ATLANTA — Epilepsy experts are getting a better picture of the long-term safety and efficacy of azetukalner, a novel and potent Kv7 potassium channel opener, in patients with treatment-resistant focal onset seizures (FOS).

Interim results of an open-label extension (OLE) study showed seizure frequency was reduced by 90.9% after 48 months, with about a third of the participants achieving complete seizure freedom for at least 12 months.

“The ideal way to really change people’s lives is to make them seizure-free, and this drug has the potential to do that,” study investigator Jacqueline French, MD, professor at Comprehensive Epilepsy Center, New York University, New York City, told Medscape Medical News.

The new analysis also confirmed the safety of the drug.

The findings were presented on December 8 at American Epilepsy Society (AES) 79th Annual Meeting 2025.

New Kid on the Block

Azetukalner is among a few potassium channel openers in development for epilepsy. The only approved potassium channel opener (ezogabine) was voluntarily removed from the market because of tissue pigmentation.

Unlike ezogabine, which was administered three times a day and even then, was still linked to fluctuations in serum concentrations, azetukalner is taken once daily and doesn’t require titration.

Focal epilepsy is marked by seizures from a single brain region that often affect one side of the body and is the most common epilepsy type, account for more than 50% of all cases, so finding effective treatments is particularly important, said French.

A double-blind phase (DBP) 2b study of 325 participants with FOS had previously evaluated 8 weeks of daily oral placebo or 10 mg, 20 mg, or 25 mg of azetukalner as an adjunct to patients’ existing antiseizure regimens.

The results, which were published in 2023 in JAMA Neurology and reported by Medscape Medical News at that time, showed the median percent reduction in monthly FOS frequency was 52.8% (P < .001) in the 25 mg group, 46.4% (P < .001) in the 20 mg group, and 33.2% (P = .04) in the 10 mg group, compared with that in the placebo group (18.2%).

At 25 mg per day, the 50% or more responder rate was 54.5% compared with 14.9% with placebo.

The study showed a rapid response to the medication. In addition, results showed that azetukalner was generally well tolerated, with treatment-emergent adverse effects (TEAEs) consistent with other antiseizure medications and balanced between study groups.

Long-Term Findings

At the AES meeting, French presented new results from the ongoing OLE study.

Of the 285 participants who completed the DBP, 96.5% enrolled in the OLE, which is evaluating the 20 mg dose. At entry, patients had a median monthly FOS frequency of 13.5 and were taking one to three antiseizure medications, with more than half (52.4%) taking three.

“These are people who are not only treatment-resistant but very treatment-resistant,” said French.

As of October this year, 122 participants (44.4%) had continued with the OLE. The median percent change in seizure frequency from DBP baseline ranged from 61.6% to 81.9% during months 1-24 of the OLE study and increased to a 90.9% reduction at OLE month 48.

That’s very “significant and good news,” especially when so many patients had tried and failed other drugs, said French.

To illustrate how potentially life-changing this drug can be, French discussed a patient who had developed severe epilepsy as a young man and failed multiple drugs and surgeries over the years. Since entering the study 4 years ago, he has been seizure free, and he is not alone, said French.

He’s not alone; a large proportion of study participants have continued taking azetukalner for 4 years and are still experiencing substantial benefit, French noted.

The investigators also examined seizure freedom, defined as a 100% reduction in seizures from OLE baseline. In those treated for 48 months or more, 38.2% had 12 months or more of seizure freedom, 25.2% had 24 or more months of seizure freedom, 19.8% had 36 or more months of seizure freedom, and 10.7% had 48 or more months of seizure freedom.

In addition, 47.3% achieved an interval of seizure freedom for 6 or more consecutive months.

“Very few drugs get a substantial number of treatment-resistant patients seizure free,” said French. “They’re very good at reducing seizure frequency, but then you still have seizures.”

However, she cautioned that there were relatively few participants included in the extension analysis. She also noted that patients who are doing well are going to stay in the study while those not doing as well are likely to drop out.

TEAEs occurred in 89.5% of participants, and 65.8% experienced treatment-related TEAEs, most of which were mild or moderate. The most common events were dizziness, headache, SARS-CoV-2 infection, somnolence, falls, weight gain, and memory impairment.

Regarding weight and memory issues, French said she advises patients that these side effects may lessen over time or with adjustments in dose or dosing frequency, noting that the drug is very long acting. Importantly, to date, no pigmentation-related adverse effects have been reported.

To date, two deaths have occurred during testing of the drug, but neither was considered treatment related. One was attributed to sudden unexpected death in epilepsy, and the other to viral pneumonia.

Results of a phase 3 study which is evaluating the 15 and 25 mg dose vs placebo are expected to be reported within about 6 months, said French.

A ‘Welcome Addition’ — With Caveats

Commenting for Medscape Medical News, Daniel M. Goldenholz, MD, PhD, assistant professor in the Division of Epilepsy at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, said the results are promising, particularly for patients who have exhausted existing treatment options.

“Having a new drug with a potentially higher efficacy rate than our standard drugs is a welcome addition,” said Goldenholz, who wasn’t involved in the research.

That said, he expressed some concerns about weight gain and cognitive side effects linked to the drug. He noted that 11.3% of participants in the OLE trial reported weight gain, and 10.9% memory impairment. In addition, in the 2023 trial, 4.3% of patients reported memory problems, 3.8% attention problems, and 4.7% aphasia, all of which were “well above placebo levels.”

He noted that the cognitive side effects are similar to those associated with topiramate, which many patients find difficult to tolerate because of problems such as foggy thinking and word-finding difficulty at higher doses. He added that the emerging data raise concerns that this new drug could pose similar challenges.

Although such side effects aren’t necessarily deal-breakers, they may give some patients and clinicians pause, especially when “easier” medications with better tolerability are available, Goldenholz said.

Xenon Pharmaceuticals Inc. funded this research.French reported being advisor to Xenon Pharmaceuticals but reported receiving no personal remuneration from this or any of the other companies she’s tied to that are developing new therapies for epilepsy; all funds are donated to the non-profit Epilepsy Study Consortium. Goldenholz reported no relevant disclosures.