ASCP 2024) — Xenon Pharmaceuticals
  5. Xenon X-TOLE Phase 2b positive topline (focal epilepsy) — Xenon Pharmaceuticals
  6. Xenon X-TOLE2 Phase 3 positive topline; Q3 2026 NDA guidance — Xenon Pharmaceuticals