Let's summarize the latest we know about neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP).

If you are new migraine research in general, you may not have heard of it, but it does play a significant role in migraine pathophysiology. Think of it the same way you would CGRP. PACAP sensitizes trigeminal neurons, promotes neuroinflammation, and dilates cranial arteries. There is a lot of theoretical promise in modulating this neuropeptide the same way we do CGRP in order to create new migraine treatments.

Overview of PACAP's role in migraine pathophysiology and treatment approaches

PACAP's Role During Migraine Attacks

During a migraine attack, we can detect elevated serum PACAP levels compared to patients without migraine. Furthermore, intravenous PACAP administration has been shown to trigger migraine-like episodes in a significant portion of those without migraine.

Clinical Trial Results

PACAP monoclonal antibodies are designed to inhibit PACAP or its major PAC1 receptor (as seen in the above picture) and these medications are currently undergoing clinical trials. We learned very recently at the 2023 International Headache Congress that Phase 2 results show that the PACAP antibody drug candidate Lu AG09222 can significantly reduce monthly migraine days compared to placebo.

PACAP vs CGRP: Key Differences

Although PACAP shares vasodilatory and nociceptive functions with CGRP implicated in migraine, PACAP activate parallel neural pathways independent of CGRP.

Comparison of PACAP and CGRP pathways in migraine

Future Treatment Potential

Anti-PACAP medications may be especially beneficial for migraine patients that don't respond or have developed antibodies against the current anti-CGRP/CGRP-receptor mAb class of medications. It's also possible both medications may be safe to use in complement to each other. Time will tell.