XEN1101: A Novel Potassium Channel Opener in Epilepsy Treatment

Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures. These seizures are the result of excessive electrical discharges in a group of brain cells. The condition can vary widely in severity and frequency, impacting individuals differently. Globally, epilepsy affects millions, making it one of the most common neurological diseases. Epilepsy manifests in various forms, and seizures can range from brief lapses of attention or muscle jerks to severe and prolonged convulsions. This variability poses challenges in diagnosis and treatment. Despite advancements in treatment, about 30-40% of people with epilepsy have refractory epilepsy, meaning their seizures are not controlled with current medications. This treatment resistance is a significant hurdle, often requiring a combination of medications, which can increase the risk of side effects. Many antiepileptic drugs have potential side effects ranging from mild (like fatigue or dizziness) to severe (like allergic reactions or cognitive impairment). These side effects can impact a patient’s quality of life and may lead to non-compliance with treatment regimes. Epilepsy can significantly affect an individual’s daily life, including limitations on driving, working in certain jobs, and even engaging in various recreational activities. The unpredictability of seizures can lead to social stigma and isolation. People with epilepsy often have comorbid conditions such as depression, anxiety, and sleep disorders, complicating treatment and impacting overall wellbeing.

There’s a pressing need for new medications that can effectively control seizures in people with refractory epilepsy. Developing drugs that target different pathways in the brain could offer new hope to those not responding to current treatments. Newer medications with fewer and less severe side effects are needed. This would improve the quality of life for individuals with epilepsy and potentially enhance treatment adherence. As our understanding of the genetic and molecular basis of epilepsy improves, there’s a growing opportunity for personalized medicine. Tailoring treatments to the individual’s specific type of epilepsy could improve outcomes. Exploring drugs that work through mechanisms different from existing AEDs could be more effective for certain types of seizures or specific patient populations. Understanding how different drugs interact and developing effective combination therapies can be key to treating complex cases of epilepsy. While current treatments have been life-changing for many with epilepsy, there remains a substantial need for new drug discoveries. These advancements are crucial for addressing the complex challenges posed by this diverse and often debilitating condition.

In a new study published in the JAMA Neurology led by Professor Jacqueline French from the New York University Comprehensive Epilepsy Center and Professor Emilio Perucca from the The University of Melbourne  conducted a phase 2b randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of XEN1101, a novel potassium channel opener, in treating adults with focal-onset seizures (FOSs).

The study was a phase 2b randomized, double-blind, placebo-controlled trial spanning from January 2019 to September 2021. It enrolled adults experiencing at least four monthly FOSs while on 1-3 antiseizure medications (ASMs). Participants were randomly assigned to receive either XEN1101 (10, 20, or 25 mg) or placebo, administered orally with food once daily for eight weeks. The primary efficacy endpoint was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) and laboratory assessments were also recorded.

The trial was conducted from January 2019 to September 2021. It was designed to test the effectiveness and safety of XEN1101 in reducing seizure frequency in adults with focal epilepsy. The study enrolled adults who experienced at least four FOSs per month despite being on one to three antiseizure medications (ASMs). Participants were randomly assigned to receive either XEN1101 or a placebo. The trial maintained a double-blind structure, meaning neither the researchers nor the participants knew who was receiving the actual medication and who was receiving the placebo. XEN1101 was administered orally with food once daily. It was given in varying doses – 10, 20, or 25 mg – to different groups of participants. The treatment period lasted for eight weeks, during which the participants continued their regular ASM regimen alongside the study medication or placebo. The main outcome measured was the median percent change from baseline in monthly FOS frequency. This metric allowed the researchers to quantify how much the seizure frequency changed compared to the baseline, or the period before the treatment started. The study also closely monitored the treatment-emergent adverse events (TEAEs) and conducted laboratory assessments to evaluate the safety and tolerability of XEN1101. The data collected on seizure frequency, response rates, TEAEs, and laboratory findings were analyzed to determine the efficacy and safety of XEN1101 compared to the placebo. Through this methodical approach, the researchers aimed to establish the effectiveness of XEN1101 as a new treatment for focal epilepsy and to assess its safety profile in a controlled clinical environment.

The authors demonstrated that XEN1101 a significant reduction in seizure frequency, showing a robust dose-response relationship. The highest dose (25 mg) achieved a median 52.8% reduction in monthly FOS frequency compared to 18.2% for the placebo group. Additionally, responder rates (patients achieving at least a 50% reduction in seizure frequency) were higher in the XEN1101 groups, particularly at higher doses. These findings validate the potential of Kv7.2/Kv7.3 potassium channels as therapeutic targets in FOS treatment. According to the authors, the onset of response was rapid, and the reduction in seizures was sustained throughout the study. Moreover, XEN1101 was generally well tolerated, with TEAEs similar to those of commonly prescribed ASMs. The most common TEAEs were dizziness, somnolence, and fatigue, and there was no significant concern regarding cardiovascular signals or laboratory findings. In conclusion, the study on XEN1101 offers a beacon of hope for many patients with focal epilepsy. Its efficacy, safety profile, and rapid onset of action position it as a potentially game-changing treatment option. The findings support the continued development of XEN1101 and its eventual integration into clinical practice, promising to transform the therapeutic landscape for epilepsy patients worldwide.