JAMA network openMay 27, 2025

Azetukalner, a New Potassium Channel Opener, in Adults with Major Depression: A Randomized Clinical Trial

Updated Jan 1, 2026

Abstract

A total of 168 participants were randomized to receive either azetukalner or placebo in a clinical trial for major depressive disorder.

The mean reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores was -16.94 points for participants receiving 20 mg of azetukalner compared to -13.90 points for placebo at week 6.
The reduction in MADRS scores with 20 mg of azetukalner compared to placebo was clinically meaningful but not statistically significant at week 6.
A significant reduction in Hamilton Depression Rating Scale (HAM-D17) scores was observed with 20 mg of azetukalner compared to placebo (-13.3 vs -10.2 points; P = .04).
Participants receiving 20 mg of azetukalner showed a significant improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) compared to placebo (-7.77 vs -5.30 points; P = .046).
Rates of treatment-emergent adverse events were similar across all groups.

Simplified

IMPORTANCE: Available antidepressants provide inadequate therapeutic responses in many patients with major depressive disorder (MDD), highlighting a substantial unmet need.

OBJECTIVE: To evaluate the efficacy and safety of azetukalner, a novel, potent KV7 potassium channel opener, in participants with MDD.

DESIGN, SETTING, AND PARTICIPANTS: X-NOVA was a multicenter, proof-of-concept, phase 2, randomized, double-blind, parallel-group, placebo-controlled clinical trial that evaluated azetukalner in participants (adults aged ≥18 to ≤65 years) with moderate to severe MDD in a current depressive episode. Participants were enrolled between April 2022 and October 2023, and data analysis occurred from January 2023 to January 2024.

INTERVENTION: Participants were randomized (1:1:1) to 10 mg of azetukalner, 20 mg of azetukalner, or placebo orally once daily with food for 6 weeks, with a 4-week follow-up. Concomitant antidepressant medications were not permitted.

MAIN OUTCOMES AND MEASURES: The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. Secondary end points included change from baseline at week 6 in the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Anxiety Inventory. Exploratory end points included change in the Hamilton Depression Rating Scale, 17-Item (HAM-D17) score and change in MADRS at week 1. Frequency and severity of treatment-emergent adverse events (TEAEs) were recorded.

RESULTS: Altogether, 168 participants were randomized (56 to placebo, 56 to 10 mg of azetukalner, and 56 to 20 mg of azetukalner); mean (SD) age was 47.2 (13.6) years, and 111 participants (66.5%) were female. The modified intent-to-treat and safety populations consisted of 164 and 167 participants, respectively. The mean (SE) reduction in MADRS scores from baseline to week 6 was -13.90 (1.41) points with placebo, -15.61 (1.34) points with 10 mg of azetukalner, and -16.94 (1.45) points with 20 mg of azetukalner; the mean (SE) reduction with 20 mg of azetukalner vs placebo was clinically meaningful but not statistically significant (-3.04 points; 95% CI, -7.04 to 0.96 points; P = .14) at week 6, while significant at week 1 (-2.66 points; 95% CI, -5.30 to -0.03 points; P = .047). The mean (SE) reduction in HAM-D17 from baseline to week 6 was significantly greater with 20 mg of azetukalner vs placebo (-13.3 [1.1] vs -10.2 [1.0] points; P = .04). The mean (SE) reduction in SHAPS scores from baseline to week 6 was significantly greater with 20 mg of azetukalner vs placebo (-7.77 [0.87] vs -5.30 [0.85] points; P = .046). Similar rates of discontinuation due to TEAEs were reported across groups.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of azetukalner, preliminary findings supported its further clinical development for the treatment of MDD and anhedonia.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05376150.

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Conflict of Interest Disclosures: Drs Butterfield, Luzon Rosenblut, Beatch, Grayson, Harden, Ms Qian, and Drs McIntosh, Namdari, and Kenney reported being employees of and holding stock in Xenon Pharmaceuticals during the conduct of the study, and Drs Fava, Correll, Rothschild, Murrough, and Mathew reported receiving personal fees from Xenon Pharmaceuticals during the conduct of the study. Dr Fava reported receiving research support from AbbVie, Acadia Pharmaceuticals, Aditum Bio Management Company LLC, Allergan, Alkermes Inc, Altimate Health Corporation, Alto Neuroscience Inc, Ancora Bio Inc, Angelini S.p.A, Aptinyx, Arbor Pharmaceuticals LLC, Atai Therapeutics Inc, Autobahn Therapeutics Inc, Axsome, Benckiser Pharmaceuticals Inc, BioClinica Inc, Biogen, BioHaven, BioShin Limited, Cambridge Science Corporation, Centrexion Therapeutics Corporation, Clexio Biosciences Ltd, Cybin IRL Limited, Damona Pharmaceuticals, EmbarkNeuro, Eliem Therapeutics LTD, Gate Neurosciences Inc, GenOmind LLC, Gentelon LLC, Gerbera Therapeutics Inc, GH Research Ireland Limited, Gilgamesh Pharmaceuticals Inc, Happify, Janssen Research & Development LLC, Janssen Pharmaceutica NV, Johnson & Johnson, Lundbeck Inc, Marinus Pharmaceuticals, Medpace Inc, Millennium Pharmaceutics Inc, Mind Medicine Inc, Minerva Neurosciences, NeuraWell Therapeutics Inc, Neurocrine Biosciences Inc, Novaremed, Otsuka, Peachtree BioResearch Solutions Inc, Pfizer, Premiere Research International, Praxis Precision Medicines, Protagenic Therapeutics Inc, Relmada Therapeutics Inc, Shenox Pharmaceuticals, Stanley Medical Research Institute, Takeda, University of Michigan, University of Florida Board of Trustees, Vistagen; WinSanTor Inc, Xenon Pharmaceuticals Inc, XW Pharma Ltd, National Institute of Drug Abuse, National Institutes of Health, National Institute of Mental Health, and Patient-Centered Research Outcomes Institute; holding a patent with royalties for sequential parallel comparison design, licensed by Massachusetts General Hospital (MGH) to Pharmaceutical Product Development LLC (patent Nos. US_7840419, US_7647235, US_7983936, US_8145504, and US_8145505); having a patent application for a combination of ketamine plus scopolamine in major depressive disorder licensed by MGH to Biohaven; holding patents for pharmacogenomics of depression treatment with folate (patent Nos. US_9546401 and US_9540691) licensed to Nestle; holding a patent for a compound for improving l-arginine bioavailability (patent No. US_11,655,210) licensed to DimeRx; holding equity in Compellis (no longer in existence), Neuromity, Psy Therapeutics, Revival Therapeutics (no longer in existence), and Sensorium Therapeutics; holding copyright for the MGH Cognitive & Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs & Symptoms Questionnaire, Symptoms of Depression Questionnaire, Anxiety Symptoms Questionnaire, and Scale for Assessment of Family Enjoyment within Routines; holding copyright with other publishers including Belvoir; Lippincott, Williams & Wilkins; Wolters Kluwer; and World Scientific Publishing Co PteLtd; and conducting consulting on behalf of MGH, Revival Therapeutics (no longer in existence), and Sensorium Therapeutics outside the submitted work. Dr Correll reported receiving personal fees from AbbVie and having been a consultant and/or advisor to or having received honoraria from AbbVie Inc, Acadia Pharmaceuticals Inc, Adcock Ingram, Alkermes, Allergan, Angelini Pharma, Aristo Pharma, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Cardio Diagnostics Inc, Cerevel Therapeutics, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor Inc, Denovo, Eli Lilly, Gedeon Richter, Hikma Pharmaceuticals, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen Pharmaceuticals, Johnson & Johnson, Karuna Therapeutics, LB Pharmaceuticals Inc, Lundbeck, MedInCell, MedLink Pharma, Merck & Co Inc, Mindpax, Mitsubishi Tanabe Pharma, MapLight Therapeutics Inc, Mylan Pharmaceuticals Inc, Neumora Therapeutics Inc, Neurocrine Biosciences, Neurelis Inc, Newron Pharmaceuticals SpA, Noven Pharmaceutical Inc, Novo Nordisk, Otsuka Pharmaceutical, PPD Biotech, Recordati, Relmada Therapeutics Inc, Reviva Pharmaceuticals, Rovi, Sage Therapeutics, Saladax Biomedical Inc, Sanofi, CSL Seqirus, SK Life Science Inc, Sumitomo Pharma America Inc, Sunovion Pharmaceuticals Inc, Sun Pharma, Supernus Pharmaceuticals, Tabuk Pharmaceuticals, Takeda Pharmaceutical Company, Teva Pharmaceuticals, Terran Biosciences, Tolmar Inc, Vertex Pharmaceuticals, Viatris Inc, and Xenon Pharmaceuticals Inc; providing expert testimony for Janssen Pharmaceuticals, Lundbeck, and Otsuka Pharmaceutical; serving on a data safety monitoring board for Compass Pathways, Denovo, Intra-Cellular Therapies, Lundbeck, Relmada Therapeutics Inc, Reviva Pharmaceuticals, Rovi, Supernus Pharmaceuticals, and Teva Pharmaceuticals; receiving grant support from Boehringer Ingelheim, Janssen Pharmaceuticals, and Takeda Pharmaceutical Company; receiving royalties from UpToDate; and being a stock option holder of Cardio Diagnostics, Küleon Bioscience, LB Pharmaceuticals Inc, MedLink Pharma, Mindpax, The Quantic Group, and Terran Biosciences outside the submitted work. Dr Rothschild reported receiving grants from Compass Pathways, Janssen Pharmaceuticals, and Otsuka Pharmaceutical; personal fees from Sage Therapeutics, Daichi Sankyo Inc, and Neumora Therapeutics; and holding a patent for Rothschild Scale for Antidepressant Tachyphylaxis with royalties paid outside the submitted work. Dr Murrough reported receiving personal fees from Allergan Pharmaceuticals (AbbVie Inc), Biohaven Pharmaceuticals Inc, Boehringer Ingelheim, Clinilabs Inc, Clexio Biosciences Ltd, Compass Pathfinder PLC, Engrail Therapeutics Inc, Fortress Biotech Inc, FSV7 LLC, Genentech Inc, Impel Neuropharma, Janssen Pharmaceuticals, KetaMed Health & Wellness, LivaNova PLC, Merck & Co Inc, Novartis, Otsuka Pharmaceutical, Sage Therapeutics, and WCG Clinical; and having a pending patent for use of potassium voltage-gated channel subfamily Q (KCNQ) channel openers to treat depression outside the submitted work. Dr Mathew reported receiving personal fees from Abbott, Almatica, Autobahn Therapeutics, Biohaven, BioXcel, Boehringer Ingelheim, Brii Biosciences, Clexio Biosciences, Compass Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Eleusis, EMA Wellness, Engrail Therapeutics, Liva Nova, Merck, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Signant Health, Sunovion, and Pharma; and having research contracts with Boehringer Ingelheim, Engrail Therapeutics, and Sage Therapeutics outside the submitted work. No other disclosures were reported.

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