CONy 2024 | Promising targets in headache research: PACAP
Alan Rapoport, MD, University of California, Los Angeles, CA, discusses the therapeutic potential of pituitary adenylate cyclase activating polypeptide (PACAP) as a target in headache management. PACAP is a neuropeptide implicated in a wide range of functions, including nociception. Studies indicate that systemic PACAP infusion triggers migraine-like attacks in patients with migraine and increased plasma levels have been recorded in migraine and cluster headache attacks. Initially, attempts to block PACAP using antibodies to its receptor failed. However, a recent study using antibodies directly to PACAP shows promise. If further studies prove successful, PACAP blockade could be a ground-breaking migraine treatment. Dr Rapoport, reflecting on his 56 years in neurology, notes the remarkable evolution of migraine therapies from one drug to numerous options today, expressing optimism for future advancements within 3 to 10 years. This interview took place at the 18th Annual Congress on Controversies in Neurology (CONy 2024) in London, UK.
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Transcript
One thing everybody is talking about is something called PACAP, which has a very long, complex name. It works something like the CGRP, which is bad for us and causes more headache and it should be blocked, but it’s a different neurotransmitter. Some studies were done on it, and many of those studies were done in Copenhagen at the Danish Headache Center, and we could see from those studies that if you give it to somebody with migraine, it’s going to cause a headache, and probably a migraine headache...
One thing everybody is talking about is something called PACAP, which has a very long, complex name. It works something like the CGRP, which is bad for us and causes more headache and it should be blocked, but it’s a different neurotransmitter. Some studies were done on it, and many of those studies were done in Copenhagen at the Danish Headache Center, and we could see from those studies that if you give it to somebody with migraine, it’s going to cause a headache, and probably a migraine headache. So they figured, well, we have to try to block it just like we block CGRP. The problem was, the first antibody that was made was made to the receptor of PACAP, the PAC1 receptor, where the PACAP has to dock to cause its problems. And it didn’t work. So they made an antibody to PACAP itself. So it would grab the ligand, the actual molecule, and prevent it from docking on the receptor. The study is somewhat positive and gives everybody the idea that if you do bigger and better studies and study it really carefully, that blocking PACAP may be good for migraine, maybe even better than blocking CGRP. Maybe it’ll work when CGRP blocking doesn’t work. So it’s kind of exciting to think about it. We’re hoping that the company that has this antibody will study it soon and maybe in 2 to 5 years we’ll have another great drug to try again.
And then, because of some research that’s going on, also at the Danish Headache Center, there’s other possibilities to block potassium channels and other things that have been found by basic research to possibly influence migraine. And if you can block those things, you’ve got another treatment for migraine. So, in the next three years, I think we might see some advances. We might not see it out in public yet, but we’ll be close to it. And in the next 5 to 10 years, I think we’ll see even more advances in migraine and in migraine treatment. I’m pretty optimistic. When I started out 56 years ago as a resident learning neurology, we had one drug for migraine that didn’t work very well and caused nausea, and most people with migraine have nausea. That wasn’t a great drug, but that’s the drug we had. And now we have so many drugs and devices, I don’t know what to start with. That’s a good place to be in.
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