Novel Agent Promising as Add-On Epilepsy Treatment

Derick Alison
Derick Alison
7 Min Read

A novel selective potassium channel opener appeared promising against focal-onset seizures when given atop other epilepsy medications, according to a phase IIb trial.

Treatment with the small-molecule agent XEN1101 reduced monthly seizure frequency in a dose-response manner by 33.2% to 52.8% across doses tested, all significant in comparison with the 18.2% reduction with placebo.

Adverse events were similar to those of currently available epilepsy medications, such as dizziness, balance problems, and other central nervous system effects, reported Jacqueline A. French, MD, of the NYU Comprehensive Epilepsy Center in New York City, and colleagues in JAMA Neurology.

Several seizure medications have entered the clinical armamentarium in recent decades to treat focal-onset seizures, they wrote, but “clinicians continue to seek new treatment options that have the potential to confer seizure freedom for patients who continue to have uncontrolled seizures and are well tolerated. The results of this study suggest that XEN1101 may be such an option.”

They suggested that the efficacy and safety findings in the trial would support a phase III trial for focal-onset seizures — the most common type experienced by individuals with epilepsy.

XEN1101 is a small-molecule selective Kv7.2/Kv7.3 potassium channel opener, which restrains epileptic hyperexcitability by opposing neuronal membrane depolarization near the spike threshold. That is the same mechanism as the partial onset seizure drug ezogabine (Potiga), which exited the market in 2017 for commercial reasons related to low clinical use. As French’s group noted, long-term use of ezogabine was associated with tissue pigmentation.

The results were encouraging, commented Lori L. Isom, PhD, a professor of pharmacology and neurology at the University of Michigan Medical School in Ann Arbor, who was not part of the trial.

“It was disappointing that ezogabine had to be taken off the market — it was the only drug showing this novel mechanism of action,” she said. “The field has been anticipating these clinical trial results — which are encouraging (including not turning people blue!). I am hoping that XEN1101 will prove to have a wider applicability.”

For example, preclinical evidence suggested ezogabine was effective in SCN1B-linked developmental and epileptic encephalopathy, Isom noted. “Maybe XEN1101 will also be effective.”

Interestingly, XEN1101 has both rapid onset of effect, with nearly the full effect achieved in the first week of treatment, but also a long half-life of about 10 days. These properties “support once-daily oral dosing without the need for titration at initiation of dosing or tapering at termination of dosing,” the researchers noted.

“These results are supported by the finding that the study was carried out in a highly treatment-resistant patient population, characterized by having previously tried and stopped a median of 6 [available antiseizure medications],” the researchers added. But despite half of the participants being on three such other seizure drugs during the trial, seizure frequency was high at baseline (median 13.5 per month).

The X-TOLE trial included 325 adults (51.7% female, average age 40.8) enrolled at 97 sites in North America and Europe based on having at least four focal-onset seizures per month despite stable treatment with at least one and up to three available antiseizure medications.

Participants were randomized double-blind to XEN1101 once daily with food as a 10-, 20-, or 25-mg oral capsule or placebo for 8 weeks during the study period from Jan. 30, 2019, to Sept. 2, 2021.

For the primary endpoint, monthly focal-onset seizure frequency dropped from baseline by a median 52.8% in the highest dose group, 46.4% for the 20-mg group, and 33.2% with 10 mg of XEN1101, compared with 18.2% on placebo (P<0.001 for the two higher dose groups and P=0.04 for the lowest dose).

Responders — those who at least halved their monthly focal-onset seizure frequency — ranged from 28.3% to 54.5% from the lowest to highest XEN1101 doses as compared with 14.9% in the placebo group.

The researchers called the drug well tolerated, with 15.8% of patients in the highest dose arm stopping it due to adverse events. Discontinuation of study drug, mainly related to side effects, were more common early in the study.

The most frequent treatment-related adverse events were dizziness (24.6%), somnolence (15.6%), and fatigue (10.9%). The most common such events leading to discontinuation of XEN1101 were dizziness (4.7%), balance disorder (2.4%), dysarthria (1.9%), and gait disturbance (1.9%).

A confusional state occurred in 4.7% of XEN1101-treated patients compared with 0.9% on placebo. “These rates are similar to the frequencies of the rates observed in placebo-controlled phase 3 trials of lacosamide and oxcarbazepine, and less than the rates in trials of eslicarbazepine, pregabalin, perampanel, and topiramate,” French and colleagues noted.

No cardiovascular signals of concern emerged in electrocardiograms or vital signs, nor were there any allergic skin rashes or deaths. Two cases of urinary retention occurred with XEN1101, neither serious or requiring catheterization or treatment discontinuation. Nor was there any tissue discoloration observed in this trial or in an interim analysis of the ongoing 5-year, open-label extension study.

The trial was limited in duration, although there is an ongoing open-label extension phase, which “is expected to provide insight into the long-term safety and efficacy of XEN1101,” the researchers noted.

Disclosures

The trial was funded by Xenon Pharmaceuticals in collaboration with Novotech Health Holdings. Some co-authors were employees of Xenon Pharmaceuticals.

French disclosed receiving salary support from the Epilepsy Foundation, for consulting work and/or attending scientific advisory boards on behalf of the Epilepsy Study Consortium during the conduct of the study, and New York University salary support from a long list of pharmaceutical companies and other industry entities, though she receives no personal income from these activities.

Primary Source

JAMA Neurology

Source Reference: French JA, et al “Efficacy and safety of XEN1101, a novel potassium channel opener, in adults with focal epilepsy: A phase 2b randomized clinical trial” JAMA Neurol 2023; DOI: 10.1001/jamaneurol.2023.3542.

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