Efficacy and Safety of Azetukalner, a Novel, Potent KV7 Potassium Channel Opener in Adults With Moderate to Severe Major Depressive Disorder: Results From the Proof-of-Concept Phase 2 X-NOVA Study

Background: Azetukalner is a novel, potent KV7 potassium channel opener in clinical development for epilepsy and major depressive disorder (MDD).
Methods: X-NOVA was a proof-of-concept, Phase 2 study that randomized 168 adults with MDD 1:1:1 to azetukalner 10 mg, 20 mg, or placebo once daily with food with no titration period. Endpoints included change from baseline at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) (primary), Snaith-Hamilton Pleasure Scale (SHAPS) (secondary), Hamilton Depression Rating Scale 17-Item (HAM-D17), and the Clinical Global Impression of Improvement (CGI-I) (exploratory).
Results: Azetukalner demonstrated a dose-dependent improvement in depression. At the 20 mg dose, change from baseline MADRS showed a clinically meaningful but not statistically significant difference of −3.04 points vs placebo (P=0.135) at week 6 and early onset of efficacy at week 1 (–2.66; P=0.047) vs placebo. Significant improvements in depression (HAM-D17 −3.1; P=0.042) and anhedonia (SHAPS −2.46; P=0.046) were observed for the 20 mg group vs placebo, as well as at least minimally improved depressive symptoms by CGI-I (P=0.004). Azetukalner was generally well tolerated with no serious adverse events reported in the azetukalner treatment groups. Azetukalner was not associated with notable weight gain (mean [SD] change from baseline, 0.84 kg [2.3]), or reports of notable sexual dysfunction (1 participant [0.9%] reported mild decreased libido).
Conclusion: Collectively, the results of X-NOVA suggest azetukalner has the potential to improve symptoms of depression and anhedonia in patients with MDD, with a potentially differentiated safety profile. A Phase 3 clinical program in MDD is planned.