azetukalner (XEN1101) / Xenon - LARVOL DELTA

X-NOVA2 enrollment has reached approximately 80% of its initial target of 450 patients, which is sufficiently powered to demonstrate a clinically meaningful change in the study’s primary endpoint of HAM-D17 (GlobeNewswire) - "The Company plans to complete the six-week dosing period for patients currently enrolled in the trial and unblind the data. Topline data for X-NOVA2 are now expected in Q1 2027."

P3 data: top line • Trial status • Major Depressive Disorder

Next-Generation Pharmacotherapies for Unipolar Mood Disorders: A Leading Article on Phase II/III Drug Development Across Diverse Mechanisms. (PubMed, CNS Drugs) - "Following the US Food and Drug Administration (FDA) approval of esketamine and brexanolone in 2019, industry investment in therapeutics with novel mechanisms for mood and anxiety disorders has expanded, catalyzing a new wave of innovative interventions...The drug names discussed are ALTO-100, ALTO-203, ALTO-207, ALTO-300, BHV-7000, BI-1569912, BPL-003, COMP360, DT120, ELE-101, GATE-251, GH001, GM-1020, GM-2505, HLP003, MK-1942, NBI-1065845, NBI-1070770, NV-5138, PIPE-307, SEP-363856, SPT-300, VLS-01, and XEN1101. The US Clinical Trials registry (clinicaltrials.gov), MEDLINE, conference proceedings, and company communications such as press releases were consulted to obtain up-to-date trial information and reported outcomes. Overall, the therapeutic landscape shows an expanding range of clinical compounds under active development; nonetheless, persistent challenges remain, including approaches to therapeutics where functional unblinding may occur, the ways in which to..."

Journal • P2/3 data • Review • CNS Disorders • Mood Disorders • Psychiatry

Xenon Pharmaceuticals…announced it has submitted a New Drug Application (NDA) for azetukalner in focal seizures (FS) to the U.S. Food and Drug Administration (FDA) (GlobeNewswire) - "The NDA submission is based on positive clinical data from two global, randomized, double-blind, placebo-controlled trials for azetukalner in focal seizures, including the Phase 2b X-TOLE study and Phase 3 X-TOLE2 study. Across the two studies, treatment with all four doses of azetukalner demonstrated a statistically significant reduction from baseline in monthly seizure frequency compared with placebo, and azetukalner was generally well-tolerated with a consistent safety profile observed in both studies."

FDA filing • CNS Disorders • Epilepsy

Xenon Pharmaceuticals Inc…submitted a New Drug Application to the U.S. Food and Drug Administration for azetukalner as a treatment for focal seizures, the company announced today in a press release statement. (Investing.com) - "The NDA submission is based on data from two clinical trials: the Phase 2b X-TOLE study and Phase 3 X-TOLE2 study."

FDA filing • Epilepsy

…The Company announced today that it has implemented a voluntary pause on enrollment for new patients in its ongoing clinical studies in major depressive disorder (MDD) and bipolar depression (BPD), following an analysis of neuropsychiatric adverse events in these studies (GlobeNewswire) - "Participants currently enrolled in the randomized controlled psychiatry studies and associated OLE studies will continue on study. The observed events, the rate of these events and their severity, are consistent with the known safety and tolerability profile of azetukalner and its mechanism; however, such adverse events had not previously been seen in the Phase 2 X‑NOVA clinical study in MDD. The enrollment pause is being implemented as a precautionary measure by Xenon in consultation with its Data Safety Monitoring Board (DSMB) and is expected to be temporary."

Enrollment status • Bipolar Disorder • Major Depressive Disorder

Antiseizure Medications in Development: Novel Mechanisms, Precision Therapy, and the Move Towards Disease Modification. (PubMed, Curr Issues Mol Biol) - "Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial...Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABAA modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen)... The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent..."

Journal • Review • CNS Disorders • Epilepsy • SCN8A

From Retigabine to Azetukalner: Reviving Voltage-Gated Potassium Channels for Epilepsy Therapy. (PubMed, Arch Pharm (Weinheim)) - "This structural analog of retigabine exhibits improved metabolic stability, increased potency, and enhanced blood-brain barrier penetration compared with its predecessor. This review details the synthesis, physicochemical properties, and clinical results of azetukalner."

Journal • Review • CNS Disorders • Epilepsy • Pain

KCNQ2 Channel as a Druggable Epilepsy Target: Advances in Pharmacological Modifiers. (PubMed, CNS Neurol Disord Drug Targets) - "Pharmacological modifiers of Kv7- mediated currents, such as retigabine, have demonstrated the restoration of impaired M-currents, but safety concerns limit their clinical application. Recent progress has led to the development of nextgeneration Kv7 activators, such as XEN1101, as well as other investigational compounds with improved potency, selectivity, and tolerability...Safety considerations, biomarkers of treatment responsiveness, and neurodevelopmental effects require careful evaluation. Nonetheless, the evolving pharmacological landscape highlights KCNQ2 channels as attractive and druggable targets in epilepsy, offering opportunities for mechanism-based therapies that could transform the management of this rare but devastating DEE."

Journal • CNS Disorders • Epilepsy

Potassium channel agonists emerging as treatment options for focal epilepsy: are we breaking new ground? (PubMed, Expert Opin Emerg Drugs) - "This mini-review summarizes the clinical evolution of Kv7 modulation, from the first-generation prototype ezogabine to more selective second-generation candidates. We outline the scientific rationale for targeting the M-current, review emerging clinical data for agents such as azetukalner (XEN1101) and opakalim (BHV-7000), and highlight preclinical strategies including dual-mechanism modulators and drug repurposing...Second-generation agents provide encouraging mechanistic and clinical proof-of-concept, but long-term success will depend on clear advantages in patient-centered outcomes over established ASMs. Future value is likely to lie in precision-medicine strategies for KCNQ2/3-related encephalopathies and a carefully defined role in managing neuropsychiatric comorbidities."

Journal • Review • CNS Disorders • Epilepsy • Psychiatry

A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (X-NOVA3) (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

Trial initiation date • 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.

Trial initiation date • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

XPF-010-B302: An Open-label Study of Azetukalner in Bipolar I or II Depression (clinicaltrialsregister.eu) - P2/3 | N=20 | 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. Separately, XEN1101 25 mg showed better treatment phase responder rates (OR 6.80[3.15, 14.7]), achieving a SUCRA ranking of 79.7% over RTG 600 mg (52.5%) and placebo (7.5%). Conclusions 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 activators Background KCNQ2/3 activators: retigabine(RTG) and azetukalner (XEN1101) are promising treatments for partial onset seizures targeting neuronal excitability to reduce seizure frequency. Hence, careful dose optimization and close patient monitoring are essential to reduce these events. In future, strategies like dose calculation tailored to patients' genetic and clinical profiles should be developed, resulting in achieving the benefits without increasing harmful effects."

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) - "Conclusions 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) - P3 | "Efficacy and safety results will be presented. Conclusions X-TOLE2 results will support the regulatory submission of AZK in FOS and could mark the next generation of ASMs available to people living with epilepsy."

Clinical • Late-breaking abstract • P3 data • CNS Disorders • Epilepsy • CYP3A4

Potassium Channelopathies and Precision Medicine Approaches in Epilepsy: A Systematic Review of Personalized Treatment Strategies. (PubMed, Curr Neuropharmacol) - "These studies collectively offer valuable insights into precision medicines for genetic epilepsy caused by pathogenic potassium variants. This review is essential because it informs clinical decision-making, including the selection of antiepileptic drugs, thereby supporting its integration into routine clinical care for this population. However, the low level of evidence and the heterogeneity of data from the included studies limit the review."

Journal • CNS Disorders • Epilepsy

X-TOLE4: An Open-label Study of XEN1101 in Epilepsy (clinicaltrials.gov) - P3 | N=880 | Enrolling by invitation | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Sep 2028 ➔ Jun 2033 | Trial primary completion date: Jul 2028 ➔ Apr 2033

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

A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (X-NOVA3) (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Trial initiation date • 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. | N=123 ➔ 400

Enrollment change • Trial initiation date • Bipolar Disorder • CNS Disorders • Depression • 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=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

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