AAN 2026 | The future of migraine treatment: new targets and combination approaches

There’s excitement that they’ve worked so well and so safely so far. Of course, vigilance is mandatory. We don’t know long-term effects. They’ve been taken by people for five or six years now. We don’t see any major problems cropping up, but there are real-world effects coming up. There is noticing to be alert for. On the whole, still safe. But what I alluded to is half the people respond with a clinically significant decrease. And even among that half, for some people, they still do keep getting migraines, just not as often or not as bad. Some people, completely cured. Those are the super responders. But most, there’s still a need. And certainly for the half who don’t show response, there’s a definite need there. So where do we go next? I say we build on the CGRP story. PACAP is another peptide that has similar activities as CGRP, but it’s different. It’s distinct. So our lab and other labs have shown that CGRP and PACAP work independently. Messoud Ashina in Denmark has done some very nice studies showing that CGRP and PACAP act independently in people. So I really think that if a drug targets PACAP, we’ll be able to help people who don’t respond to the CGRP drugs. And indeed, those trials have been successful so far through Phase II trials, been done by Lundbeck. So in the future, we have another peptide coming down the path, PACAP. And it’s more than just another CGRP. Similar, but different. I think a combination treatment of CGRP and PACAP drugs together will be effective. We’ve noticed in our mice that they work by different mechanisms, but their phenotypes, the response is very similar for PACAP and CGRP. Not the same, but similar. So I think that we can sort of like a one-two punch, get CGRP and get PACAP. So combinatorial therapy. Right now, combinatorial therapy with the CGRP drugs is working for many people. So people are taking a CGRP preventative monoclonal antibody, a MAB. They notice towards the end of the few months treatment time before they get the next injection that they’re getting more migraines. So they take a gepant, which is a small molecule oral drug, an antagonist of the CGRP receptor. So it’s called layering. So you’re already on one treatment, take another CGRP treatment on top of that, and that increases the efficacy. I think we should be considering higher doses of the CGRP drugs. There’s always a safety concern, but perhaps this layering observation is a sign we need to start working on something as simple just as dosing regimens. But certainly, so we have PACAP drugs, they’re on the pipeline, combination with CGRP drugs with PACAP, and then layering of the CGRP drugs with other drugs that are already out there, including the CGRP drugs, and onabotulinumtoxinA, or Botox for short. That’s also been showing efficacy. So combinatorial treatments. That’s what’s really right now. I think those are all available and possible. Further down in dreamland, there are so many options. It’s a great time to be a migraine researcher. There’s channels, the NAV 1.8 blocker, potassium channels, the TRAAK and TRESK channels are targets. I think those would be tricky to get at, but short term, in the long term, not immediate, but the next wave coming, there’s a protease receptor, PAR2. It’s involved in the inflammatory response caused by mast cells in the meninges. There’s other receptors on mast cells. The immune system in general, I think, should be a target. The local immune response. So those are some of the targets. There’s a lot of others out there. TRPM8, another ion channel. So other peptides. I could name a half dozen or 10 possibilities that are all in the preclinical stage now. And some are moving into clinical TRPM8 just at the American Neurology meeting. There’s a report there that TRPM8 was successful in a Phase II trial.

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