azetukalner (XEN1101) / Xenon - LARVOL DELTA

An Open-label Study of Azetukalner in Bipolar I or II Depression (X-CEED-OLE) (clinicaltrials.gov) - P3 | N=400 | Enrolling by invitation | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE3) (clinicaltrials.gov) - P3 | N=360 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Aug 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Kr233: selective kcnq2/3 opener with best-in-class potential for epilepsy (Neuroscience 2025) - "Ezogabine (retigabine), the first KCNQ opener approved in 2011 for the treatment of focal seizures, was voluntarily withdrawn from the market in 2017 due to chemical issues unrelated to its action on Kv7.2/3...In preclinical models, KR233 provided robust protection against seizures in both the pentylenetetrazole (PTZ) and maximal electroshock (MES) -induced seizure models, with a good PK/PD correlation (EC50,plasma <50 ng/ml)...In contrast, XEN-1101 induced significant impairments at equivalent doses with TD50 < 40 mg/kg in the same condition...Overall, these results indicate that KR233 is a promising novel therapeutic candidate for the treatment of epilepsy. IND filling expected in Q3 2025."

CNS Disorders • Epilepsy

A Randomized, Controlled Trial of the Novel, Potent Kv7 Channel Opener Azetukalner in Individuals with Major Depressive Disorder and Anhedonia: Neural Response to Reward, Clinical Outcomes, and Safety. (PubMed, Res Sq) - P2 | "Despite not meeting the primary neuroimaging endpoint , secondary and exploratory outcomes suggested potential improvement in depressive and anhedonia symptoms, consistent with recent studies. Trial Registration: Clinicaltrials.gov ID NCT04827901."

Clinical • Clinical data • Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

X-CEED: A Randomized Study of Azetukalner Versus Placebo in Depressive Episodes Associated With Bipolar I or II Disorder (Bipolar Depression) (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

X-TOLE2: A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (clinicaltrials.gov) - P3 | N=360 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy

A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (X-NOVA3) (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

X-ACKT: A Study to Evaluate XEN1101 as Adjunctive Therapy in Primary Generalized Tonic-Clonic Seizures (clinicaltrials.gov) - P3 | N=160 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Oct 2025 ➔ Jun 2027 | Trial primary completion date: Jun 2025 ➔ Apr 2027

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

X-TOLE2: A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (clinicaltrials.gov) - P3 | N=360 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Jun 2025 ➔ Feb 2026 | Trial primary completion date: Apr 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Long-Term Safety and Efficacy of Azetukalner (XEN1101), a Novel, Potent KV7 Potassium Channel Opener in Adults With Focal Epilepsy: Update From the Ongoing 7-Year Open-Label Extension of X-TOLE (AAN 2025) - "In the ongoing X-TOLE OLE, azetukalner was generally well tolerated with no new safety signals. These promising interim data continue to suggest long-term safety and efficacy of azetukalner in a difficult-to-treat population."

Clinical • Alzheimer's Disease • CNS Disorders • Epilepsy • Infectious Disease • Novel Coronavirus Disease • Pain • Respiratory Diseases

X-NOVA2: A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Xenon Pharmaceuticals Inc.

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

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 (AES 2024) - "Rationale: Azetukalner (XEN1101) is in development as a treatment for epilepsy and major depressive disorder... In the ongoing X-TOLE OLE, azetukalner was generally well tolerated with no new safety signals. These promising interim data continue to suggest long-term safety and efficacy of azetukalner in a difficult-to-treat population."

Clinical • Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Infectious Disease • Major Depressive Disorder • Mood Disorders • Novel Coronavirus Disease • Pain • Psychiatry • Respiratory Diseases

New kv7 Channel Opener Chemistry for Treatment of Seizures (AES 2024) - "Kv7 channel opening is a validated target for epilepsy with the approval of ezogabine (EZG) in 2011 as a first-in-class molecule; it was removed from the market in 2017. Kv7 openers BHV7000 and azetukalner (XEN1101) are currently in clinical development... In vivo, PO efficacy in rodent MES is >10-fold over aztukalner (ED50 > 4 mg/kg) and BHV7000 (full protection at 3 mg/kg). It is anticipated that the lead molecule, based on an in vivo minimum effective brain concentration of >20 nM for MES in mice and rats, a half maximal voltage shift of ~7 mV at 0.7 in rodents, may be effective at a plasma conc. of 30 nM, as a threshold conc., for clinical seizure protection in humans."

CNS Disorders • Depression • Epilepsy • Mood Disorders • Psychiatry

XEN1101 for Major Depressive Disorder (clinicaltrials.gov) - P2 | N=44 | Completed | Sponsor: James Murrough | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

XEN1101 for Major Depressive Disorder (clinicaltrials.gov) - P2 | N=44 | Active, not recruiting | Sponsor: James Murrough | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development. (PubMed, Epilepsia) - "These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve..."

Journal • Metastases • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry • NAV1

XEN1101, a novel potassium channel opener: hope or hype for adults with focal seizure. (PubMed, Ann Med Surg (Lond)) - No abstract available

Journal • CNS Disorders • Epilepsy

Efficacy and Safety of XEN1101, a Novel, Kv7 Potassium Channel Opener in Adults With Moderate to Severe Major Depressive Disorder: Results From the Phase 2 X-NOVA Study (ASCP 2024) - "Despite not achieving statistical significance in its primary endpoint, XEN1101 demonstrated a clinically meaningful reduction of depression measured by the MADRS, a significant reduction in HAMD-17, an early onset of action, a significant reduction in anhedonia, and a potentially differentiated safety profile compared to other ADs. The X-NOVA results are particularly meaningful given that there was a 2 in 3 chance of receiving active treatment, which has been previously shown to increase the placebo response (Papakostos GI, et al. 2009)."

Clinical • P2 data • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry

X-TOLE: A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (clinicaltrials.gov) - P2 | N=325 | Active, not recruiting | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Oct 2026 ➔ Oct 2028

Trial completion date • CNS Disorders • Epilepsy

A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy. (PubMed, Expert Rev Clin Pharmacol) - "A literature review on the pharmacology, efficacy, tolerability, and safety of azetukalner (XEN1101), a second-generation opener of neuronal potassium channels currently in Phase 3 development as ASM...The upcoming Phase 3 clinical trials are expected to provide further insight into the efficacy, tolerability, and safety of azetukalner in treating focal-onset and primary generalized tonic-clonic seizures. Structurally distinct from currently marketed ASMs, azetukalner has the potential to be the only-in-class Kv7.2/7.3 opener on the market upon regulatory approval."

Journal • Review • CNS Disorders • Epilepsy • CYP3A4

Interim Long-term Safety and Efficacy of XEN1101, a Potent, Selective Potassium Channel Opener: Update from an Ongoing Open-label Extension of a Phase 2b Study (X-TOLE) in Adults with Focal Epilepsy (AAN 2024) - "XEN1101 was generally well tolerated and demonstrated an OLE safety profile similar to that seen in the DBP and other antiseizure medications used in FOS treatment. No new safety signals emerged. These promising data suggest long-term efficacy of XEN1101 in a difficult-to-treat population."

Clinical • P2b data • CNS Disorders • Epilepsy • Infectious Disease • Novel Coronavirus Disease • Pain • Respiratory Diseases

The Impact of Disease Severity on Responder Rates in a Phase 2b Study of XEN1101, a Potent, Selective Potassium Channel Opener, in Adults with Focal Epilepsy (X-TOLE) (AAN 2024) - "Consistent with the significant MPC seizure reduction, 54.5% of patients in the 25-mg XEN1101 group achieved RR50. XEN1101 was relatively more effective in patients with indicators of less-severe disease. XEN1101 may be appropriate for patients with focal epilepsy across the spectrum of disease severity."

Clinical • P2b data • CNS Disorders • Epilepsy

X-NOVA: A Study to Evaluate the Safety, Tolerability and Efficacy of XEN1101 in Major Depressive Disorder (clinicaltrials.gov) - P2 | N=168 | Completed | Sponsor: Xenon Pharmaceuticals Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

X-TOLE4: An Open-label Study of XEN1101 in Epilepsy (clinicaltrials.gov) - P3 | N=880 | Enrolling by invitation | Sponsor: Xenon Pharmaceuticals Inc. | Trial completion date: Jun 2027 ➔ Sep 2028 | Trial primary completion date: Jun 2026 ➔ Jul 2028

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

XEN1101 for Major Depressive Disorder (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: James Murrough | Trial completion date: Jan 2024 ➔ Dec 2024 | Trial primary completion date: Jan 2024 ➔ Nov 2024

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry