XEN1101 · program

Azetukalner (XEN1101) for Epilepsy

Phase 3ActiveXenon Pharmaceuticals Inc. (XENE)

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

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.

Data current as of

Development timeline

Phase 3Nov 2022 – Oct 2026
  1. UpcomingX-TOLE3 Phase 3 topline (second pivotal focal-onset-seizure trial) anticipated; primary completion ~Oct 2026.
  2. UpcomingFDA NDA submission for azetukalner in focal onset seizures planned for Q3 2026.↗
  3. 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.↗
  4. 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).
Phase 2Oct 2021
  1. 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.↗

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. ↗

Clinical trials in Epilepsy

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.

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.

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. medchemexpress.com — Reference
  2. X-TOLE Phase 2b (NCT03796962) — ClinicalTrials.gov
  3. X-TOLE2 Phase 3 (NCT05614063) — ClinicalTrials.gov
  4. X-TOLE3 Phase 3 (NCT05716100) — ClinicalTrials.gov
  5. 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
  6. Xenon X-TOLE Phase 2b positive topline (focal epilepsy) — Xenon Pharmaceuticals
  7. Xenon X-TOLE2 Phase 3 positive topline; Q3 2026 NDA guidance — Xenon Pharmaceuticals