There’s no shortage of epilepsy drugs — the FDA has approved more than 30 antiseizure medications for the condition to date. Yet roughly a third of epilepsy patients continue to have uncontrolled seizures, and most of the available drugs use the same handful of mechanisms.
Now, the pipeline is broadening in two directions: genetic medicines that aim to alter the course of rare epilepsies, and more selective drugs designed to improve seizure control for more patients.
Investigational drugs, such as gene therapies, are targeting new brain pathways and looking to correct underlying drivers of epilepsy. And innovations are in the clinic for both broad epilepsy indications and rarer forms of the disease, said Myles Minter, a biotechnology analyst at William Blair.
Treatments for Dravet syndrome, a rare and severe type of epilepsy that begins in infancy, are also progressing through the clinic. More than 90% of people diagnosed with Dravet syndrome have an SCN1A mutation, typically a loss-of-function mutation affecting one copy of the gene.
When asked about some of the notable highlights in pharma’s epilepsy pipeline, Minter pointed to Stoke Therapeutics and Biogen’s zorevunersen, which was designed to spur production of a missing protein from the unaffected copy of the SCN1A gene.
“The phase 3 Emperor study is ongoing but earlier trials have shown that by restoring the protein missing in these patients, not only can seizures be reduced, but quality of life and long-term functional outcomes can benefit,” Minter said. “This is very different from what you would expect treating these patients with other symptomatic therapies.
Stoke said a data readout in the third quarter of 2027 could support a rolling new drug application submission to the FDA.
Encoded Therapeutics is chasing the same target using a different mechanism. Its ETX101, a one-time gene therapy, also takes aim at SCN1A, and in earlier phase 1/2 trials, it reduced seizure frequency and triggered "substantial" gains in cognitive growth scales “with development trajectories approaching the range of expected for neurotypical children,” the company said.
Encoded recently closed $275 million in series F financing, which, among other things, will bring the treatment through a pivotal trial in infants and young children with SCN1A and Dravet syndrome, as well as an expansion study in older children up to age 18.
Genetic treatments are also gaining ground beyond Dravet syndrome, including those for SYNGAP1-related disorder, which causes intellectual disability and often epilepsy, Minter said.
Camp4 Therapeutics’ CMP-002 is designed to upregulate SYNGAP1 expression. In preclinical models, Camp4 reported restoring SYNGAP protein levels while improving disease-related phenotypes. Its first-in-human phase 1/2 trial is expected to begin in the fourth quarter. Praxis Precision Medicines and Stoke Therapeutics, among others, have earlier programs targeting the same condition, he said.
While genetic programs aim at underlying drivers of rare epilepsies, another group of late-stage drugs is trying to improve seizure control and tolerability in the much larger focal-seizure market.
“This is very different from what you would expect treating these patients with other symptomatic therapies.”
Myles Minter
Biotechnology analyst, William Blair
New drugs for focal seizures
Xenon Pharmaceuticals’ azetukalner is one of the most advanced candidates for focal seizures. Minter pointed to its phase 3 anti-seizure efficacy data from the X-Tole2 study and differentiated mechanism. The drug, a Kv7.2/7.3 potassium channel opener, targets an ion channel that helps regulate electrical signals in the body. By opening this channel, azetukalner is designed to dampen neuron activity to lessen seizures in people with epilepsy. In a phase 3 trial, the treatment reduced median monthly seizure frequency from baseline by 53.2% in the 25 milligram group.
The company submitted its new drug application to the FDA this month as an add-on treatment for focal seizures. It’s also in phase 3 for tonic-clonic seizures and two types of depression. It hit a snag recently when its depression studies paused enrollment after patients experienced neuropsychiatric adverse events, but the company expects the trials to resume, potentially after dosing modifications. A stock dip followed that announcement, but if the drug clears regulatory hurdles, it could be on track to reach $1.7 billion in annual sales, according to RBC Capital Markets analyst Brian Abrahams.
Azetukalner could also have competition from Rapport Therapeutics’ RAP-219, a phase 3 investigational focal seizure drug, which was designed to improve on the tolerability of Fycompa from Catalyst Pharmaceuticals, Minter said. RAP-219 targets the same broad pathway as Fycompa, but focuses on the narrower TARPγ8 protein, an approach Minter said could improve tolerability while preserving efficacy.
Beyond its strong phase 2a results, the treatment could also distinguish itself with a dosing advantage, Minter said. And the drug has a long half-life, which could enable development of a convenient, long-acting injectable. But Rapport will need to navigate a crowded market that also includes an approved drug called Xcopri from SK Life Science, and potentially other investigational treatments still in the clinic from Praxis Precision Medicines and Biohaven.
Filling the epilepsy gaps
Some of the epilepsy field’s notable candidates target forms of the disease with few treatment options.
Among the hardest to treat are developmental and epileptic encephalopathy, a group of epilepsies that are not only severe and marked by developmental delays, but that are often drug-resistant. Some patients with DEE can have multiple seizures per day and as many as 30-100 seizures per month, Minter said.
While many companies have targeted individual types of DEE, such as Dravet syndrome, Lundbeck is looking to address multiple subtypes at once with its drug bexicaserin. The company picked up the 5-HT2C receptor superagonist through its $2.6 billion acquisition of Longboard Pharmaceuticals, and the drug is now in phase 3 testing across multiple DEE subtypes.
“The Deep Ocean trial represents a comprehensive pivotal program in DEEs, with the most diverse DEE population studied to date,” Ingrid Scheffer, a professor and lead investigator of the trial, said in a press release. “By including a broad range of DEE syndromes and more than 60 different genetic DEEs, this study is designed to reflect the real-world heterogeneity of these devastating conditions.”
The company expects results by the end of 2026 or early 2027.
Praxis Precision Medicines, meanwhile, is knocking on the door of a potential approval for its first-in-class small molecule for a type of DEE. In a phase 2 study, the treatment, which targets SCN2A and SCN8A-related DEEs, reduced placebo-adjusted motor seizure frequency by up to 53% and increased motor seizure-free days by 66%. The results were strong enough that the data monitoring committee stopped the trial early for efficacy.
But after filing for an approval, the FDA asked Praxis to submit additional sensitivity analyses, leading to a delay in the agency’s decision date. Now, the PDUFA date has been set to Dec. 27.
Analysts are also watching BrightMinds Biosciences’ BMB-101, Minter said. The drug, a 5-HT2C receptor agonist, saw favorable results in an open-label phase 2 study that included a very small number of DEE patients, reducing major motor seizures by 63.3%, and it’s preparing for global registrational trials.
Taken together, the pipeline is widening beyond another generation of broadly acting antiseizure drugs — toward therapies aimed at specific genetic drivers on one end and more selective seizure-control mechanisms on the other. For the roughly one-third of patients whose seizures remain uncontrolled, either path could matter.
