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. Trial Registration: ClinicalTrials.gov Identifier: NCT05376150.