A novel drug reduces the monthly frequency of seizure in adults with focal epilepsy

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Focal-onset seizures (FOSs) are the most common type of seizure experienced by epileptic individuals.

A recent randomized control trial published in JAMA Neurology evaluated the effect of a novel Kv7.2/Kv7.3 potassium channel opener XEN1101 in reducing monthly seizure frequency in adults who experience FOSs, despite being treated with antiseizure medications (ASMs).

Study: Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy. Image Credit: Barabasa/Shutterstock.comStudy: Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy. Image Credit: Barabasa/Shutterstock.com

Background

Many individuals experience epileptic seizures despite being treated with ASMs. Therefore, there is a need for more effective ASMs to reduce or free these patients from seizures. Mechanistically, ASMs interact with a broad spectrum of molecular targets in brains, reducing seizure occurrence.

One of the potential targets of ASMs is Kv7.2/Kv7.3 voltage-gated potassium channels, which are associated with axonal and perisomatic expression in brain neurons. Inhibition of these ion channels resists neuronal membrane depolarization near the spike threshold, suppressing epileptic hyperexcitability.

Mutations of KCNQ2 and KCNQ3 genes are associated with familial neonatal seizures and early onset of epileptic encephalopathy.

The first-generation drug, ezogabine, was designed based on Kv7.2/Kv7.3 voltage-gated potassium channels that revealed an effective reduction in FOSs. However, long-term use of this drug caused tissue pigmentation and was voluntarily removed from the commercial market.

XEN1101 is a novel molecule that can selectively target the Kv7.2/Kv7.3 potassium channel opener and can be used to treat FOSs. The pharmacokinetic properties and a long elimination half-life of approximately ten days support the oral use of XEN1101 once daily.

About the study

A previous phase 1 clinical evaluation indicated that XEN1101 is well tolerated up to 25 mg and could effectively reduce FOSs.

The current study reported the assessment of a phase 2b randomized, multicentre, double-blind, placebo-controlled clinical trial to elucidate the safety and efficacy of XEN1101 in adults with FOSs. This study has been referred to as the X-TOLE study.

The X-TOLE study determined the safety, efficacy, and tolerability of three oral doses of XEN1101 compared to placebo at monthly seizure frequency in adults with FOSs. This study also evaluated the overall health status of individuals with FOSs after receiving XEN1101 treatment. 

In this study, participants received one of the three doses of XEN1101, i.e., 10 mg, 20 mg, or 25 mg, as an oral capsule daily with food. All participants were between 18 and 75 years of age with FOSs.

One of the important eligibility criteria was that participants must experience four or more countable FOSs on average each month. All participants received between one and three ASM treatments. Participants' randomization was stratified based on their use of CYP3A4 inducer medications. 

Study findings

325 participants were included in the control group and 323 in the treatment group. Among 285 patients who completed the trial's double-blind phase (DBP), 275 participants entered the open-label extension (OLE) that enabled the assessment of the tolerability, long-term safety, and efficacy of XEN1101.

The mean age of the participants was approximately 41 years of age, and the median age at the time of disease onset was 17.1 years. Around 52% of the cohort was female, and ~92% were White participants. Most participants were recruited from Europe or North America.

Around 8.9% of the cohort received 1, 40.6% received two, and 50.5% received three stable ASM at baseline. Most participants were under the CYP3A4 inducer at baseline and experienced an FOS frequency of 13.5 every month.

The open-label long-term extension study revealed that 17.5% of the patients who received XEN1101 for six months or more were free from seizure. This effect was sustained for twelve months or more.

In comparison to all test doses, 25 mg of XEN1101 per day exhibited a significant reduction in seizure frequency.

Furthermore, this dose manifested a greater reduction in seizure frequency compared with the control (placebo) group as well. At the highest dose, FOS frequency was reduced by 52.8%, compared to 18.2% with placebo. 

The 25 mg dose was also well tolerated by the participants, while 15.8% of patients discontinued the treatment due to dizziness or other adverse events. The negative effect of a confused state was observed in 4.7% of the treated group, which was higher than the placebo group.

Tissue discoloration was not observed in the treated group during the study period. No deaths were recorded during the study period.

Conclusions

The current study has some limitations, including a relatively short study period, i.e., an 8-week treatment duration.

However, the ongoing open-label extension phase will enable a long-term assessment of the safety and efficacy of XEN1101 against FOSs. In addition, fewer participants were in the 10 mg and 20 mg groups compared to the 25 mg group.

Despite the limitations, the current study indicated that seizure reduction was statistically significant in all three doses of XEN1101 compared to the placebo. However, treatment with 25 mg of XEN1101 daily exhibited the best result. The findings of this study support the use of XEN1101 in treating FOSs.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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