Noam N Butterfield, Constanza Luzon Rosenblut, Maurizio Fava, Christoph U Correll, Anthony J Rothschild, James W Murrough, Sanjay J Mathew, Gregory N Beatch, Celene Grayson, Cynthia Harden, Jenny Qian, Joe McIntosh, Rostam Namdari, Christopher Kenney
{"title":"一种新型KV7钾通道开启剂Azetukalner用于成人重度抑郁症的随机临床试验","authors":"Noam N Butterfield, Constanza Luzon Rosenblut, Maurizio Fava, Christoph U Correll, Anthony J Rothschild, James W Murrough, Sanjay J Mathew, Gregory N Beatch, Celene Grayson, Cynthia Harden, Jenny Qian, Joe McIntosh, Rostam Namdari, Christopher Kenney","doi":"10.1001/jamanetworkopen.2025.14278","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>Available antidepressants provide inadequate therapeutic responses in many patients with major depressive disorder (MDD), highlighting a substantial unmet need.</p><p><strong>Objective: </strong>To evaluate the efficacy and safety of azetukalner, a novel, potent KV7 potassium channel opener, in participants with MDD.</p><p><strong>Design, setting, and participants: </strong>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.</p><p><strong>Intervention: </strong>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.</p><p><strong>Main outcomes and measures: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions and relevance: </strong>In this randomized clinical trial of azetukalner, preliminary findings supported its further clinical development for the treatment of MDD and anhedonia.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT05376150.</p>","PeriodicalId":14694,"journal":{"name":"JAMA Network Open","volume":"8 5","pages":"e2514278"},"PeriodicalIF":10.5000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117446/pdf/","citationCount":"0","resultStr":"{\"title\":\"Azetukalner, a Novel KV7 Potassium Channel Opener, in Adults With Major Depressive Disorder: A Randomized Clinical Trial.\",\"authors\":\"Noam N Butterfield, Constanza Luzon Rosenblut, Maurizio Fava, Christoph U Correll, Anthony J Rothschild, James W Murrough, Sanjay J Mathew, Gregory N Beatch, Celene Grayson, Cynthia Harden, Jenny Qian, Joe McIntosh, Rostam Namdari, Christopher Kenney\",\"doi\":\"10.1001/jamanetworkopen.2025.14278\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Importance: </strong>Available antidepressants provide inadequate therapeutic responses in many patients with major depressive disorder (MDD), highlighting a substantial unmet need.</p><p><strong>Objective: </strong>To evaluate the efficacy and safety of azetukalner, a novel, potent KV7 potassium channel opener, in participants with MDD.</p><p><strong>Design, setting, and participants: </strong>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.</p><p><strong>Intervention: </strong>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.</p><p><strong>Main outcomes and measures: </strong>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.</p><p><strong>Results: </strong>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). 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Azetukalner, a Novel KV7 Potassium Channel Opener, in Adults With Major Depressive Disorder: A Randomized Clinical Trial.
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.
期刊介绍：
JAMA Network Open, a member of the esteemed JAMA Network, stands as an international, peer-reviewed, open-access general medical journal.The publication is dedicated to disseminating research across various health disciplines and countries, encompassing clinical care, innovation in health care, health policy, and global health.
JAMA Network Open caters to clinicians, investigators, and policymakers, providing a platform for valuable insights and advancements in the medical field. As part of the JAMA Network, a consortium of peer-reviewed general medical and specialty publications, JAMA Network Open contributes to the collective knowledge and understanding within the medical community.
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