Poster
12
(#12) Azetukalner, a Novel, Potent Kv7 Channel Opener: Updates From the Ongoing Clinical Development Program in Major Depressive Disorder
Psych Congress 2025
Abstract: Background: Azetukalner is a novel, potent Kv7.2/7.3 potassium channel opener currently in Phase 3 development for epilepsy and major depressive disorder (MDD), with planned development for bipolar depression. We report on the design of two ongoing Phase 3 trials evaluating azetukalner as monotherapy for MDD.
Methods: X-NOVA2 (NCT06775379) and X-NOVA3 (NCT07076407) are identical Phase 3, multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy, safety, and tolerability of azetukalner as monotherapy in adults with MDD. In each study, an estimated 450 participants with moderate to severe MDD will be randomized 1:1 to azetukalner 20 mg or placebo once daily with food for 6 weeks with no titration period. The primary endpoint is the change from the baseline at week 6 in Hamilton Depression Rating Scale 17-Item (HAMD-17). Upon completion of the double-blind phase, eligible patients may enter an open-label extension study for up to 12 months.
Results: The X-NOVA Phase 2 proof-of-concept results collectively highlighted the potential of azetukalner to improve symptoms of depression and anhedonia in MDD (Butterfield N, et al. JAMA Netw Open, 2025). Building on the promising results of X-NOVA, the ongoing X-NOVA2/3 Phase 3 studies will further evaluate the efficacy and safety of azetukalner in MDD.
Conclusions: Azetukalner has the potential to improve symptoms of depression in MDD with a rapid onset of efficacy and a safety profile differentiated from existing antidepressants. Ongoing and planned Phase 3 trials in MDD and bipolar depression are expected to provide additional evidence of the potential clinical benefit of azetukalner.
Short Description: Azetukalner is a novel, potent Kv7 potassium channel opener being studied in major depressive disorder (MDD). The results of X-NOVA, a proof-of-concept Phase 2 study, suggest that azetukalner may improve symptoms of depression and anhedonia in patients with MDD, with a potentially differentiated safety profile. We present the study designs of X-NOVA2 and X-NOVA3, two identical ongoing Phase 3 studies evaluating the safety and efficacy of azetukalner monotherapy in adults with MDD.
Name of Sponsoring Organization(s): This study was funded by Xenon Pharmaceuticals Inc.
Methods: X-NOVA2 (NCT06775379) and X-NOVA3 (NCT07076407) are identical Phase 3, multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy, safety, and tolerability of azetukalner as monotherapy in adults with MDD. In each study, an estimated 450 participants with moderate to severe MDD will be randomized 1:1 to azetukalner 20 mg or placebo once daily with food for 6 weeks with no titration period. The primary endpoint is the change from the baseline at week 6 in Hamilton Depression Rating Scale 17-Item (HAMD-17). Upon completion of the double-blind phase, eligible patients may enter an open-label extension study for up to 12 months.
Results: The X-NOVA Phase 2 proof-of-concept results collectively highlighted the potential of azetukalner to improve symptoms of depression and anhedonia in MDD (Butterfield N, et al. JAMA Netw Open, 2025). Building on the promising results of X-NOVA, the ongoing X-NOVA2/3 Phase 3 studies will further evaluate the efficacy and safety of azetukalner in MDD.
Conclusions: Azetukalner has the potential to improve symptoms of depression in MDD with a rapid onset of efficacy and a safety profile differentiated from existing antidepressants. Ongoing and planned Phase 3 trials in MDD and bipolar depression are expected to provide additional evidence of the potential clinical benefit of azetukalner.
Short Description: Azetukalner is a novel, potent Kv7 potassium channel opener being studied in major depressive disorder (MDD). The results of X-NOVA, a proof-of-concept Phase 2 study, suggest that azetukalner may improve symptoms of depression and anhedonia in patients with MDD, with a potentially differentiated safety profile. We present the study designs of X-NOVA2 and X-NOVA3, two identical ongoing Phase 3 studies evaluating the safety and efficacy of azetukalner monotherapy in adults with MDD.
Name of Sponsoring Organization(s): This study was funded by Xenon Pharmaceuticals Inc.
