Xenon Pharmaceuticals Inc. (Nasdaq: XENE) presented compelling long-term data from its ongoing X-TOLE open-label extension (OLE) study of azetukalner in patients with focal onset seizures (FOS) at the American Epilepsy Society Annual Meeting (AES 2024) in Los Angeles. The data, covering up to 36 months of treatment, demonstrate sustained seizure reduction, impressive seizure freedom rates, and a consistent adverse event profile, suggesting long-term efficacy and tolerability of azetukalner.
Long-Term Efficacy and Safety of Azetukalner
The X-TOLE OLE study administered open-label azetukalner at a dose of 20 mg once daily (QD) with food. Interim results revealed that monthly median percent change (MPC) reductions in FOS frequency ranged from 61% to 82% during month 1 to OLE study month 24 and were maintained at 85% at OLE study month 36. Notably, patients receiving 1 to 2 anti-seizure medications (ASMs) at baseline experienced higher monthly MPC reductions in FOS frequency from baseline at OLE study month 36 (100% seizure reduction, n=67), compared to those receiving 3 ASMs (80.6% seizure reduction, n=80).
According to Dr. Christopher Kenney, Chief Medical Officer of Xenon, approximately one-third of patients who have been on azetukalner for at least 36 months achieved 100% seizure reduction, or seizure freedom, for a period of one year or longer. He emphasized that seizure freedom translates directly into improved quality of life for people living with epilepsy.
Seizure Freedom and Tolerability
For participants treated for > 36 months in the OLE, 32.7% (48/147) achieved seizure freedom for a period of at least 12 months. Azetukalner continued to be generally well-tolerated, with adverse events (AEs) consistent with prior results in the double-blind period and other ASMs; no new safety signals were identified.
Long-term retention rates in the OLE study were 66% at 12 months, 60% at 24 months, and 52% at 36 months, with a total of 182 participants treated for ≥12 months, 165 for ≥24 months, and 143 for ≥36 months.
Mental Health and Comorbidity Burdens in Focal Onset Seizures
In addition to the azetukalner data, Xenon presented findings from a patient-reported outcomes study and a literature review highlighting the mental health and comorbidity burdens of focal onset seizures. The patient-reported survey indicated that patients with epilepsy reporting FOS experience considerable mental health burden, with most experiencing ≥3 non-seizure symptoms despite ongoing treatment with existing anti-seizure medications. Mood issues such as depression and anxiety ranged from moderate to severe.
The targeted literature review of comorbidity burden in focal onset seizures revealed that patients with FOS and comorbid conditions experience greater disease burden compared to those without comorbidities, highlighting an area of unmet need in this population.
Pre-clinical Data on Nav1.1 Potentiators in Dravet Syndrome
Xenon also presented new pre-clinical data from its Nav1.1 potentiator program. Studies in a Dravet mouse model showed that Nav1.1 potentiators modulated brain rhythms and improved motor function. Acute dosing of XPC-837, an orally available, small molecule, CNS-penetrant, highly selective Nav1.1 potentiator, suppressed induced seizures and improved motor performance. Chronic dosing over 14 days with XPC-837 suppressed spontaneous seizures, prevented sudden unexpected death in epilepsy (SUDEP), and increased long-term potentiation.
These pre-clinical data suggest that XPC-837 could represent a novel, mechanistically differentiated, orally available compound with the potential to provide an improved therapeutic profile for the overarching treatment of Dravet Syndrome.
Xenon's Scientific Exhibit at AES 2024
Xenon hosted a Scientific Exhibit at AES 2024 to provide an overview of its clinical and research programs. The exhibit included information related to the azetukalner Phase 3 epilepsy program, ongoing clinical trials in focal onset seizures and primary generalized tonic-clonic seizures, and topline results from the Phase 2 X-NOVA clinical trial evaluating azetukalner in major depressive disorder.
Ian Mortimer, President and Chief Executive Officer of Xenon, stated that the latest long-term OLE results further validate the company's substantial clinical experience with azetukalner and reinforce their belief that azetukalner represents a potentially best-in-class anti-seizure medication.
