XEN1101 · program

Azetukalner (XEN1101) for Major depressive disorder

Phase 3RecruitingXenon Pharmaceuticals Inc. (XENE)

Indications for XEN1101: Epilepsy · Phase 3 Major depressive disorder · Phase 3 Bipolar depression · Phase 3

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.

Data current as of

Development timeline

Phase 3Dec 2024
  1. Phase 3 MDD program initiated (X-NOVA2, then X-NOVA3).
Phase 2Sept 2023
  1. Phase 2 X-NOVA completed; MADRS 20 mg vs placebo difference 3.04 (p=0.135), significant week-1 separation + anhedonia benefit.↗

Clinical trials in Major depressive disorder

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)

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.

NCT04827901Phase 2Completedn=44

XEN1101 for Major Depressive Disorder

Started Oct 2021· Primary completion Oct 2024· 📍 2 sites across 1 country (United States)

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—

Mechanism of action (compound-wide)

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—ⓘ

← Full XEN1101 compound page (identity, identifiers, all indications)

Sources

  1. clinicaltrials.gov — clinicaltrials.gov
  2. clinicaltrials.gov — ClinicalTrials.gov
  3. medchemexpress.com — Reference
  4. X-NOVA (NCT05376150) — ClinicalTrials.gov
  5. X-NOVA2 (NCT06775379) — ClinicalTrials.gov
  6. 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
  7. Xenon X-NOVA Phase 2 MDD data (ASCP 2024) — Xenon Pharmaceuticals