Interim Analysis Highlights Long-Term Safety of Azetukalner for Focal Epilepsy

Jacqueline A. French, MD

(Credit: NYU Langone)

New interim data from the ongoing open-label extension (OLE) of the phase 2b X-TOLE trial (NCT03796962) showed that treatment with azetukalner (Xenon Pharmaceuticals), formally known as XEN1101, was generally well tolerated with no new safety signals in patients with focal epilepsy. These findings continue to suggest the promise of long-term safety and efficacy of this investigational agent in a difficult-to-treat population.¹

Presented at the 2024 American Epilepsy Society Annual Meeting, held December 6-10, in Los Angeles, California, 285 participants completed the double-blind period and 275 (96.5%) enrolled in the OLE. At the double-blind period baseline, participants had a median of 13.5 focal onset seizures per month and were on stable treatment with 1 to 3 antiseizure medications (ASMs), with 52.4% on 3 concomitant ASMs. As of the data cut from April 2024, 182 participants in the OLE were treated for at least 12 months and 152 patients were treated for at least 30 months; 142 (51.6%) participants are ongoing.

"It is very exciting to see the number of [participants] who experienced seizure freedom or a substantial reduction in seizures, and maintained that response now for quite a while. Very close to 20% of all [participants] entering open label extension have now been seizure free for [at least] 36 months. This is higher than we have seen for other ASMs, with the exception of cenobamate," lead author Jacqueline A. French, MD, a professor of neurology at NYU Grossman School of Medicine, told NeurologyLive^®.

Those that completed the double-blind period and were eligible enrolled in the 7-year OLE to receive 20 mg once a day in the fed state. Investigators performed assessments at week 3 in the OLE and then at 3-month intervals thereafter. In terms of safety assessments, researchers evaluated frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) as well as clinically significant changes in laboratory results. Authors noted that the primary efficacy outcome was median percentage change in monthly (28 days) focal onset seizures frequency from double-blind period baseline.

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The most common reasons for discontinuation reported were lack of efficacy (n = 42, 15.3%), withdrawal by participant (n = 37, 13.5%), and adverse event (n = 34, 12.4%). Authors noted that the OLE study has generated over 600 participant-years of safety data. Overall, as of the study cutoff date, investigators noted that TEAEs were reported in 241 (87.6%) participants, and 172 (62.5%) of patients reported a treatment-related TEAE. Notably, the majority of TEAEs were considered as mild or moderate and 46 participants (16.7%) reported severe TEAEs.

"We now have 2 new ASMs (cenobamate and azetukalner) that have the potential of making a substantial number of previously treatment resistant [patients] seizure free. But azetukalner also has the advantage of not requiring a titration, which will make it much easier to use for non-specialists," French said. "We are still waiting for the conclusion of the phase 3 replication study, which we hope will confirm the findings of the phase 2 study. Azetukalner is also being investigated for use in idiopathic generalized epilepsy."

Researchers noted that the most common TEAEs included dizziness (n = 62, 22.5%), coronavirus infection (n = 45, 16.4%), headache (n = 44, 16.0%), somnolence (n = 38, 13.8%), fall (n = 36, 13.1%), memory impairment (n = 32, 11.6%), and weight increase (n = 29, 10.5%). Furthermore, authors reported that the mean weight gain was 0.32 (SD, 8.0) kg at 2.5 years in the OLE. Investigators observed that 39 (14.2%) participants reported SAEs, which 6 (2.2%) of them were considered treatment related. Additionally, there were 2 cases of sudden unexpected death in epilepsy, neither were reported as treatment related. Moreover, the median percentage change was –86.9% at 30 months in the OLE.

Azetukalner, a potent small-molecule selective KCNQ2/3 potassium channel opener, is among many antiseizure medications currently being assessed in clinical trials. The medication is being assessed for primary generalized tonic-clonic seizures and major depressive disorder in addition to its clinical development for focal onset seizures. Published in JAMA Neurology, previous findings from the phase 2b X-TOLE trial assessing azetukalner showed that treatment with the therapy was associated with seizure reduction in a robust dose-response manner.²

Recently, French, who also serves as the director of The Epilepsy Study Consortium, sat down with NeurologyLive to discuss the clinical development of XEN1101 and the results from the phase 2b trial. In the conversation, she highlighted that the drug’s once-daily dosing without titration offers a major advantage over other treatments, such as cenobamate (Xcopri; SK Life Science), which requires slow titration because of the risk of serious adverse effects.

Click here for more AES 2024 coverage.

REFERENCES
1. French J, Porter R, Perucca E, et al. 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. Presented at: AES 2024; December 6-10; Los Angeles, CA.
2. French JA, Porter RJ, Perucca E, et al. Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial [published correction appears in JAMA Neurol. 2024 Feb 1;81(2):200. doi: 10.1001/jamaneurol.2023.5238]. JAMA Neurol. 2023;80(11):1145-1154. doi:10.1001/jamaneurol.2023.3542