azetukalner (XEN1101) / Xenon - LARVOL DELTA

X-CEED: A Randomized Study of Azetukalner Versus Placebo in Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) (clinicaltrials.gov) - P3 | N=97 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

X-TOLE2: A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (clinicaltrials.gov) - P3 | N=380 | Completed | Sponsor: Xenon Pharmaceuticals Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Epilepsy

XPF-010-B301: A Randomized Study of Azetukalner Versus Placebo in Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) - X-CEED (clinicaltrialsregister.eu) - P2/3 | N=21 | Not yet recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P2/3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Therapeutic Efficacy and Seizure Control with KCNQ2/3 Activators in Partial-onset Epilepsy: A Dose-response Network Meta-analysis of Randomized Controlled Trials (AAN 2026) - "Objective: To compare the efficacy of different doses of KCNQ2/3 activators—retigabine (RTG) and XEN1101—against placebo in reducing partial-onset seizure frequency.Background: KCNQ2/3 activators are promising adjunctive treatments for partial onset seizures, targeting neuronal excitability to reduce seizure frequency. RTG 1200 mg represents the most effective dose for reducing seizure frequency and achieving seizure freedom, emphasizing the importance of selecting an adequate dose to maximize Kv7.2/7.3 channel activation."

Retrospective data • CNS Disorders • Epilepsy

Safety Outcomes of KCNQ2/3 Activators in Partial-onset Epilepsy: A Meta-analysis of Randomized Trials (AAN 2026) - "Objective: To analyze the safety outcomes of KCNQ2/3 activatorsBackground: KCNQ2/3 activators: retigabine(RTG) and azetukalner (XEN1101) are promising treatments for partial onset seizures targeting neuronal excitability to reduce seizure frequency. KCNQ2/3 activators significantly improve seizure control but have very high adverse events, particularly CNS-related effects. Several adverse events, including dysarthria and tremor, showed markedly elevated odds compared with placebo. This can be due to their mechanism of enhancing neuronal hyperpolarization."

Retrospective data • CNS Disorders • Epilepsy • Movement Disorders

Azetukalner, a Novel, Potent KV7 Channel Opener, in Adults with Focal Epilepsy: =42-Month Interim Analysis of the Ongoing 7-year X-TOLE Open-label Extension (AAN 2026) - "In the ongoing X-TOLE OLE, azetukalner was generally well tolerated, with no new safety signals. These data support the long-term safety and efficacy of azetukalner in a difficult-to-treat population of patients with FOS."

Clinical • Alzheimer's Disease • Bipolar Disorder • CNS Disorders • Depression • Epilepsy • Infectious Disease • Major Depressive Disorder • Mood Disorders • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Results From the Phase 3 X-TOLE2 Study Evaluating Azetukalner, a Novel, Potent KV7 Channel Opener, in Adults With Focal Onset Seizures (FOS) (AAN 2026) - No abstract available

Clinical • Late-breaking abstract • P3 data • CNS Disorders • Epilepsy

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=300 | Not yet recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P2 trial • CNS Disorders • Epilepsy

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=325 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Oct 2026 ➔ Oct 2028

Trial completion date • CNS Disorders • Epilepsy

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=325 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Oct 2024 ➔ Oct 2026

Trial completion date • CNS Disorders • Epilepsy

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=300 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2022 ➔ Oct 2024 | Trial primary completion date: Jun 2021 ➔ Sep 2021

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Jul 2020 ➔ Jun 2022 | Trial primary completion date: Jul 2020 ➔ Jun 2021

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

XPF-010-D302: A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (clinicaltrialsregister.eu) - P2/3 | N=140 | Not yet recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P2/3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Novel pharmacological therapies in development. (PubMed, Curr Opin Neurol) - "New paradigms in drug discovery have brought to development innovative treatments with diverse targets and mechanisms of action. Many of these treatments are etiology-targeting and have the potential for disease-modifying effects. Although high-quality evidence is awaited, there is hope that over the next few years, much needed life-changing therapies will be widely available for millions of people with disabling, drug-resistant epilepsies."

Journal • CNS Disorders • Epilepsy

Efficacy of a K+ Channel Agonist, XEN1101, For Preserving Contractility in Mouse Models of Hypokalemic Periodic Paralysis. (PubMed, Muscle Nerve) - "The KV7 potassium channel agonist XEN1101 is effective as both a prophylactic agent and as abortive therapy for management of low-K+ induced weakness in murine models of HypoPP. XEN1101 is more potent than the first-generation Kv7 agonist, retigabine, in our murine models of HypoPP and is also better tolerated in patients. These improvements provide a rationale for future clinical trials of XEN1101 in HypoPP patients."

Journal • Preclinical • CAV1 • NAV1

Long-Term Safety and Efficacy of Azetukalner, a Novel, Potent Kv7 Potassium Channel Opener, in Adults With Focal Epilepsy: ≥42-Month Interim Analysis of the Ongoing 7-Year X-TOLE Open-Label Extension (AES 2025) - "In this updated analysis of the ongoing X-TOLE OLE, azetukalner was generally well tolerated, and no new safety signals were identified. These promising interim data continue to support the long-term safety and efficacy of azetukalner in a difficult-to-treat population of patients with FOS."

Clinical • Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Infectious Disease • Major Depressive Disorder • Mood Disorders • Novel Coronavirus Disease • Pneumonia • Psychiatry • Respiratory Diseases

Characterization of Long-Term Seizure Freedom in the Ongoing Open-Label Extension of X-TOLE: Potential Implications for Future Clinical Practice (AES 2025) - "This post hoc analysis of the X-TOLE OLE highlights the potential of azetukalner to support long-term seizure freedom. These findings may help inform future clinical decision making by providing a more nuanced understanding of treatment response patterns over time, including the possibility to regain periods of seizure freedom with long-term treatment with azetukalner."

Clinical • CNS Disorders • Epilepsy

Industry Supported Scientific Exhibit | Azetukalner, a Novel Potassium Channel Opener: Clinical Program Update (AES 2025) - "Sponsored by Xenon Pharmaceuticals Inc."

Clinical

Kr233: selective kcnq2/3 opener with best-in-class potential for epilepsy (Neuroscience 2025) - "Ezogabine (retigabine), the first KCNQ opener approved in 2011 for the treatment of focal seizures, was voluntarily withdrawn from the market in 2017 due to chemical issues unrelated to its action on Kv7.2/3...In preclinical models, KR233 provided robust protection against seizures in both the pentylenetetrazole (PTZ) and maximal electroshock (MES) -induced seizure models, with a good PK/PD correlation (EC50,plasma <50 ng/ml)...In contrast, XEN-1101 induced significant impairments at equivalent doses with TD50 < 40 mg/kg in the same condition...Overall, these results indicate that KR233 is a promising novel therapeutic candidate for the treatment of epilepsy. IND filling expected in Q3 2025."

CNS Disorders • Epilepsy

An Open-label Study of Azetukalner in Bipolar I or II Depression (X-CEED-OLE) (clinicaltrials.gov) - P3 | N=400 | Enrolling by invitation | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE3) (clinicaltrials.gov) - P3 | N=360 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Aug 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

A Randomized, Controlled Trial of the Novel, Potent Kv7 Channel Opener Azetukalner in Individuals with Major Depressive Disorder and Anhedonia: Neural Response to Reward, Clinical Outcomes, and Safety. (PubMed, Res Sq) - P2 | "Despite not meeting the primary neuroimaging endpoint , secondary and exploratory outcomes suggested potential improvement in depressive and anhedonia symptoms, consistent with recent studies. Trial Registration: Clinicaltrials.gov ID NCT04827901."

Clinical • Clinical data • Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

X-CEED: A Randomized Study of Azetukalner Versus Placebo in Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

X-TOLE2: A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (clinicaltrials.gov) - P3 | N=360 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy