Azetukalner, a Novel K<sub>V</sub>7 Potassium Channel Opener, in Adults With Major Depressive Disorder
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
Journal: JAMA Network Open (2025)

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 K V 7 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