XEN1101, a Novel Potassium Channel Opener has Potential as Novel Treatment for Patients with Focal Epilepsy

Many individuals with epilepsy continue to experience seizures despite treatment with available antiseizure medications (ASMs). There is therefore a need for more efficacious ASMs, and particularly for ones that confer greater seizure reduction or seizure freedom. Results of a recent phase II RCT published in JAMA Neurology, show the potential of a novel molecule for management of foca lseziures in adults.

Antiseizure medications act through an interaction with diverse molecular targets in the brain. The Kv7.2/Kv7.3 voltage-gated potassium channels, which exhibit perisomatic and axonal expression in brain neurons, represent a particularly attractive target. These inhibitory ion channels oppose neuronal membrane depolarization near spike threshold, restraining epileptic hyperexcitability. The drugs that enhance the opening of Kv7.2/Kv7.3channels have been shown to confer seizure reduction.

XEN1101 is a novel, small-molecule, selective Kv7.2/Kv7.3 potassium channel opener being developed for the treatment of focal seizures, the most common type of seizures experienced by individuals with epilepsy. The pharmacokinetic properties of XEN1101, including a long terminal elimination half-life (approximately 10 days), support once-daily oral dosing without the need for titration at initiation of dosing or tapering at termination of dosing.The molecule was previously evaluated in phase I studies in healthy volunteers, including a pharmacodynamic crossover study using transcranial magnetic stimulation. Data from these studies demonstrated that dosing XEN1101 up to 25 mg is generally well tolerated and that following a single 20-mg oral dose cortical excitability is reduced to an extent that correlates well with the XEN1101 plasma concentration.

The phase 2b RCT called X-TOLE, conducted by French et al was a randomised, double-blind placebo-controlled study of XEN1101 in adults with focal seizures dosed orally with food, with the objectives to assess the efficacy, safety, and tolerability of 3 doses of XEN1101 in comparison with placebo in adults with focal epilepsy.

The researchers found that an impressive 17.5% of patients exhibited seizure freedom after six or more consecutive months of XEN1101 treatment. This percentage stood at 10.5% for those treated for 12 months or more, hinting at the drug's prolonged effectiveness.

XEN1101, when administered at 25 mg daily, was linked to a marked reduction in seizure frequency – a change that nearly half of the study's participants deemed clinically significant.  Furthermore, the trial recorded a 54.5% responder rate, where the seizure frequency was halved or more, contrasting starkly with the 14.9% rate seen in the placebo group. Importantly, the 25-mg dose was predominantly well-tolerated. Dizziness was the most common side effect, leading to early discontinuation for a minority of patients.

One standout feature of XEN1101 is its extended half-life of roughly ten days, eliminating the need for dose titration. This trait allows for a swift onset of its therapeutic effects, with the majority of seizure reduction noticeable within the first week, especially in the 20- and 25-mg dosage groups.

The overall tolerance profile for XEN1101 was favorable. Most treatment-emergent adverse events (TEAEs) were related to the central nervous system. Notably, the adverse event rates for XEN1101 were largely in line with or better than those documented for other ASMs in respective phase 3 trials.

However, the study isn't devoid of limitations. The 8-week treatment duration can be considered relatively short. The effects of the COVID-19 pandemic on the study outcomes remain uncertain. Despite these potential drawbacks, the study's results are promising, propelling further clinical exploration of XEN1101 for FOSs treatment. In summary, XEN1101 emerges as a promising candidate to fill the therapeutic void for a novel, effective, and well-tolerated treatment for focal epilepsy.

Reference:

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. JAMA Neurol. Published online October 09, 2023.

doi:10.1001/jamaneurol.2023.3542