Potent KV7 potassium channel opener shows promise in MDD treatment

The K_V7 potassium channel opener azetukalner helps improve symptoms of major depressive disorder (MDD) in adults, according to the results of the proof-of-concept, phase II X-NOVA study.

X-NOVA included 168 adults (mean age 47.2 years, 66.5 percent female) with moderate-to-severe MDD who had a current depressive episode. These participants were randomly assigned to receive treatment with azetukalner at 10 (n=56) or 20 mg (n=56) or placebo for 6 weeks. Treatment was taken orally, once daily with food. Concomitant antidepressant medications were prohibited.

Researchers measured the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6 as the primary efficacy endpoint. Secondary endpoints were changes in the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Anxiety Inventory at week 6. Exploratory endpoints included changes in the 17-Item Hamilton Depression Rating Scale (HAM-D17) score at week 6 and in MADRS score at week 1. Frequency and severity of treatment-emergent adverse events (TEAEs) were also documented.

The modified intent-to-treat and safety populations comprised 164 and 167 participants, respectively. At week 6, MADRS score decreased by 16.94 points with azetukalner 20 mg, by 15.61 points with the 10-mg dose, and by 13.90 points with placebo.

The difference in the change in MADRS scores at week 6 between 20 mg of azetukalner and placebo did not reach statistical significance, although it was clinically meaningful (–3.04 points, 95 percent confidence interval [CI], –7.04 to 0.96 points; p=0.14). Meanwhile, the difference in the change in MADRS scores at week 1 between 20 mg of azetukalner and placebo was statistically significant (–2.66 points, 95 percent CI, –5.30 to –0.03 points; p=0.047).

HAM-D17 scores at week 6 dropped with significantly greater magnitude with azetukalner 20 mg vs placebo (–13.3 vs –10.2 points; p=0.04), as were SHAPS scores (–7.77 vs –5.30 points; p=0.046).

In terms of safety, treatment discontinuation due to TEAEs occurred similarly across treatment groups.