by Theodoros Mavridis, EAN Scientific Panel on Headache
For October, we have selected Ashina M, Phul R, Khodaie M, Löf E, Florea I. A Monoclonal Antibody to PACAP for Migraine Prevention. N Engl J Med. 2024;391(9):800-809. doi:10.1056/NEJMoa2314577.
Migraine is a debilitating neurological disorder affecting over a billion people globally, with current preventive repurposed treatments, like beta-blockers and antiseizure drugs, often yielding inadequate results or adverse side effects. Even the newer migraine-specific approach of targeting the calcitonin gene-related peptide (CGRP) still leaves around 40 to 70% of patients without sufficient relief.
Back in 2009, Prof. Messoud Ashina and his team published a study in Brain demonstrating that intravenous infusion of PACAP—a key endogenous signaling molecule—can trigger migraine attacks in people with migraine1. This was the first evidence linking PACAP to migraine, and Ashina proposed that targeting PACAP signalling could offer therapeutic potential. Fifteen years later, this initial discovery has now led to the development of a potential new drug for migraine prevention.
The selected study is a phase 2, double-blind, randomised, placebo-controlled trial investigating the efficacy of a monoclonal antibody (Lu AG09222) that inhibits PACAP signalling. Conducted at 25 sites across Europe and North America, the trial enrolled 237 adult participants aged 18 to 65 who had previously failed to respond to at least two preventive migraine treatments (including anti-CGRP/R monoclonal antibodies and gepants). The study evaluated Lu AG09222 at two doses (750 mg and 100 mg) and compared it to a placebo, with the primary outcome being the reduction in migraine days over four weeks.
The results were encouraging, showing a significant reduction of two migraine days per month in the 750 mg group compared to placebo (mean reduction of 6.2 days vs. 4.2 days, P=0.02). Secondary endpoints, including headache frequency and the use of acute migraine treatments, also showed improvement. Importantly, adverse events such as fatigue and nasopharyngitis were more common in the treatment group, but no serious adverse effects directly related to the antibody were noted.
In conclusion, this study demonstrates the potential of Lu AG09222 as a new preventive treatment for migraine, offering hope for patients who have not benefited from other therapies. As further studies confirm these findings and expand on the safety profile, Lu AG09222 may become a key player in migraine management, particularly for those who have exhausted other treatment options.
1Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25. doi:10.1093/brain/awn307
Insights from a conversation with the first author, Prof. Messoud Ashina:
“My team has been studying migraine since 2006, focusing on molecules that play a key role in its development. We aim to identify the molecules involved in triggering migraine attacks to deepen our understanding of its mechanisms. Our research is conducted directly on humans and focuses on molecules that act on nerves around the brain’s blood vessels, as well as those responsible for pain transmission.
I hypothesise that certain molecules may trigger migraine attacks in individuals with migraine. This research could pave the way for new therapeutic approaches to block these processes, improving migraine treatment.
We use specific molecules to trigger migraine attacks. In people without migraine, these molecules may only cause mild, short-lived headaches, but in individuals with migraine, they provoke a full attack. This allows us to better understand how migraine develops at a molecular level, guiding the creation of new targeted treatments.
Our method provides a unique opportunity to study migraine in its active phase, opening up new perspectives for finding effective therapies.
New approaches to treating migraine include developing antibodies against molecules like PACAP. One such method involves creating monoclonal antibodies that block not the receptors, but the PACAP molecule itself, preventing its interaction with receptors and neutralising its effect. This approach is different from traditional ones, as it targets an earlier stage in the pathological process, eliminating the molecule responsible for triggering migraine.
The main goal of the study was to test the effectiveness of a high dose of the drug (750 mg) compared to placebo. The study showed significant improvement in individuals receiving 750 mg, confirming its effectiveness in preventing migraine attacks. This result validated the concept and opened the door to the next phase – phase 3 clinical trials.
Phase 3 will involve more participants and last longer to definitively confirm the drug’s efficacy and safety. If the results are positive, this medication could soon be available, offering a new preventive option for migraine.
It’s also crucial to identify which receptor plays a central role in PACAP’s migraine pathway. This will aid in developing more precise treatments. We continue to explore these mechanisms to offer more effective and targeted migraine therapies in the future.”
