Zeroing in on PACAP to Treat Migraine

A phase 2, placebo-controlled clinical trial found that an anti-PACAP antibody decreased monthly migraine days.

Drugs that target the CGRP system have transformed the treatment of migraine. And yet, roughly 40% of patients fail to respond to these agents, propelling a search for new medications targeting different systems. Will that effort succeed? While it’s still relatively early days, results from a recent clinical trial (called HOPE) targeting a different neuropeptide implicated in migraine pathophysiology offers promise that the migraine field is on the right track towards another therapeutic success.

Researchers led by Messoud Ashina, Danish Headache Center, Copenhagen University Hospital–Rigshospitalet, Denmark, are reporting that an antibody targeting pituitary adenylate cyclase-activating polypeptide (PACAP), which has a role in a number of physiological processes, significantly decreased the number of migraine days per month, compared to placebo, in patients taking part in their phase 2, double-blind, randomized, placebo-controlled trial.

The effect sizes observed in the study were similar to those seen in trials of currently approved monoclonal antibodies targeting CGRP. And, the drug appeared safe.

The trial results appeared September 5, 2024, in the New England Journal of Medicine, along with an accompanying editorial by Elizabeth Loder, Brigham and Women’s Hospital, Boston, US.

The authors “have shown that the PACAP antibody has potential as a novel and effective treatment for migraine, particularly for individuals for whom other options have been exhausted. If future trials confirm its efficacy, this treatment could provide much-needed relief for many people with migraine and open the door to new treatments for other headache disorders,” wrote Dimos Mitsikostas, National and Kapodistrian University of Athens, Greece, and Alan Rapoport, David Geffen School of Medicine at UCLA, US, in a News & Views published October 7, 2024, in Nature Reviews Neurology.

A shift of focus from the receptor to PACAP itself
Ashina’s group has been at the forefront of advancing understanding of PACAP’s role in migraine. About fifteen years ago, he and his colleagues reported results from a small placebo-controlled trial, published in the journal Brain, implicating PACAP in migraine.

“We demonstrated that if we gave an intravenous infusion of PACAP, we could actually trigger migraine attacks in people with migraine,” Ashina told Migraine Science Collaborative in an interview. “This was probably the first evidence that really linked PACAP to migraine, and I proposed that targeting PACAP signaling could be a new therapeutic [possibility],” he said.

Ashina’s group continued to work on PACAP over the years, trying to understand how it might be acting to produce migraine. One line of investigation looked at the various receptors for PACAP, of which there are three: VPAC1, VPAC2, and PAC1.

Fast forward to 2020, when Ashina and colleagues would test an antibody that had been developed by the biotechnology company Amgen, in a phase 2 trial for migraine prevention. That antibody was directed against the PAC1 receptor, considering that PACAP has much higher affinity for PAC1 than the other receptors. But the results were negative, with no difference in monthly migraine days or other outcome measures between treatment and placebo groups.

Drug development attention then shifted to the ligand itself, PACAP, rather than on the receptors. Ashina said that Lundbeck, the company developing the anti-PACAP antibody tested in the new trial, approached him for advice about how to move forward with clinical development of the drug.

That led to a “proof of mechanism” study, which demonstrated that the drug prevented vasodilation – a proposed mechanism for how PACAP acts physiologically –  in healthy subjects who had been pretreated with PACAP-38 (one of the two isoforms of PACAP).

“We showed that the drug completely blocked the vasodilator response and reduced head pain,” Ashina said of the study, which was a phase 1, placebo-controlled trial called CHALLENGE.

Specifically, while PACAP-38 had increased the diameter of the superficial temporal artery, facial blood flow, and heart rate, and had induced mild headache in those pretreated with it, the drug inhibited all of those effects.

The stage was now set for the current study: A proof-of-concept trial that would test the efficacy of the antibody in people with migraine.

Encouraging results
For the new study, which was sponsored by Lundbeck, Ashina and colleagues enrolled 237 patients, aged 18-65 years and 88% female, who had received a diagnosis of migraine without aura, migraine with aura, or chronic migraine. Only those who did not benefit from two to four preventive migraine medications taken previously in the last 10 years could take part in the trial.

Participants were randomized to one of three groups: 750 mg of the anti-PCACP antibody, called Lu AG09222, 100 mg of the antibody, or saline (placebo), all delivered intravenously. Each treatment was infused as a single dose at a baseline study visit. The primary endpoint was the mean change from baseline in monthly migraine days, during weeks 1 through 4 of the study, in the 750 mg drug treatment group. A number of secondary and exploratory endpoints were included as well.

For the primary endpoint, those in the 750 mg group reported 6.2 fewer migraine days per month, compared to 4.2 fewer days in the placebo group – a difference of 2 days. The overall study population had an average of 16.7 migraine days per month at baseline.

When looking at secondary endpoints, the investigators saw that 32% of the 750 mg group had a reduction from baseline of at least 50% in the number of migraine days per month, compared to 27% in the placebo group. The team also examined headache days per month. Here, the 750 mg group had 5.8 fewer headache days per month, compared to 4.1 fewer days in the placebo group, a difference of 1.7 days.

Finally, exploratory endpoints included changes in the number of migraine attacks per month, the number of headache episodes per month, and the number of days each month when participants used headache or migraine medications. On all of those measures, the 750 mg group showed benefit over the placebo group, with effect sizes similar to those observed with the other endpoints.

The effect size for the primary endpoint – two fewer migraine days per month, on par with findings from trials of anti-CGRP antibodies –  “might not seem like much, but over a year that adds up to almost a month of better-quality life,” Loder wrote in her editorial.

Looking at the data from a similarly optimistic perspective, “[t]he efficacy is particularly notable given that the participants had refractory, high-frequency migraine,” according to Mitsikostas and Rapoport in their News & Views.

Finally, the drug appeared to be safe. The most notable adverse events were an increase in COVID-19, nasopharyngitis, and fatigue in the 750 mg group, compared to placebo.

What’s in store for anti-PACAP antibodies and migraine?
The next drug development step for anti-PACAP treatment for migraine is already underway. A phase 2b study, called PROCEED, has been initiated by Lundbeck. That trial’s goal is to determine the optimal dose of the anti-PACAP antibody, this time delivered subcutaneously, which could set the stage for a phase 3 trial.

If the anti-PACAP antibody makes it through phase 3 testing and ultimately receives regulatory approval, how might it fit into the current treatment landscape? Ashina said that he can envision patients who are not benefiting from anti-CGRP treatment switching to an anti-PACAP antibody, or vice-versa.

He also speculated that combination therapy with both antibodies might be a possibility, particularly because the antibodies target different signaling pathways.

In the meantime, is it time to abandon hopes for an anti-PACAP treatment that would affect one of the PACAP receptors, rather than the ligand?

“It’s a very good question. I would say that receptors are not out of the picture,” Ashina said.

“To make the story more exciting,” he continued, “in addition to the three receptors – VPAC1, VPAC2, and PAC1 – there is also one receptor associated with degranulation of mast cells. This was first described in animals, but later this receptor subtype was also shown in humans. So I wonder whether blocking this receptor could also have some potential if you have an antibody against it, or an antagonist against it. The future will show whether the PACAP receptors are a viable target in this context. But I wouldn’t exclude their role – absolutely not.”

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on X (formerly Twitter) @NeilAndrews

Image credit: ID 129679979 © Stanislav Rykunov | Dreamstime.com

References
A monoclonal antibody to PACAP for migraine prevention.
Ashina et al.
N Eng J Med. 2024 Sep 5;391(9):800-9.

A new antibody treatment for migraine.
Loder E.
N Eng J Med. 2024 Sep 5;391(9):855-7.

Continuing evolution of migraine-specific therapies – targeting migraine with precision and persistence.
Mitsikostas DD, Rapoport  A.
Nat Rev Neurol. 2024 Nov;20(11):645-6.