The word migraine comes from the Greek word “hemicrania” meaning “half of the head” — a perfect illustration of the throbbing head pain that individuals so often feel on one side (1). While it’s not clear why, women are three times more likely to suffer from migraines compared to men, and some estimates suggest that nearly one in five women are impacted by this painful neurological disease (2,3). Beyond the pulsing pain, symptoms also include nausea, vomiting, dizziness, and vision problems. The attacks can happen as frequently as several times a week — severely limiting quality of life.

“It's a large disease of young people who are at the prime of their life and can be working and having families, and it impacts all of that,” said Jessica Ailani, a neurologist and headache specialist at MedStar Georgetown University Hospital. “Women decide not to have children because of this disease.”

Ailani chose to specialize in this area after treating many young women who “tended to not be well treated or ignored, or many times were told it's just because you have a hormonal problem and nothing else known about it,” she said. Although changes in hormones like estrogen and prolactin during the menstrual cycle are thought to play a role, doctors and scientists still don’t have a good understanding of why migraines disproportionately affect women. Nor do they have a complete understanding of the mechanisms that lead to migraine pain in the first place.

“The thought is that migraine somehow starts in the brain. Nobody knows exactly where,” said Dan Levy, a neuroscientist at the Beth Israel Deaconess Medical Center at Harvard Medical School, adding that evidence suggests the origin of a migraine attack begins in either the hypothalamus or the brainstem. “How you get from there to pain is unclear,” he said. Work from Levy’s lab and others shows that the meninges, the three membrane layers that cover the brain, are involved in the sensation of pain, and recent discoveries point to the role of the cerebrospinal fluid in activating neurons in the trigeminal nerve, which sends signals back and forth from the brain to the face (4,5).

Even without a full understanding, recent treatments have been successful and even life-changing for some. In 2018, the Food and Drug Administration (FDA) approved the monoclonal antibody Aimovig from Amgen as the first drug in a new class of anti-calcitonin gene-related peptide (CGRP) medications that seek to both prevent and treat migraines. These drugs work by blocking the CGRP neuropeptide, which causes vasodilation. Neurons in the trigeminal nerve release these peptides onto blood vessels in the meninges, and other sensory nerves release them into the peripheral nervous system outside the brain (6). CGRP inhibitors have reduced the number of attacks in about half of patients treated. However, around 20 to 30 percent of migraine sufferers see no relief from CGRP inhibitors at all. For these nonresponders, new medications are still urgently needed.

Based on promising data from a Phase 2 clinical trial, a new treatment may not be far off. Lundbeck Therapeutics, whose CGRP inhibitor Vyepti was FDA-approved in 2020, is now testing a monoclonal antibody, Lu AG09222, that targets another neuropeptide involved in migraines: the pituitary adenylate cyclase activating polypeptide (PACAP).  While CGRP and PACAP are both involved in regulating vasodilation throughout the body, PACAP acts more broadly since it also binds to receptors in the parasympathetic nervous system. Thus, blocking PACAP could potentially aid a larger group of migraine sufferers.

“Given that there's still millions of people with migraine and still hundreds of thousands of people with severe migraine, I think we're on a mission here to do something about the very debilitating disease,” said Johan Luthman, the Executive Vice President of Research and Development at Lundbeck Therapeutics.

Putting PACAP to the test

In 2019, Luthman and his colleagues at Lundbeck Therapeutics bought a company called Alder BioPharmaceuticals. In addition to developing eptinezumab into what would become the FDA-approved CGRP inhibitor Vypeti, Alder BioPharmaceuticals also had a PACAP inhibitor in its portfolio. “That was a very purposeful acquisition by us,” said Luthman. “We knew [targeting PACAP] was an interesting new mechanism of action. … We got that molecule from that acquisition at a preclinical stage, and then we decided to take it into humans and bring it forward.”

But there was reason to worry that their new PACAP inhibitor wouldn’t be effective, Luthman said. In 2020, Amgen tested a monoclonal antibody that sought to block PACAP activity by targeting the PACAP type 1 (PAC1) receptor and found that it offered patients no benefit in preventing migraines (7). “There was a little bit of nervousness. What have we got here? Should we really [go forward] with this?” said Luthman. Yet, he remained hopeful because he knew their PACAP inhibitor antibody had a different mechanism of action. Instead of binding to the PAC1 receptor itself to block PACAP activity, Lu AG09222 attaches to the PACAP ligand and then inhibits it from binding to three receptors that regulate vasodilation and a variety of other homeostatic processes: the PAC1 receptor, and vasoactive peptide 1 (VPAC1) and 2 (VPAC2) receptors. By blocking the signaling of PACAP onto all three receptors that it binds to, “we're better and broader,” said Luthman.

These three receptors are expressed not only in neurons, but also in smooth muscle cells outside the brain. Because the PACAP inhibitor is a monoclonal antibody, only a very small fraction of it crosses the blood-brain barrier to reach the brain. That means both PACAP and CGRP inhibitors mostly target cells in the periphery to block pain signaling pathways that lead to migraine pain. Whether or not migraine pain comes from the central or peripheral nervous system remains a hotly debated topic, though more research is showing that it comes from both sources (8).

The big question now is whether a PACAP inhibitor will be able to help patients who did not respond well or at all to CGRP inhibitors. Lundbeck Therapeutics’ researchers can’t answer that question just yet. So far, results from their Phase 2a HOPE trial showed that PACAP was well-tolerated and reduced the number of migraine days by about two days, on average, compared to placebo (9). This trial used intravenous administration, and they now plan to test a subcutaneous administration to determine the proper dosage in their Phase 2b trial before moving ahead to a larger Phase 3 trial.

“2004 was the last time a new mechanism worked in migraine. So, it's 20 years since someone showed that something worked. Here [we] have a new biology that also seems to work,” said Luthman.

To combine or not to combine

Of all the drugs under development right now to treat migraine, Ailani said that PACAP inhibitors show the most promise. Scientists who study the mechanisms behind migraine and headaches are also excited about the potential for Lundbeck Therapeutics’ PACAP inhibitor to progress through the pipeline and reach patients. “As an alternative to CGRP, I think that's exciting enough and the possibility of combination therapy [with CGRP inhibitors],” said Yu-Qing Cao, a neuroscientist at the Washington University School of Medicine in St. Louis.

Ailani agreed that it may be worth looking into whether combining PACAP and CGRP inhibitors could offer more relief to patients who partially responded to the CGRP medications, but it would require a clinical trial that looked at the safety of combining them. Levy said that combining them is probably not a good idea. “Taking out CGRP [on its own] is okay because there's some redundancy in the system. So, something else will allow you to control blood flow and things like this. If you're taking two out of the system — side effects,” he said.

Regardless of whether a combination treatment would work or not, Cao and Levy both emphasized that it would be helpful for the field to invest more research in genetic profiling and biomarker development to identify the best treatment for each patient. “Migraine is so heterogeneous, it's not possible to have one blockbuster for everyone,” said Cao. “It's really important if we have some predictive power. … Maybe this one is more responsive to CGRP, or maybe that one is more responsive to PACAP, and that will, I think, reduce lots of the trial and error.”

Moving forward in migraine drug development, both Cao and Levy would also like to see more of the mechanisms behind the disease mapped out. In particular, they are both interested in studying neuro-immune interactions to identify ways that immune responses may contribute to migraines. “We know there's probably an inflammatory mechanism. We don't know how it starts,” said Levy.

Once scientists have a more comprehensive understanding of what is going on in the brain to trigger migraines, Cao hopes that future drugs will be able to safely penetrate and act directly on neurons in the brain rather than primarily acting only on the peripheral nervous system. “At this point, I think all possibilities should be pursued,” she said.

A waiting game

Luthman is hopeful that the results from Lundbeck Therapeutics’ PACAP inhibitor will lead to a drug approval for patients. “That's the crown jewel of drug development, when you have something new, completely novel, that works. It doesn't happen that often, unfortunately, in our business,” he said. “You can spend a whole lifetime in pharma and not be part of a new mechanism tested like this.”

2004 was the last time a new mechanism worked in migraine. So, it's 20 years since someone showed that something worked. Here [we] have a new biology that also seems to work. 
– Johan Luthman, Lundbeck Therapeutics

Luthman said the team at Lundbeck Therapeutics is not stopping there. “We are not just set settling down with this PACAP readout. … Now we have even more molecules to play with, and we're actively pursuing this,” he said. “Lundbeck is one of the few companies that is really actively building an R&D portfolio in migraine.”

But until new drugs have been proven to work, patients who have not yet responded to approved treatments like CGRP inhibitors will have to wait. “Patients are asking us every day, who aren't doing well, when is the next thing coming?” said Ailani, adding that it can be heartbreaking for these patients when they see their friends or loved ones respond well to current medications. “For us, in the clinical realm and also doing trials, you really hope this is going to work.”

References

1. Weatherall, M.W. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis  6, 115–123 (2015).
2. Broner, S.W., Bobker, S. & Klebanoff, L. Migraine in Women. Semin Neurol  37, 601–610 (2017).
3. Lipton, R.B., Stewart, W.F., Diamond, S., Diamond, M.L. & Reed, M. Prevalence and Burden of Migraine in the United States: Data From the American Migraine Study II. Headache  41, 646–657 (2001).
4. Levy, D. & Moskowitz, M.A. Meningeal Mechanisms and the Migraine Connection. Annu Review Neurosci  46, 39–58 (2023).
5. Kaag Rasmussen, M. et al.  Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model. Science  385, 80–86 (2024).
6. Wattiez, A.-S., Sowers, L.P. & Russo, A.F. Calcitonin gene-related peptide (CGRP): Role in migraine pathophysiology and therapeutic targeting. Expert Opin Ther Targets  24, 91–100 (2020).
7. Ashina, M. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia  41, 33-44 (2021).
8. Do, T.P., Hougaard, A., Dussor, G., Brennan, K.C. & Amin, F.M. Migraine attacks are of peripheral origin: the debate goes on. J Headache Pain 24, 3 (2023).
9. Ashina, M., Phul, R., Khodaie, M., Löf, E. & Florea, I. A Monoclonal Antibody to PACAP for Migraine Prevention. N Engl J Med  391, 800–809 (2024).