Migraine is driven by multiple pathways.
Migraine is a complex neurological disorder in which neuropeptides play a central role in driving the underlying disease. Beyond CGRP, Pituitary adenylate cyclase-activating peptide (PACAP) has emerged as a next-generation neuropeptide target, with evidence for an even broader role in migraine biology than CGRP. In addition to triggering migraines, PACAP is associated with a broader spectrum of migraine symptoms, including premonitory and autonomic features such as fatigue, neck stiffness, lacrimation, and facial swelling. Early clinical results with a PACAP‑targeting antibody are encouraging, suggesting that PACAP offers a promising new target to address these unmet needs and expand treatment options for patients who may achieve suboptimal relief with existing therapies.
PACAP Biology
PACAP acts through a CGRP-independent pathway.
PACAP drives migraine pathophysiology by activating PAC1, VPAC1, and VPAC2 receptors on trigeminal and cranial parasympathetic neurons, increasing vasodilation, neurogenic inflammation, and nociceptive sensitization. Additionally, PACAP activates MRGPRX2 receptors to induce mast cell degranulation. PACAP infusion can trigger migraine even when CGRP pathways are pharmacologically blocked, demonstrating that PACAP can drive migraine through CGRP‑independent mechanisms and serves as a complementary target to CGRP‑directed therapies.
Vedana’s Approach
Vedana is developing a portfolio of long-acting subcutaneously dosed monoclonal antibodies targeting PACAP and other clinically emerging pathways. These programs are designed for patients whose migraines remain inadequately controlled with current treatments. By targeting multiple disease pathways, Vedana’s pipeline aims to deliver best‑in‑indication efficacy and lasting relief for people living with migraine.
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