XEN496 Being Developed for KCNQ2 Epileptic Encephalopathy


Xenon Pharmaceuticals announced the expansion of its ion channel pipeline as a result of feedback from the FDA.

Dr Simon Pimstone

Simon Pimstone, MBChB, PhD, the chief executive officer of Xenon

Simon Pimstone, MBChB, PhD

Xenon Pharmaceuticals has announced the introduction of XEN496, a Kv7 potassium channel modulator with ezogabine as the active ingredient, for the treatment of epilepsy into clinical development.

This expansion of the company’s ion channel pipeline is a result of feedback from the FDA, with the initiation of a phase III clinical trial now being planned for mid-2019. The trial would evaluate XEN496’s efficacy as a precision therapy for KCNQ2 epileptic encephalopathy (KCNQ2-EE) or EIEE7, a rare and severe form of pediatric epilepsy.1

To date, no drug has been studied and approved for this specific indication. The president of the KCNQ2 Cure Alliance, Jim Johnson, said that the group is excited about the announcement and supports the development of new and better therapies for this unmet need.

“We have done an immense amount of diligence leading up to the addition of XEN496 to our novel and robust pipeline of ion-channel, antiepileptic drugs,” Simon Pimstone, MBChB, PhD, the chief executive officer of Xenon, said in a statement. “Based on feedback from key opinion leaders, advocacy groups, pre-existing literature, and promising data generated to date, we believe there is tremendous support for us to vigorously pursue the development and commercialization of XEN496 in order to reach the pediatric KCNQ2-EE patient population as rapidly as possible.”

Previously, case studies have been published supporting the use of the therapy as a potential treatment for KCNQ2-EE. The company believes XEN496 could improve long-term outcomes in the condition due to the active ingredient’s enhancement of the transmembrane potassium currents facilitated by the Kv7.2/7.3 channels. This mechanism of action is believed to stabilize the resting membrane potential and reduce brain excitability, thus possibly improving brain function and cognitive development, as well as decreasing seizures.

In 2016, a study of 11 patients showed ezogabine was associated with improvement in seizures and/or development in 3 of 4 patients treated prior to 6 months of age, and 2 of the 7 patients treated post-6 months, without any serious adverse effects (AEs).2 Another study the next year of 8 children with KCNQ2-EE revealed ezogabine was safe and effective, improving seizure frequency over a sustained period in 5 of 6 patients with weekly seizures, in addition to cognitive improvements in all patients. Urinary retention was the only AE reported, in 3 patients.3

Pimstone noted that the company has already completed several steps to speed up the process, including obtaining a right of reference authorization from GlaxoSmithKline to allow for regulatory filing references to support Xenon’s submission to the FDA, and additionally, Xenon has been granted an Orphan Drug designation for XEN496 by the FDA. Ezogabine was previously approved by the agency in 2011 and marketed by GSK as Potiga, however, in June 2017, it was withdrawn from the market due to a lack of return from sales.

In 2013, the FDA issued a safety communication and placed a black boxed warning on the GSK drug label, related to risks of retinal abnormalities, potential vision loss, and blue discoloration of the skin, nail, mucous membrane, and white-of-the-eye. It was unknown if these were reversible at the time. The FDA also advised all patients taking the medication to have baseline eye exams, followed by periodic eye exams every 6 months.4

“Additionally, our completed pre-IND interactions with the FDA, supported by the KCNQ2 Cure Alliance, key opinion leaders and parents of children with KCNQ2-EE, have been very positive and we believe they indicate support for a small, single, pivotal phase III clinical trial in approximately 20 pediatric patients to support registration,” he said. “Our ongoing work includes final pediatric formulation development in order to start the XEN496 phase III clinical trial in approximately mid-2019.”

Xenon has stated that a formal steering committee has been established for the clinical development process. It plans to provide additional details about the program in the coming months.


1. Xenon Expands Ion Channel Neurology Pipeline with Addition of XEN496, a “Phase 3 Ready” Potassium Channel Modulator for the Treatment of Epilepsy [press release]. Burnaby, BC: Xenon; Published September 6, 2018. investor.xenon-pharma.com/phoenix.zhtml?c=253202&p=irol-newsArticle&ID=2366293. Accessed September 7, 2018.

2. Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet. 2016;2(5):e96. doi: 10.1212/NXG.0000000000000096.

3. Olson HE, Kelly M, LaCoursiere CM, et al. Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Anna Nuerol. 2017;8(13):419-429. doi: 10.1002/ana.24883.

4. FDA Drug Safety Communication: FDA determines 2013 labeling adequate to manage


of retinal abnormalities, potential vision loss, and skin discoloration with anti-seizure drug Potiga (ezogabine); requires additional study [press release]. Bethesda, MD: FDA; Published October 31, 2013. http://wayback.archive-it.org/7993/20161022053232/http://www.fda.gov/Drugs/DrugSafety/ucm372774.htm. Accessed September 7. 2018.

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