Anti-PACAP Antibody Bocunebart Meets Primary Endpoint in Phase 2b Migraine Prevention Trial

Two positive studies of bocunebart (Lu AG09222; H. Lundbeck A/S), an investigational anti-pituitary adenylate cyclase-activating polypeptide (PACAP) monoclonal antibody, were presented at the 2026 American Headache Society (AHS) Annual Scientific Meeting in Orlando, Florida, offering new efficacy and safety data for the agent in migraine prevention.^1,2

The results, drawn from the phase 2b PROCEED trial (NCT06323928) and a dedicated phase 1 pharmacokinetic study, support continued clinical development of bocunebart as a potentially first-in-class therapeutic option targeting the PACAP pathway, which acts independently of the calcitonin gene-related peptide (CGRP) axis currently targeted by approved preventive therapies.

PROCEED Phase 2b Results

Presented by Jessica Ailani, MD, Director of the MedStar Georgetown Headache Center, PROCEED was a phase 2b adaptive, randomized, double-blind, placebo-controlled study evaluating bocunebart across subcutaneous (SC) and intravenous (IV) routes in adults with migraine and 1 to 4 prior preventive treatment failures.¹ An interim SC analysis triggered initiation of the IV part per the adaptive design; the IV part formed the primary analysis.

All told, the IV part of PROCEED met its primary efficacy endpoint. Participants receiving bocunebart IV dose A (n = 84) showed a statistically significant reduction in monthly migraine days (MMDs) over weeks 1 to 12 compared with placebo (n = 171), with a mean change from baseline of −4.24 (SE, 0.63) versus −2.86 (SE, 0.53); difference vs placebo, −1.38 (SE, 0.58); two-sided P = .0178.¹ The two higher IV doses (B and C) did not reach statistical significance.

In pooled post-hoc analyses across both phase 2 trials (PROCEED and the earlier phase 2a proof-of-concept HOPE trial; NCT05133323), participants with chronic migraine (CM) treated with bocunebart demonstrated consistently greater reductions from baseline than placebo in MMDs, monthly headache days, and MMDs with acute medication use over weeks 1 to 12. At weeks 9 to 12, bocunebart-treated patients with CM showed a mean MMD reduction of −5.94 versus −3.28 for placebo (P < .001). Improvements in migraine-specific quality of life, measured by the Migraine-Specific Quality of Life Questionnaire (MSQ), were also greater with bocunebart across all three domains (role function-restrictive, role function-preventive, and emotional function) at weeks 8 and 12 (P < .05 for all).¹

Safety findings were consistent across the pooled program. Among 697 bocunebart-treated participants and 413 placebo-treated participants, treatment-emergent adverse events (TEAEs) occurred in 37.7% and 32.7%, respectively. Serious adverse events were reported in 0.7% of both groups. No deaths were recorded. TEAEs with an incidence of 3% or greater included nasopharyngitis (5.7% bocunebart vs 4.8% placebo) and injection site erythema (4.0% vs 0.7%). No findings of clinical concern were observed for vital signs, ECGs, laboratory values, or Columbia-Suicide Severity Rating Scale assessments.¹

Gepant Coadministration: Phase 1 Safety and PK Data

A second poster, presented by Amaal Starling, MD, of Mayo Clinic Arizona, reported findings from a phase 1, randomized, double-blind, placebo-controlled trial evaluating bocunebart coadministered with ubrogepant (Ubrelvy; AbbVie), an approved oral CGRP receptor antagonist for acute migraine (NCT06578585).²

Forty-three participants with episodic migraine were enrolled; 38 (88%) completed the trial. The four-period design isolated ubrogepant alone, bocunebart alone, and the two agents in combination, with a washout period between phases. During coadministration, AE frequency was similar to ubrogepant administered alone. All TEAEs were mild, transient, and nonserious, and none led to withdrawal. No clinically meaningful changes were observed in vital signs, ECGs, laboratory values, or anti-drug antibody-related hypersensitivity reactions.²

Critically, bocunebart did not meaningfully alter ubrogepant PK. The estimated ratios for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-inf) were both 1.04 (90% CI, 0.92-1.17 and 0.96-1.13, respectively), with P values of .6167 and .3990, indicating no pharmacokinetic interaction.² These findings are clinically relevant given that patients on preventive therapy routinely use acute medications for breakthrough attacks, and previously, no safety data existed for this specific combination.

Context and Disclosures

PACAP and CGRP act on independent neuropeptide pathways in migraine pathophysiology, raising the possibility that PACAP inhibition could benefit patients who have not responded adequately to CGRP-targeted therapies.¹ Lundbeck has stated that preparations for further clinical development are ongoing based on the PROCEED outcome. Multiple authors from both posters are employees of H. Lundbeck A/S, which sponsored both studies and funded medical writing support.

REFERENCES
1. Ailani J, Phul R, Florea I, Josiassen MK, Schmidt SN, Ashina M. Targeting PACAP in migraine prevention: Outcomes from the PROCEED phase 2b trial of bocunebart (Lu AG09222). Poster presented at: American Headache Society Annual Scientific Meeting; June 4-7, 2026; Orlando, FL. Poster T110.
2. Starling A, Ailani J, Florea I, et al. Safety and tolerability of anti-PACAP monoclonal antibody bocunebart (Lu AG09222) when coadministered with an acute gepant in participants with migraine. Poster presented at: American Headache Society Annual Scientific Meeting; June 4-7, 2026; Orlando, FL. Poster T10.
3. Ashina M, Doganay Erdogan B, Kokturk Newby A, et al. Bocunebart for migraine prevention. N Engl J Med. 2024;391:800-809. doi:10.1056/NEJMoa2312100. https://doi.org/10.1056/NEJMoa2312100
4. Eigenbrodt AK, Ashina H, Khan S, et al. Diagnosis and management of migraine in ten steps. Nat Rev Neurol. 2021;17(8):501-514. doi:10.1038/s41582-021-00509-5. https://doi.org/10.1038/s41582-021-00509-5