In cases where standard therapies fail, an investigational medication called XEN1101 reduces seizure frequency by more than 50 percent in some patients and sometimes eliminates them altogether, a new study shows. Unlike several treatments that must be started at low doses and slowly ramped up, the new drug can safely be taken at its most effective dose from the start, the authors say.

Focal seizures, the most common type seen in epilepsy, occur when nerve cells in a particular brain region send out a sudden, excessive burst of electrical signals. Along with seizures, this uncontrolled activity can lead to abnormal behavior, periods of lost awareness, and mood changes. While many available therapies control or reduce seizures, they fail to stop seizures in about one-third of patients and may cause harsh side effects, experts say.

Researchers at NYU Grossman School of Medicine participated in a new phase 2b clinical trial, which found that patients who added XEN1101 to their current antiseizure treatments saw a 33 to 53 percent drop in monthly seizures, depending on their dose. By contrast, those given a placebo had on average 18 percent fewer seizures during the treatment phase of the trial, which lasted eight weeks. Most patients then volunteered to extend the trial, with about 18 percent of those treated with the new drug remaining entirely seizure-free after six months, and about 11 percent having no seizures after a year or longer.

“Our findings show that XEN1101 may offer a swift, safe, and effective way to treat focal epilepsy,” said study lead author, neurologist Jacqueline A. French, MD. “These promising results offer hope for those who have struggled for decades to get their symptoms under control.”

Dr. French, a professor in the Department of Neurology at NYU Langone Health, notes that XEN1101 was well tolerated by the study participants, who reported side effects similar to other antiseizure treatments, including dizziness, nausea, and fatigue, and the majority felt well enough to continue the regimen. Another benefit of the drug, she adds, is that it takes more than a week to break down, so levels in the brain remain consistent over time. This steadiness allows the treatment to be started at full strength and helps to avoid dramatic spikes that worsen side effects, and dips that allow seizures to return. This lengthy breakdown time also allows for a “grace period” if a dose is accidentally skipped or taken late.

XEN1101 is part of a class of chemicals called potassium-channel openers, which avert seizures by boosting the flow of potassium out of nerves, stopping them from firing. Dr. French, who is also a member of NYU Langone’s Comprehensive Epilepsy Center, notes that while other drugs of this kind have been explored for patients with epilepsy in the past, such treatments were taken out of use because the compounds were later found to gradually build up in the skin and eyes, prompting safety concerns, the researchers say.

A report on the phase 2b trial published October 9 in the journal JAMA Neurology. For the study, which included 285 men and women with epilepsy and ran from January 2019 to September 2021, the research team recruited adults with epilepsy who had already tried and stopped taking an average of six drugs that failed to treat their focal seizures. Patients in the trial had to have experienced at least four episodes a month despite ongoing treatment to qualify. The patients were randomly provided either a daily oral capsule of XEN1101 (in doses of 10 milligrams, 20 milligrams, or 25 milligrams) or an inert placebo tablet that appeared identical to the real drug.

Among the results, the trial revealed no signs of dangerous side effects such as heart problems, allergic reactions, or concerning skin discolorations. However, Dr. French says that the research team plans to expand the number of patients exposed to the drug and monitor for potential issues that could arise in the long term, or include specific groups of people, such as pregnant women. In addition, the team also intends to explore XEN1101 for other types of seizures, including those that broadly affect the brain at the same time (generalized seizures).

“Our study highlights the importance of finding as many therapeutic options as possible for those who have seizures,” says Dr. French. “Since everyone responds differently, treating epilepsy cannot be a one-size-fits-all approach.”

The study sponsor was Xenon Pharmaceuticals Inc., a biotechnology company based in Vancouver, Canada, that develops therapies for neurologic disorders, including epilepsy and major depressive disorder. Xenon Pharmaceuticals is the developer of the investigational drug XEN1101, which is currently being evaluated in phase 3 clinical trials and is not approved for use in the United States outside of a clinical trial.

Dr. French has served as a consultant for Xenon Pharmaceuticals Inc. and has received past research and travel support from the company. She has also similarly received support from groups not involved in the study, including the Epilepsy Foundation, Aeonian/Aeovian, Alterity Therapeutics, Anavex, Angelini Pharma, Arkin Holdings, Arvelle Therapeutics, Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics, Baergic Bio, Beacon Biosignals, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical, BioXcel Therapeutics, Bloom Science, BridgeBio Pharma, CAMP Therapeutics, Cerebral Therapeutics, Cerevel Therapeutics, Clinical Education Alliance, Coda Biotherapeutics, Corlieve Therapeutics, Crossject, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel, the Epilepsy Study Consortium, the Epilepsy Foundation, Equilibre BioPharmaceuticals, Greenwich Biosciences, GRIN Therapeutics, GW Pharmaceuticals, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Korro Bio, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus Pharmaceuticals, Mend Neuroscience, Merck, NeuCyte, Neumirna Therapeutics, Neurocrine Biosciences, Neuroelectrics USA Corp., Neuronetics, NeuroPace, NxGen MDx, Ono Pharmaceutical, Otsuka Pharmaceutical Development, Ovid Therapeutics, Paladin Labs, Passage Bio, Pfizer, Praxis Precision Medicines, PureTech Health, Rafa Laboratories, Receptor Holdings, SK Life Science, Sofinnova, Stoke Therapeutics, Supernus, Synergia Medical, Takeda Pharmaceuticals, Third Rock Ventures, UCB, Ventus Therapeutics, Xeris Biopharma Holdings, Zogenix, and Zynerba. The terms and conditions of all of these relationships are being managed by NYU Langone.

In addition to Dr. French, other investigators involved in the study are Roger Porter MD, at the University of Pennsylvania in Philadelphia; Emilio Perucca, MD, PhD, at the University of Melbourne in Australia; Martin Brodie, MD, at the University of Glasgow in Scotland; Michael Rogawski, MD, PhD, at the University of California, Davis, in Sacramento; and Simon Pimstone, MD, PhD, Ernesto Aycardi, MD, Cynthia Harden, MD, Jenny Qian, MS, Constanza Luzon Rosenblut, MD, Christopher Kenney, MD, and Gregory Beatch, PhD, at Xenon Pharmaceuticals.

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