Long term data from ongoing X-TOLE open-label extension (OLE) study of azetukalner in patients with focal onset seizures.- Xenon Pharmaceuticals

“We are excited for this opportunity to engage with the broad epilepsy community at AES 2024 and share new long-term azetukalner data from our ongoing X-TOLE open-label extension study showing compelling evidence of sustained seizure reduction and seizure freedom rates,” stated 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. This is a meaningful metric for epileptologists who tell us that seizure freedom translates directly into improved quality of life for people living with epilepsy. Further, we continue to see an impressive, sustained monthly reduction in seizure frequency – approximately 85% at month 36 – while importantly maintaining a consistent safety profile that suggests azetukalner continues to be generally well-tolerated.”

Dr. Kenney added, “There remains a substantial need for new, efficacious and well-tolerated epilepsy therapies, especially for those patients who continue to experience the debilitating impacts of focal seizures even while taking multiple anti-seizure medications. As we continue to build upon the foundation of strong X-TOLE results, amass a growing amount of supportive data from the ongoing open-label extension study, and drive towards Phase 3 completion, we believe that azetukalner could be paradigm-shifting in the treatment of epilepsy in the future.”

Poster Presentation #2.361: 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; The results presented at AES 2024 are interim data from the X‑TOLE OLE in which participants received open‑label azetukalner at a dose of 20 mg once daily (QD) with food.

• i. Sustained reductions in seizure frequency: For ongoing OLE patients, monthly median percent change (MPC) reductions in FOS frequency ranged from 61%‑82% during month 1 to OLE study month 24 and were maintained at 85% at OLE study month 36. Patients who were 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).
• ii. Achieving seizure freedom: For those participants who were treated for >36 months in the OLE, 32.7% (48/147) achieved seizure freedom for a period of at least 12 months.
• iii.. Consistent tolerability and safety profile: Azetukalner continues to be generally well‑tolerated in the OLE, with AEs consistent with prior results in the double-blind period and other ASMs; no new safety signals were identified.
• iv.. Long-term retention: A total of 182 participants were treated in the OLE for ≥12 months, 165 participants were treated for ≥24 months, and 143 participants were treated for ≥36 months at the time of the analysis cutoff (October 7, 2024). Retention rates with azetukalner at 12, 24, and 36 months into the OLE study period were 66%, 60%, and 52%, respectively.

“With over 600 patient-years of azetukalner exposure in people living with epilepsy – and some patients now on drug for more than 5 years – these latest long-term OLE results further validate our substantial clinical experience with azetukalner and reinforce our belief that azetukalner represents a potentially best-in-class anti-seizure medication,” stated Ian Mortimer, President and Chief Executive Officer of Xenon. “In addition to the interim long-term OLE data, we will present important results from a patient-survey and a literature review study looking at the impacts of the mental health burden and comorbidities of focal onset seizures. We will also highlight new data from our Nav1.1 potentiator program that showed protection against spontaneous seizures and SUDEP in a pre-clinical model, suggesting that targeting Nav1.1 could potentially address the underlying cause and symptoms of Dravet Syndrome,” added Mr. Mortimer.

Poster Presentation #2.347: Is the Mental Health Burden of Epilepsy Under-Recognized in Patients Reporting Focal Onset Seizures? A Patient-Reported Outcomes Study

• Patients with epilepsy reporting FOS experience considerable mental health burden in addition to their recurring seizure burden. Most patients experienced ≥3 non-seizure symptoms despite ongoing treatment with existing anti-seizure medications, with most experiencing mood issues (e.g., depression, anxiety) that ranged from moderate to severe.
• The high positive screening rates for depression and anxiety, in contrast to lower self-reported physician-diagnosed depression and anxiety, suggest mental health burden may be under-recognized in patients with epilepsy reporting FOS.

Poster Presentation #2.338: A Targeted Literature Review of Comorbidity Burden in Focal Onset Seizures

• Patients with FOS and comorbid conditions experience greater disease burden compared to those without comorbidities, highlighting an area of unmet need in this population.
• Enhanced understanding of the association between comorbidities, particularly mental health comorbidities like depression and the burden of FOS may enable personalized treatment and help in improving patient outcomes.

Poster Presentation #3.389: Nav1.1 Potentiators Modulate Brain Rhythms Measured Through Quantitative Electrocorticography (qECoG) in a Dravet Mouse Model

• These data suggest Scn1a^+/‑ mouse brain activity is differentiated from that in wild‑type littermates. XPC 418, a Nav1.1 potentiator, altered brain activity in Scn1a^+/‑ mice, making the phenotype more similar to that of wild‑type animals, and also changed brain activity in wild‑type mice in a dose‑ and time‑dependent manner.
• These pre-clinical data indicate that Nav1.1 potentiation could normalize the power spectrum phenotype of Dravet mice to the wild‑type phenotype.

Poster Presentation #3.395: Selective Potentiation of Nav1.1 Channels in Dravet Mice Restores Interneuron Function and Improves Motor Function

• Acute dosing of XPC 837 – an orally available, small molecule, CNS-penetrant, highly selective Nav1.1 potentiator – suppressed induced seizures in the 6Hz assay and improved motor performance in the Rotarod assay, supporting the potential for improvements in Dravet patient motor function. Chronic dosing over 14 days with XPC 837 in chow suppressed spontaneous seizures, prevented sudden unexpected death in epilepsy (SUDEP) and increased long-term potentiation, a potential cellular correlate of learning and memory.
• These pre-clinical data suggest that XPC837 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.