Azetukalner for Depression

(X-NOVA-OLE Trial)

Enrolling by invitation at 23 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Xenon Pharmaceuticals Inc.

Disqualifiers: Pregnancy, Suicidal risk, Protocol deviations, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called azetukalner to evaluate its safety and effectiveness in treating major depressive disorder (MDD) when used alone. It targets individuals who have completed a previous study with azetukalner for MDD. Participants must have finished the earlier study without major issues or early withdrawals. The researchers aim to confirm that azetukalner remains safe over a long period and continues to effectively treat depression. As a Phase 3 trial, this study serves as the final step before FDA approval, offering participants an opportunity to contribute to the potential availability of a new treatment for MDD.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, since the study is evaluating azetukalner as a monotherapy (treatment using only one drug), it might be likely that you will need to stop other medications. Please consult with the study team for specific guidance.

Is there any evidence suggesting that azetukalner is likely to be safe for humans?

Research has shown that azetukalner has undergone testing in several studies to assess its safety. In past research with adults who have Major Depressive Disorder (MDD), azetukalner was generally well-tolerated, with most participants experiencing no serious side effects. Eight clinical trials consistently demonstrated its stable safety profile.

One study with 168 adults carefully evaluated the safety of azetukalner. Although specific side effects were not listed, the consistent safety results from multiple trials suggest that the treatment is generally safe. This is encouraging for those considering participation in a clinical trial for azetukalner. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for depression, like SSRIs or SNRIs, work by altering neurotransmitter levels in the brain. But Azetukalner works differently, targeting a novel pathway that may regulate mood more effectively. Researchers are excited about Azetukalner because it's designed to act faster and with potentially fewer side effects than current antidepressants. This could mean a quicker improvement in symptoms for patients and a better overall experience during treatment.

What evidence suggests that azetukalner might be an effective treatment for depression?

Research shows that azetukalner, the treatment under study in this trial, holds promise for treating major depressive disorder (MDD). Studies have found that azetukalner can significantly reduce depression symptoms. It acts quickly, offering early relief from symptoms such as the inability to feel pleasure. The safety profile of azetukalner is favorable, indicating it is generally safe for patients. Overall, evidence supports azetukalner as an effective option for those dealing with depression. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for adults who have Major Depressive Disorder and were part of a previous Phase 3 study of Azetukalner. It's not specified who can't join, but typically people with certain health issues or taking conflicting medications might be excluded.

Inclusion Criteria

Participant successfully completed the treatment period of an antecedent azetukalner Phase 3 study in MDD

Participant is willing to comply with the contraception requirements

I understand and agree to the study's requirements.

Exclusion Criteria

Participant had any protocol deviations in an antecedent azetukalner study that, in the opinion of the investigator, would preclude participation in this study

Participant met any of the withdrawal criteria, or discontinued study drug early, or was terminated early from an antecedent study

Participant is unable to comply with study procedures or is inappropriate for the study, as judged by the investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azetukalner as a monotherapy for long-term evaluation of safety, tolerability, and efficacy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants continue to receive azetukalner for long-term evaluation

What Are the Treatments Tested in This Trial?

Interventions

• Azetukalner

Trial Overview The focus is on Azetukalner as a solo treatment for depression. Participants from an earlier study will continue to use this medication to see how safe it is over time and if it keeps working well.

How Is the Trial Designed?

Group I: Azetukalner 20 mg Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Xenon Pharmaceuticals Inc.

Lead Sponsor

Trials

19

Recruited

3,400+

Published Research Related to This Trial

A study analyzing 720 cases of esketamine-related neurological adverse events (AEs) from 2019 to 2021 identified 21 safety signals, with sedation being the most concerning (ROR of 204.00), indicating potential long-term safety issues with esketamine.

The severity of neurological AEs was influenced by factors such as esketamine dosage and co-prescription with other medications, highlighting the need for careful monitoring and management of these risks in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. Guo, H., Wang, B., Yuan, S., et al.[2022]

A review of 10 clinical trials on esketamine for resistant depression found that 90% of the trials had low-quality reporting of adverse events (AEs), indicating significant gaps in safety data.

The study revealed that 41.5% of serious AEs and 39% of non-serious AEs were not reported in published articles, particularly psychiatric and cardiovascular events, suggesting that the assessment of esketamine's risk-benefit balance may be inaccurate due to incomplete harm reporting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reporting of harms in clinical trials of esketamine in depression: a systematic review. Taillefer de Laportalière, T., Jullien, A., Yrondi, A., et al.[2023]

In a study of 23 adults with treatment-resistant depression, 91.8% reported significant improvements in emotional and daily functioning after using esketamine nasal spray (ESK) alongside an oral antidepressant (OAD).

Patients noted key benefits of ESK treatment, including its effectiveness, rapid onset of action, and a side-effect profile consistent with existing safety data, leading to high satisfaction rates (100% reported satisfaction).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-reported review of the value of esketamine in patients with treatment-resistant depression: Understanding the patient experience in the STRIVE Study. Starr, HL., Abell, J., Larish, A., et al.[2021]

In 2006, several drugs were associated with significant safety concerns, including cardiovascular events linked to erythropoietins and macular edema associated with rosiglitazone, highlighting the need for careful monitoring by prescribers.

Other notable adverse reactions included serious complications from aprotinin, long-term use of linezolid, and congenital anomalies linked to paroxetine and lamotrigine, emphasizing the importance of understanding the safety profiles of medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance and teratovigilance]. Livio, F., Buclin, T., Biollaz, J.[2013]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2834419

Azetukalner, a Novel KV7 Potassium Channel Opener, in ... Findings This phase 2 randomized clinical trial of 168 adults with MDD found that 20 mg of azetukalner resulted in clinically meaningful, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12117446/

Azetukalner, a Novel KV7 Potassium Channel Opener, in ... These results suggest that azetukalner has the potential to improve symptoms of depression in patients with MDD, with a safety profile ...

3. investor.xenon-pharma.com investor.xenon-pharma.com/news-releases/news-release-details/xenon-pharmaceuticals-presents-data-phase-2-x-nova-clinical

Xenon Pharmaceuticals Presents Data from Phase 2 X- ... The X-NOVA results demonstrated a clinically meaningful reduction in depression, in addition to an early onset of action, a significant reduction in anhedonia.

4. aesnet.org aesnet.org/abstractslisting/long-term-safety-and-efficacy-of-azetukalner-a-novel-potent-kv7-potassium-channel-opener-in-adults-with-focal-epilepsy-update-from-the-ongoing-7-year-open-label-extension-of-x-tole

long-term safety and efficacy of azetukalner, a novel, potent ... The primary efficacy outcome was median percentage change (MPC) in monthly (28 d) FOS frequency from DBP baseline. Results: 285 participants ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT07172516

NCT07172516 | A Randomized Study of Azetukalner ... A Randomized Study of Azetukalner Versus Placebo in Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) (X-CEED).

6. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.pn.2025.07.7.12

Med Check: FDA Clears At-Home Calming Device for ... ... data demonstrating that the compound's safety profile has remained consistent over eight clinical trials. ... major depressive disorder · MDD ...

7. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/epi4.70015

Interim analysis of the long‐term efficacy and safety ... The efficacy demonstrated by azetukalner in reducing FOS seizure frequency in the DBP was sustained in this interim analysis.