XEN1101 Posts Positive Efficacy, Safety in Focal-Onset Epilepsy in Interim Phase 2b Open-Label Data

Jacqueline French, MD

Interim data from the open-label extension of the phase 2b X-TOLE study (NCT03796962) of the investigational antiseizure medication (ASM) XEN1101 (Xenon Pharmaceuticals) suggest that a 20-mg dose yielded long-term efficacy and good retention rates (68%) after 1 year among individuals with focal-onset epilepsy.¹

Ultimately, during study months 14 to 20, there was a sustained reduction in monthly seizure frequency from the double-blind period baseline (median percent change, 80%-90%) among the 168 adults (full cohort, n = 275; 96.5%) who continued into the extension. Seizure freedom for durations of 6 or more months and 12 or more months was reported by 17.5% (48 of 275) and 10.5% (29 of 275) of patients, respectively. At 18 months, 4.7% (12 of 275) of patients were seizure-free, while 9.5% (26 of 275) reported a reduction of at least 75%, and 5.8% met the 90% reduction threshold (15 of 275).

The data were presented in a poster by Jacqueline French, MD, professor of neurology at NYU Grossman School of Medicine and chief medical officer of the Epilepsy Foundation, at the 2022 American Epilepsy Society Annual Meeting, held December 2 to 6, in Nashville, Tennessee. “XEN1101 continues to be generally well-tolerated in the [open-label extension] with AEs [adverse events] consistent with prior results and other ASMs; no new safety signals were identified,” French and colleagues wrote.

All told, the extension trial’s cohort included 188 patients who had been treated for at least 12 months, with 111 patients treated for at least 18 months at the analysis cutoff of September 22, 2022. The percentages of individuals continuing on XEN1101 at 6 and 12 months in into the extension period were 76% and 68%, respectively. The mean age at study entry was 41.1 years (SD, 13.3), and the mean percent of individuals on 1 background ASM was 8.4% (n = 23), on 2 ASMs was 39% (n = 1028), and on 3 ASMs was 52.4% (n = 144). Overall, 58.2% (n = 160) of patients were using CYP3A4 inducers.

“This interim analysis shows XEN1101 continues to be generally well-tolerated, yielding long-term efficacy at the 20-mg once-daily dose, with patients experiencing continued seizure reduction during the OLE and extended periods of seizure freedom,” Ian Mortimer, MBA, CPA, CMA, president and CEO of Xenon, said in a statement.² “Two other XEN1101-related posters outline additional subanalyses of the X-TOLE data that suggest a rapid onset of efficacy of XEN1101, with statistically significant reduction in focal onset seizures within 1 week for all doses studied when compared to placebo.”

“Further, based on the number of concomitant ASMs, baseline seizure frequency, and number of failed antiseizure medications, the X-TOLE study enrolled more ‘difficult-to-treat’ patients than other similar focal onset seizure studies. We believe this is important as it suggests that the efficacy of XEN1101 may be robust in patients with less severe disease, which may represent the most common use of XEN1101 if commercially approved,” Mortimer continued.²

Regarding safety in the extension period, treatment-emergent AEs occurred in 85.5% (n = 235) of the safety population, of which at least 1 serious AE occurred in 9.5% (n = 26) of individuals. Treatment-emergent AEs that led to treatment discontinuation occurred in 11.3% (n = 31) of patients, with 0.4% (n = 1) leading to death. The only serious AEs reported in more than 1 patient were seizures (1.8%; n = 5), paresthesia (0.7%; n = 2), and deep vein thrombosis (0.7%; n = 2).

The most common AEs, occurring at a rate of 5% or more in the extension period, were dizziness (20.7%; n = 57), headache (13.5%; n = 37), COVID-19 infection (11.6%; n = 32), fall (11.3%; n = 31), somnolence (9.8%; n = 27), weight increase (9.1%; n = 25), gait disturbance (8.7%; n = 24), fatigue (7.3%; n = 20), aphasia (6.9%; n = 19), urinary tract infection (6.5%; n = 18), memory impairment (6.2%; n = 17), confusional state (5.5%; n = 15), attention disturbance (5.1%; n = 14), and tremor (5.1%; n = 14). After 1 year, patients reported a mean weight gain of 1.1 kg (SD, 5.9).

XEN1101 is a potent small-molecule selective KCNQ2/3 potassium channel opener. In addition to its clinical development for focal onset seizures, it is also being assessed for primary generalized tonic-clonic seizures and major depressive disorder. In early November 2022, Xenon announced that it had initiated its phase 3 program, including the parallel X-TOLE2 (NCT05614063) and X-TOLE3 studies.³ “We hope to confirm these encouraging results and continue to execute on our goal to deliver a new, differentiated therapeutic that could potentially play a key role in treating patients with epilepsy,” Moritmer said in a statement.²

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REFERENCES
1. French J, Porter R, Perucca E, et al. XEN1101, a novel potassium channel modulator: Interim data from an ongoing, long-term, open-label extension of a phase 2b study (X-TOLE) in adults with focal epilepsy. Presented at: AES Annual Meeting; December 2-6, 2022; Nashville, TN, and virtual. Poster 235.
2. Xenon Pharmaceuticals Provides Updates on Proprietary Neurology Pipeline Programs at the Annual Meeting of the American Epilepsy Society (AES 2022). News release. Xenon Pharmaceuticals. December 2, 2022. Accessed December 4, 2022. https://www.biospace.com/article/releases/xenon-pharmaceuticals-provides-updates-on-proprietary-neurology-pipeline-programs-at-the-annual-meeting-of-the-american-epilepsy-society-aes-2022-/
3. Xenon Pharmaceuticals Announces Launch of XEN1101 Phase 3 Program with Initiation of X-TOLE2 Clinical Trial in Patients with Focal Onset Seizures. News release. Xenon Pharmaceuticals. November 3, 2022. Accessed December 4, 2022. https://www.globenewswire.com/en/news-release/2022/11/03/2547669/33485/en/Xenon-Pharmaceuticals-Announces-Launch-of-XEN1101-Phase-3-Program-with-Initiation-of-X-TOLE2-Clinical-Trial-in-Patients-with-Focal-Onset-Seizures.html