AAN 2026 | Headache clinical trial highlights from AAN 2026

During the recent American Academy of Neurology meeting in Chicago, there was a trial session, presented some of the most interesting things that are happening in the clinical trial arena, and I’m just going to pick a couple of them out. First one I’ll pick out, and I have conflicts of interest with these because I’m interested in these and I’ve certainly advised the companies, I want to say that straight up. The first one I’ll highlight, because it’s entirely new, is a drug called elismetrep, E-L-I-S-M-E-T-R-EP. If you’ve never heard of it, you probably haven’t. It’s a TRPM8 receptor antagonist. Now, the TRPM8 receptor is the cold receptor. If you take menthol and put it on your head and it feels cold, it’s because you’re activating that receptor. So what was done was a double-blind, placebo-controlled, randomized, dose-ranging study, 2, 5, 10, and 20 milligrams of elismetrep in the acute treatment of migraine. About 30%, a third of the folks in the study were triptan-resistant, meaning having failed at least one triptan, and about a third of them were on a preventive. The primary endpoint was two-hour pain-free for the 20 milligram dose. And it’s worthwhile saying that’s a modest dose in the context of this drug, which had been developed in another indication it didn’t go forward, not in migraine. And there’s over a thousand people who’ve already been dosed with this drug. So it’s really quite de-risked in terms of safety. So the primary endpoint, two-hour pain-free, 9.1% for placebo, 17.6% for the active. This wasn’t significant. And the primary endpoint was done using an electronic diary. By making inquiry of one patient who didn’t fill the electronic diary in at two hours, but filled it in earlier and later, the two-hour pain-free rate was 19.6%, problem of relatively small numbers, although there were nearly 400 patients in the study across all of the four doses and the placebo. And that was significant against placebo, which was at 9%. Without any sort of adjustments, the two-hour most bothersome symptom rate, 24% versus 38% for active, was significant. These are nominal p-values. And the two-hour pain relief data, 42% versus 59%, was also significant. And pain relief is quite important because it correlates quite tightly with improvement in disability improvement in function. So entirely new entity, the TRPM8 receptor. Certainly have to watch what happens with that.

Quite importantly, from a practice point of view, it’s been very difficult to get studies sorted out with the pediatric and adolescents. And Dr Bryson presented a study, the two studies in children and adolescents in episodic and chronic migraine with fremanezumab. These are Phase III studies. Patients were six to 17 years old. The standard differential diagnosis in the sense that episodic migraine 14 days or less and chronic migraine 15 or more days. They’re randomized one-to-one with fremanezumab and placebo. Importantly, there was dose adjustment, so 120 milligrams if the participant was under 45 kilos and 225 if they were 45 kilos or more, took placebo or active for three months. And the primary endpoint showed that for episodic migraine, there are 234 patients in the episodic study, 289 participants, I should say, in the chronic study. For the episodic study, fremanezumab beat placebo. And for the chronic study, it didn’t, which is great for those with episodic migraine. It’s great to see a pediatric adolescent study positive. It’s, I have to say, I thought the audience thought, and I’d have to join them, it’s a bit mystifying why it’s difficult that the chronic migraine study was not successful. All of that said, we had a positive randomized placebo-controlled trial in episodic migraine in children and adolescents.

An interesting study that was presented tried to look at the cognitive toll, you might say, using real-world evidence in what was called a MIND cohort, M-I-N-D, so Migraine Impact on Neurocognitive Dynamics. Dr Ezzati presented this, and they enrolled 129 adults with migraine via social media. And for 30 consecutive days, got them to record their daily headache status. And they did three brief smartphone cognitive tests, a simple search test for attention and processing, colour dots for item localization, visual working memory, and colour shapes, feature binding detection in visual working memory. And they looked at the performance across time. This is a pretty typical cohort of 38-year-olds, predominantly females. And what they showed was on headache days, on the symbol search, there was a reduction in response times compared to their baseline and similarly on the coloured dots, but not on the coloured shapes. And the first two were significant. It’s quite remarkable. And I think it’s been underappreciated by physicians, but certainly it is appreciated by patients that there is a cognitive penalty to migraine and that those cognitive reductions were tracked with the attacks. And you can do that in an objective way. And it goes to show you more broadly, this use of real-world digital endpoints, real-world digital technologies will enable us to get some very important insights into what’s going on on a day-to-day basis in people with migraine.

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