A Breakthrough on the Horizon: PACAP-Targeting Antibodies Offer New Promise for Migraine Prevention
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Targeting PACAP with Monoclonal Antibodies
A recent study published in the New England Journal of Medicine offers promising results for a new approach to migraine prevention - targeting a peptide called PACAP with monoclonal antibodies.
CGRP and PACAP: Two Crucial Neuropeptides in Migraine Pathophysiology
You are probably familiar with CGRP (calcitonin gene-related peptide), which has been the target of several successful migraine treatments in recent years. CGRP is a neuropeptide involved in pain signaling and blood vessel dilation. Monoclonal antibodies targeting CGRP or its receptor have shown efficacy in preventing migraine attacks.
Now, researchers are exploring another neuropeptide called PACAP (pituitary adenylate cyclase-activating polypeptide) as a potential target for migraine prevention. While both CGRP and PACAP are involved in migraine pathophysiology, they likely play distinct roles, offering the potential for multiple therapeutic approaches.
What is PACAP?
PACAP is a neuropeptide that plays several roles in the body - much like CGRP - including regulating blood flow in the brain and modulating pain signals. Research has shown that PACAP is involved in the pathophysiology of migraine:
- PACAP is found in sensory nerves that innervate blood vessels in the brain and meninges
- Infusion of PACAP can trigger migraine-like attacks in susceptible individuals
- PACAP levels are elevated in the serum (blood) during migraine attacks
This evidence suggests that blocking PACAP could potentially prevent migraine attacks from occurring.
The Lu AG09222 Study
Researchers conducted a phase 2 clinical trial to test the efficacy and safety of Lu AG09222, a monoclonal antibody that binds to and inhibits PACAP. The study included 237 participants with difficult-to-treat migraine who had failed 2-4 previous preventive treatments.
Key findings:
- A single 750 mg intravenous dose of Lu AG09222 reduced migraine days by 6.2 days per month on average, compared to 4.2 days with placebo
- The treatment was generally well-tolerated, with mild side effects like nasopharyngitis and fatigue occurring slightly more often than with placebo
These results are encouraging, especially for patients who haven't found relief with existing preventive medications. The 2-day greater reduction in monthly migraine days compared to placebo is clinically meaningful and similar to other migraine preventives. It is important to note that this was done in patients who have difficut-to-treat migraine and failed other preventives. The efficacy will likely be higher in studies with a general migraine patient population.
How does Lu AG09222 Compare to Other Treatments?
Lu AG09222 represents a new approach by targeting the PACAP peptide itself. This differs from previous attempts that targeted the PACAP (PAC1) receptor, which were unsuccessful in clinical trials.
The PACAP-targeting strategy also distinguishes Lu AG09222 from the anti-CGRP monoclonal antibodies. Having multiple therapeutic targets could allow for more personalized treatment approaches, potentially benefiting patients who don't respond to CGRP-targeted therapies.
Moreover, the PACAP pathway is independent of the CGRP pathway. This suggests that CGRP and PACAP may act in parallel ways to cause migraine-like symptoms, further supporting the potential for PACAP-targeted therapies to offer an alternative for patients who don't respond well to CGRP-based treatments.
What to Expect
While these phase 2 results are promising, larger and longer studies are still needed to confirm the efficacy and safety of Lu AG09222.
There are ongoing clinical trials for other PACAP-targeting monoclonal antibodies like LY3451838. Results from those studies could provide additional insights into the potential of PACAP inhibition for migraine prevention.
The success of Lu AG09222 also validates PACAP as a therapeutic target, potentially opening the door for development of other PACAP-modulating drugs.
