Pituitary Adenylate Cyclase-Activating Polypeptide

PACAP is the second peptide-pathway migraine target to reach controlled-trial validation after the CGRP class, and the editorial arc is one of the cleaner four-decade mechanism-to-medicine translations in neurology — the 1989 isolation paper on the basis of pituitary adenylate cyclase activation, the 2009 provocation experiment demonstrating that intravenous PACAP-38 triggers migraine-like attacks in migraineurs, and the 2024 HOPE Phase 2 trial demonstrating that an anti-PACAP monoclonal antibody reduces monthly migraine days in patients who failed prior preventives. The migraine and peptides dossier develops the broader clinical-decision landscape across the CGRP class and the emerging PACAP class; this peptide entry covers the molecule, the receptor pharmacology, and the clinical-development pipeline.

The causal-provocation evidence is the load-bearing translational result. Schytz, Birk, Wienecke, Kruuse, Olesen and Ashina, Brain 2009, 132:16–25 randomised 12 patients with migraine without aura and 12 healthy controls to a double-blind crossover infusion of either PACAP-38 at 10 pmol/kg/min for 20 minutes or placebo. PACAP-38 produced immediate headache in both groups and delayed migraine-like attacks specifically in the migraine population — replicating the Lassen 2002 paradigm with intravenous CGRP that established the CGRP-causal-sufficiency case, but with a different neuropeptide. The headache time course (immediate mild headache followed by delayed migraine-like attack at a median of approximately six hours post-infusion) and the migraineur-versus-control asymmetry were the same pattern that the CGRP provocation studies had reported. The 2009 result established PACAP as causally sufficient to trigger migraine in susceptible patients and licensed the multi-decade therapeutic-development effort. The subsequent provocation literature surveyed in Ashina, Hansen and Olesen, Nat Rev Neurol 2017, 13:713–724 extended the causal-sufficiency picture across cluster headache and other primary headache phenotypes.

The PACAP class development arc has had two failure modes before the 2024 HOPE success and is worth describing honestly. The first attempted target was the PAC1 receptor — the PACAP-specific receptor isoform that the trigeminal-sensory expression pattern made the obvious receptor pharmacology target. AMG 301 (Amgen) was a humanised monoclonal antibody to the PAC1 receptor, evaluated in Ashina, Doležil, Bonner et al., Cephalalgia 2021, 41:33–44 — a Phase 2 randomised double-blind placebo-controlled trial in 343 patients with episodic migraine, with 12 weeks of subcutaneous AMG 301 at 210 mg every four weeks, 420 mg every two weeks, or placebo. The primary endpoint of mean change in monthly migraine days from baseline did not separate from placebo: least-squares mean reduction of −2.2 days in both AMG 301 arms versus −2.5 days on placebo. The trial concluded that PAC1-receptor blockade as implemented by AMG 301 offered no benefit over placebo for migraine prevention. The molecule was discontinued. The 2021 negative result raised the open question of whether PAC1-receptor antibody pharmacology was the wrong therapeutic strategy (insufficient potency, insufficient receptor coverage, the wrong receptor isoform target) or whether the PACAP pathway was simply not therapeutically tractable for migraine — a question the second-generation development effort has partially answered.

The second-generation approach pivoted from receptor-targeting to ligand-targeting — binding the PACAP peptide in circulation before it reaches the receptor, in the same pharmacological pattern that fremanezumab, galcanezumab, and eptinezumab pursued for CGRP against the receptor-targeting erenumab. Lu AG09222 (bocunebart, Lundbeck) is a humanised IgG1 monoclonal antibody to the PACAP ligand, evaluated in the HOPE Phase 2 trial — Ashina, Phul, Khodaie, Löf and Florea, N Engl J Med 2024, 391:800–809. The trial randomised 237 adults aged 18–65 with episodic or chronic migraine and two or more prior preventive treatment failures (including anti-CGRP-class failures) in a 2:1:2 ratio to a single intravenous infusion of Lu AG09222 750 mg, Lu AG09222 100 mg, or placebo, with primary endpoint of mean change from baseline in monthly migraine days over the four weeks after infusion. The 750 mg arm produced 6.2 fewer monthly migraine days versus 4.2 on placebo — a between-arm difference of −2.0 days (95% CI −3.8 to −0.3; P=0.02). The 100 mg arm did not separate from placebo on the primary endpoint, establishing a dose-response signal. The safety profile across the four-week observation window was unremarkable, with no drug-related serious adverse events. The HOPE result is the first controlled-trial evidence that PACAP-pathway blockade reduces monthly migraine days in patients who have failed prior preventives — and the validation of the ligand-targeting strategy that the AMG 301 receptor-targeting failure had left open.

The Phase 2b PROCEED trial extended the HOPE signal across multiple doses and routes of administration through 2025–2026. The trial design included subcutaneous and intravenous administration arms in patients with one to four prior preventive failures. The subcutaneous cohort was discontinued at a planned interim futility analysis in early 2025; Lundbeck pivoted the remaining program to intravenous dosing. The intravenous PROCEED arm met its primary endpoint, with the 750 mg dose producing a 5.8-day reduction in monthly headache days versus 4.1 days on placebo over 12 weeks, and Lundbeck announced plans for a Phase 3 program in 2026 — see the investigational peptide pipeline tracker for the broader pipeline context. The pivotal Phase 3 readouts that would license a PACAP-class therapeutic are expected in the 2027–2028 window. As of mid-2026, no anti-PACAP or anti-PAC1 therapeutic is FDA-approved.

The clinical-positioning question is the one the migraine and peptides dossier develops in detail: the CGRP class produces a 50%-response rate in roughly 40–60% of trial populations, with substantial numbers of patients who do not respond to one CGRP-class agent and who do not respond to switching across the four monoclonal antibodies. The HOPE trial enrolled patients who had failed two or more prior preventives including anti-CGRP-class therapy, and the positive result in that population is the proof-of-concept that PACAP-pathway blockade addresses migraine pathophysiology that the CGRP class does not fully engage. The two pathways are not redundant — the trigeminal sensory release of both peptides during a migraine attack appears to drive partially independent signalling that the two therapeutic classes can address separately. The honest framing is that the PACAP class, if approved, would extend the mechanism-specific preventive options for the ~30–40% of patients in whom the CGRP class is inadequate, rather than replacing it as a first-line therapy. The class would not be expected to be uniformly effective either — the HOPE 50%-responder rate was 32% on the 750 mg dose versus 27% on placebo in the prior-treatment-failure population, indicating substantial residual non-response that future trial work will need to characterise.

The receptor-pharmacology comparison with VIP is structurally informative. The two peptides share VPAC1 and VPAC2 receptors but have distinct primary biology — PACAP signals through PAC1 with high specificity, while VIP does not. The VIP entry covers the immunomodulatory pulmonary, gastrointestinal, and CIRS-context applications of VIP itself; the PACAP entry is principally a migraine-mechanism page because the therapeutic development pipeline that targets the PACAP system is migraine-focused. The shared-receptor-family framing matters for the peptide receptor pharmacology atlas categorisation — both molecules sit in the secretin/glucagon/VIP/PACAP class B GPCR family, alongside the CGRP-receptor CLR-RAMP1 heterodimer covered in the CGRP-class entry. The class B GPCR family is the receptor-superfamily target for the bulk of the modern migraine-pathway pharmacology.