PACAP in Migraine: Bridging Preclinical Studies and Clinical Translation

Migraine is a highly prevalent and disabling neurologic disorder affecting more than 1 billion people worldwide and characterized by recurrent attacks of moderate to severe headache. Migraine is the leading cause of years lived with disability among neurologic disorders, particularly in individuals younger than 50 years old. Woman are disproportionately affected, with a prevalence approximately 3 times higher than that observed in men.¹

While calcitonin gene-related peptide (CGRP)-targeted therapies remain the standard of care in preventive and acute migraine management, approximately 40% of patients experience inadequate symptom control or treatment intolerance^2–4, highlighting the need to identify additional molecular pathways involved in migraine pathophysiology.

Current understanding of migraine pathogenesis is not fully understood⁵ but is thought to result from dysfunction within central nervous system networks that activate the trigeminovascular system.^3,6 Primary afferent neurons from the trigeminal ganglion innervate the meninges and intracranial vessels, and upon activation they release vasoactive neuropeptides that promote neurogenic inflammation, meningeal vasodilation, mast cell degranulation, and sensitization of nociceptors.^3,7 As research continues to elucidate the causes of migraine pain, CGRP has been the most established mediator, but pituitary adenylate cyclase-activating polypeptide (PACAP) has emerged as an independent and clinically relevant signaling system.

PACAP is a highly conserved neuropeptide in the vasoactive intestinal peptide (VIP), secretin, and glucagon peptide family.³ It exists predominantly as a 38-amino acid isoform (PACAP-38) consisting about 90% in the human body, with PACAP-27 as a shorter biologically active form generated by C-terminal truncation.³ PACAP is predominantly distributed in the sphenopalatine ganglion.⁸ This distribution in the parasympathetic ganglia helps explain why PACAP may influence pain, autonomic symptoms, and premonitory features rather than just headache alone.⁸

PACAP signals through three G-protein coupled receptors (PAC1, VPAC1, and VPAC2) with the highest affinity for PAC1.^5,9 PACAP also has broader biologic effects than VIP at PAC1, while VIP preferentially activates VPAC1 and VPAC2.^9,10 Activation of PAC1 receptors stimulates Gs-mediated adenylate cyclase activity, resulting in increased intracellular cyclic adenosine monophosphate (cAMP) production and subsequent activation of protein kinase A.⁹ Unlike CGRP, PACAP also activates noncanonical cAMP signaling pathways through mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways.^2,9

This receptor pharmacology matters because when PACAP-38 is infused intravenously it reliably provokes migraine-like attacks in healthy volunteers and migraine patients without aura, whereas VIP has weaker and less consistent migraine-inducing effects despite causing vasodilation.⁵ PAC1 signaling increases cAMP formation and can engage additional pathways which together can increase neuronal excitability and promote sensitization leading to migraine.⁸

The preclinical literature supports PACAP as a migraine mediator. In rodent models, PACAP-38 induces light aversion, mechanical allodynia, and other migraine-like behaviors that overlap with but are not dependent on CGRP signaling.² Importantly, these PACAP-induced pain and hypersensitivity behaviors persist despite pharmacological blockade or genetic deletion of CGRP signaling components, confirming that PACAP operates through a largely independent pathway.^2,8

Human provocation studies provide especially strong translational evidence. Intravenous PACAP-38 induces delayed migraine-like attacks in about 65-75% of patients with migraine without aura, and the attacks are often accompanied by more premonitory symptoms, and longer flushing than CGRP-provoked attacks.³ PACAP levels are also elevated during spontaneous migraine attacks compared with the interictal period.^3,7 Mechanistic studies show prolonged dilation of extracranial and meningeal arteries, especially the middle meningeal artery, while cerebral arteries are less affected.¹¹ PACAP-induced attacks also respond to sumatriptan, which supports the clinical relevance of this provocation model.¹² These findings suggest that PACAP is not a biomarker of migraine attacks but also an endogenous trigger that can initiate migraine.³

Recognition of PACAP as a migraine effector has driven the development of targeted therapies. In a randomized, double-blind, placebo-controlled phase 2a trial involving 343 patients with episodic migraine, participants received AMG 301, a monoclonal antibody to the PAC1 receptor.¹³ The primary endpoint was change from baseline in monthly migraine days from baseline to the last 4 weeks of the 12-week treatment period.¹³ In this trial, the least-squares (LS) mean reduction in monthly migraine days at week 12 was 2.5 days for placebo versus 2.2 days across AMG 301 treatment groups, resulting in no statistically significant treatment difference of 0.3 days (95% confidence interval, -0.9 to 1.4). The AMG 301 results failed to show significant benefit over placebo and prompted reconsideration of PAC1 receptor blockade.

Consequently, research shifted from receptor blockade to direct ligand neutralization, aiming to sequester PACAP before they can engage in any of their downstream receptors. Lu AG09222 (bocunebart), a humanized monoclonal antibody against PACAP, was evaluated in a randomized, placebo-controlled phase 2a trial (HOPE) involving patients with episodic and chronic migraine (CM) who failed 2 to 4 preventive migraine medications.¹⁴ The primary endpoint was mean change in monthly migraine days over a 4-week evaluation period and achieved a reduction of -6.2 days vs -4.2 days in the placebo group (LS mean difference, -2.0 days; 95% confidence interval, -3.8 to -0.3; P =0.02).¹⁴

Furthermore, 32% of patients receiving the 750 mg dose achieved at least a 50% reduction in monthly migraine days compared with 27% in the placebo group, with consistent improvements across secondary measures including headache days and acute medication use, all displaying acceptable safety and tolerability profiles.¹⁴ Treatment was generally well tolerated without evidence of significant cardiovascular safety concerns, considering PACAP’s physiologic vascular functions with the primary adverse events being Covid-19, nasopharyngitis, and fatigue.¹⁴ These findings provided the viability of ligand-directed PACAP inhibition to reduce migraine frequency in humans while also reaching safety end points.

Bocunebart was further evaluated in an interventional, randomized, double-blind, placebo-controlled phase 2b trial (PROCEED).¹⁵ The trial was an adaptive dose-finding trial that also compared subcutaneous (SC) and intravenous (IV) administration routes of bocunebart.¹⁵ The primary end point looked at changes from baseline in monthly migraine days (MMDs) from weeks 1 to 12 using a Restricted Maximum Likelihood-based Mixed Models for Repeated Measures (MMRM).¹⁶ The IV Dose A group of PROCEED met the primary efficacy endpoint with a statistically significant reduction (two-sided p-value = 0.0178) in MMDs with a difference of -1.38 days compared to placebo (-4.24 days in IV Dose A vs -2.86 days in placebo).¹⁶

Pooled data across the phase 2 trials (HOPE and PROCEED) were also evaluated in a post-hoc analysis of bocunebart in CM to detect LS mean change in MMDs, monthly headache days (MHDs), and MMDs with use of acute medications when compared to placebo.¹⁶The change from baseline in MMDs in CM was seen as soon as weeks 1 to 4 (-4.50 vs -3.28 in placebo; p<0.05) and remained significant throughout weeks 5 to 8 (-5.43 vs -3.91 in placebo; p<0.05) and weeks 9 to 12.¹⁶ The most notable adjusted treatment effect was observed on weeks 9 to 12 with bocunebart patients having -5.94 MMDs compared to -3.63 MMDs from baseline when compared to placebo (p<0.001).¹⁶ Similar improvements were observed for MHDs in CM throughout weeks 1 to 4 (-4.72 vs -3.51MHDs in placebo; P <0.05), weeks 5 to 8 (-5.99 vs -4.56 days in placebo; P <0.05), and weeks 9 to 12 (-6.90 vs -4.32 days in placebo; PP<0.001).¹⁶

Bocunebart also reduced the number of MMDs requiring acute medications with LS mean reductions from baseline than placebo during weeks 1 to 4 (-4.16 vs -3.47 days), weeks 5 to 8 (-4.87 vs -3.97 days), and a statistically significant difference (P <0.05) during weeks 9 to 12 (-5.21 vs -3.53 days).¹⁶ The concordant improvements in both MMDs, MHDs, and use of acute medications during MMDs suggest that PACAP inhibition not only addresses migraine but also addresses overall headache burden and dependence on acute medications. These outcomes, although exploratory, addresses disease burden and provides a clinically meaningful endpoint for patients with CM.

In another study, LY3451838, another antibody to PACAP, did not show clear superiority over placebo in a small proof-of-concept study, although the sample size was limited and the trial may have been underpowered due to expected efficacy.¹⁷ Despite these results, further research into ligand-targeted therapies should be explored with an attention to sample size and treatment duration to evaluate efficacy and safety.^14,17

The evolution of PACAP-targeted therapeutics marks a transformative chapter in migraine treatment, uniting preclinical discovery and clinical translation to establish PACAP as a validated and distinct neuropeptide signaling pathway operating independently of CGRP. Although selective inhibition of PAC1 receptor proved unsuccessful, the transition to ligand-targeted therapies such as bocunebart has clinically validated upstream peptide blockade as a potential effective treatment option, particularly for treatment-resistant patients who fail to achieve symptomatic relief from CGRP-directed medications.

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15. H. Lundbeck A/S. Interventional, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Finding Trial of Lu AG09222 for the Prevention of Migraine in Participants With Unsuccessful Prior Preventive Treatments. clinicaltrials.gov; 2026. Accessed August 3, 2026. https://clinicaltrials.gov/study/NCT06323928
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