{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:36:43Z","timestamp":1790127403566,"version":"4.0.1"},"reference-count":45,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Available antidepressants provide inadequate therapeutic responses in many patients with major depressive disorder (MDD), highlighting a substantial unmet need.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the efficacy and safety of azetukalner, a novel, potent KV<\/jats:sub>7 potassium channel opener, in participants with MDD.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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 \u226518 to \u226465 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.<\/jats:p><\/jats:sec>Intervention<\/jats:title>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.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary efficacy end point was change in Montgomery-\u00c5sberg 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.<\/jats:p><\/jats:sec>Results<\/jats:title>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 \u201313.90 (1.41) points with placebo, \u201315.61 (1.34) points with 10 mg of azetukalner, and \u201316.94 (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 (\u20133.04 points; 95% CI, \u20137.04 to 0.96 points; P<\/jats:italic>\u2009=\u2009.14) at week 6, while significant at week 1 (\u20132.66 points; 95% CI, \u20135.30 to \u20130.03 points; P<\/jats:italic>\u2009=\u2009.047). The mean (SE) reduction in HAM-D17 from baseline to week 6 was significantly greater with 20 mg of azetukalner vs placebo (\u201313.3 [1.1] vs \u201310.2 [1.0] points; P<\/jats:italic>\u2009=\u2009.04). The mean (SE) reduction in SHAPS scores from baseline to week 6 was significantly greater with 20 mg of azetukalner vs placebo (\u20137.77 [0.87] vs \u20135.30 [0.85] points; P<\/jats:italic>\u2009=\u2009.046). Similar rates of discontinuation due to TEAEs were reported across groups.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this randomized clinical trial of azetukalner, preliminary findings supported its further clinical development for the treatment of MDD and anhedonia.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT05376150<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.14278","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T15:00:30Z","timestamp":1748358030000},"page":"e2514278","source":"Crossref","is-referenced-by-count":13,"title":["Azetukalner, a Novel KV<\/sub>7 Potassium Channel Opener, in Adults With Major Depressive Disorder"],"prefix":"10.1001","volume":"8","author":[{"given":"Noam N.","family":"Butterfield","sequence":"first","affiliation":[{"name":"Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanza","family":"Luzon Rosenblut","sequence":"additional","affiliation":[{"name":"Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Fava","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph U.","family":"Correll","sequence":"additional","affiliation":[{"name":"The Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, New York"},{"name":"Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York"},{"name":"Department of Child and Adolescent Psychiatry, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Rothschild","sequence":"additional","affiliation":[{"name":"UMass Chan Medical School, UMass Memorial Health Care, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Murrough","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai, New York, New York"},{"name":"VISN 2 Mental Illness Research, Education, and Clinical Center, James J. 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