After CGRP: What the Next Generation of Migraine Drugs Still Has to Prove

Published by RichStorm.co

Key Takeaways

• CGRP drugs established the first large migraine market built around a disease-related biological pathway, with products for both acute and preventive treatment.

• PACAP may cover biology that CGRP drugs do not fully address, but the evidence for bocunebart remains limited to mid-stage trials.

• Phase 3 must confirm the dose, reproduce the benefit and show enough clinical value to justify monthly intravenous treatment.

The arrival of CGRP drugs changed migraine treatment from a field dominated by medicines borrowed from other diseases into one with therapies designed around a migraine-related pathway. Between 2018 and 2023, eight CGRP-targeting drugs reached the US market. Several now generate annual sales above $1 billion, and the American Headache Society considers the class a first-line option for prevention.

That success has raised the standard for what comes next. A new mechanism must produce a meaningful benefit for a definable group of patients and compete with treatments that are already effective and convenient.

PACAP is one of the candidates now attracting attention. Bocunebart, an experimental antibody against PACAP, has produced positive Phase 2 results. The question is whether those results are strong enough to support a new clinical and commercial category.

1. Migraine treatment has two separate jobs

Migraine is a neurological disease. An attack can involve pain, nausea, sensitivity to light and sound, and sometimes visual or sensory disturbances. Its biology involves several parts of the nervous system, including the trigeminal sensory network and chemical messengers called neuropeptides. Two of those messengers, CGRP and PACAP, are central to the current drug-development story.

The precise sequence that starts an attack remains uncertain. CGRP and PACAP can affect both pain-signaling nerves and blood vessels, and the biology extends well beyond blood-vessel widening. The success of CGRP antibodies, which do not enter the brain in substantial quantities, suggests that important parts of the treatment effect occur outside the blood-brain barrier, possibly in structures such as the trigeminal ganglion and the membranes surrounding the brain.

There are also two different treatment markets.

Acute medicines are taken during an attack to reduce pain and other symptoms. Preventive medicines are taken regularly to reduce how often attacks occur. The distinction matters commercially: an acute treatment competes on speed, reliability and ease of use, while a preventive treatment must justify repeated use over months or years.

2. What the CGRP generation established

CGRP became a drug target through a sequence of human experiments. In a small placebo-controlled study published in 2002, an infusion of CGRP triggered migraine-like attacks in people with migraine. Two years later, an intravenous drug that blocked the CGRP receptor relieved acute attacks more often than placebo.

The resulting US market now spans preventive and acute treatment.

Sources: current US prescribing information and FDA approval records.

The four antibodies are preventive treatments. The gepants are smaller molecules: three are oral, while Zavzpret is a nasal spray. Depending on the drug, they can be used for acute treatment, prevention or both.

In 2024, the American Headache Society concluded that CGRP-targeting therapies could be considered a first-line option for migraine prevention, without requiring patients to fail older preventive drug classes first. That recommendation reflects how far the class has moved from specialist novelty toward routine care, although insurance rules and access still vary.

3. The treatment effect has to be read against placebo

Migraine trials often show meaningful improvement in placebo groups. That improvement can reflect patient expectations, natural fluctuations in attack frequency, regression toward the average and the effect of participating in a trial.

For that reason, the relevant efficacy number in a randomized trial is the difference between the treatment and placebo groups, rather than the improvement in the treatment group alone.

A meta-analysis of CGRP-antibody trials found placebo-adjusted reductions of approximately 1.5 monthly migraine days in episodic migraine and 2.2 days in chronic migraine. A broader meta-analysis of preventive migraine trials found that placebo groups themselves improved by an average of 2.83 monthly migraine days, while 28% of placebo recipients reached a reduction of at least 50%.

Placebo-group responses vary with the patient population, treatment route, endpoint and study design. A large change from baseline can therefore become a much smaller advantage once the placebo group is included.

The safety picture has also evolved. CGRP drugs were generally well tolerated in randomized trials. However, current US labels for all four CGRP antibodies warn about serious constipation, new or worsening hypertension and Raynaud’s phenomenon.

These postmarketing warnings do not show that the events are common. The available data still support a generally favorable tolerability profile, while leaving questions about long-term use and higher-risk patients.

4. How large is the remaining need?

A new migraine drug could compete through better efficacy, faster action, fewer side effects, greater convenience or better access. For a drug based on a new biological pathway, patients who remain inadequately controlled after existing treatment provide the clearest initial test of added value.

Even the size of that population is difficult to define.

In a prospective observational study of 771 people receiving CGRP antibodies, 65.6% met the study’s response threshold after 12 weeks, leaving 34.4% classified as nonresponders. Of those initial nonresponders, 55.1% went on to respond between weeks 13 and 24.

As an observational study without a placebo group, it addresses the timing of response rather than drug efficacy. It also studied patients with high-frequency or chronic migraine who had already experienced several treatment failures, so its percentages do not define the entire migraine market.

For investors, the practical implication is that “CGRP nonresponder” is not a fixed commercial category. Its size depends on the response threshold, treatment duration, reimbursement policy and whether partial improvements in disability or quality of life are considered sufficient to continue treatment.

5. Why researchers are looking at PACAP

PACAP is one of the most advanced pathways being tested after CGRP. It is a neuropeptide in the trigeminal system that can influence pain signaling and vascular activity.

Human provocation studies supplied the first clinical clue. In a small randomized study published in 2009, seven of 12 people with migraine developed migraine-like attacks after receiving PACAP38, compared with none after placebo. A 2025 study then examined whether this effect depended on CGRP. Pretreatment with the CGRP antibody eptinezumab did not significantly reduce attacks triggered by PACAP38. The study included only 38 participants, so the relationship between the two pathways remains uncertain. Its results gave researchers a reason to test PACAP directly.

The first drug design was unsuccessful. AMG 301 blocked the PAC1 receptor, one of several receptors through which PACAP signals, and failed in Phase 2: monthly migraine days fell by 2.2 days in both treatment groups and by 2.5 days with placebo. Bocunebart instead binds PACAP itself, allowing it to interfere with a broader part of the pathway.

6. What the bocunebart trials have shown

Bocunebart, previously known as Lu AG09222, is supported mainly by two randomized trials.

The Phase 2a HOPE trial enrolled 237 people for whom two to four previous preventive treatments had failed. After a single intravenous infusion, monthly migraine days over the following four weeks fell by 6.2 days with the 750 mg dose and by 4.2 days with placebo, a difference of 2.0 days. The proportion achieving a reduction of at least 50% was 32% with bocunebart and 27% with placebo. The study provided proof of concept, although the responder rates were less clearly separated.

The Phase 2b PROCEED trial first tested subcutaneous treatment. That part was stopped after a predefined interim analysis, and the intravenous part subsequently enrolled 431 participants with previous preventive treatment failures. Over three months, one of the three intravenous doses reduced monthly migraine days by 4.24 days, compared with 2.86 days on placebo, a difference of 1.38 days. The other two doses missed the prespecified threshold for statistical significance, leaving the dose-response relationship unresolved.

Short-term tolerability was broadly similar between treatment and placebo. Longer and larger trials are needed to assess safety. Detailed PROCEED results have so far been reported mainly through scientific meetings and a conference abstract. Lundbeck stated in its 2026 half-year report that it expected bocunebart to progress into Phase 3 by the end of the year.

Phase 3 will need to select a credible dose, reproduce the placebo-adjusted benefit and show whether the improvement is sufficient to justify monthly intravenous treatment.

7. What the commercial market is actually saying

The established CGRP market is already substantial. Pfizer reported $1.424 billion in 2025 revenue from Nurtec ODT and its international brand Vydura. AbbVie reported $1.271 billion from Ubrelvy and $1.036 billion from Qulipta, for a combined $2.307 billion.

These figures show that both acute and preventive CGRP products can support billion-dollar franchises.

Pfizer’s $11.6 billion acquisition of Biohaven in 2022 should be interpreted separately. The transaction included the marketed product Nurtec, zavegepant and preclinical CGRP assets. It valued a portfolio with an established commercial product and additional pipeline opportunities. That makes it a poor numerical benchmark for bocunebart alone.

Bocunebart’s commercial case will depend on four questions.

First, who will receive it? Its trials have focused on people with previous preventive treatment failures. This may support an initial position in more difficult-to-treat migraine. The eventual label, reimbursement rules and continuation rates will determine the commercial population.

Second, how much differentiation will Phase 3 show? Clinicians and payers will look for a reproducible advantage in migraine days, responder rates, disability, tolerability or quality of life.

Third, can the delivery method compete? PROCEED used monthly intravenous infusions. Existing options include daily or alternate-day pills, monthly home injections and Vyepti infusions every three months. Unless the eventual schedule changes, bocunebart will need sufficient clinical value to offset that inconvenience.

Fourth, can the pathway be validated beyond one drug? With few advanced PACAP programs, bocunebart currently carries much of that burden.

8. What still has to be proved

CGRP became a major drug class because biological evidence, randomized trials, approved products and commercial adoption converged.

PACAP is at an earlier point. Its biological rationale is plausible, and one ligand-blocking antibody has produced two positive mid-stage results. Those findings do not yet establish the size of the clinical or commercial opportunity.

Phase 3 will need to clarify the dose, reproduce the placebo-adjusted benefit, identify which patients gain the most and provide longer safety data. The commercial question will then be whether those benefits justify a monthly infusion in a market that already offers multiple injections and oral drugs.

Bocunebart can become useful by establishing a clear place alongside CGRP therapy and showing what it adds.

ABOUT THE AUTHOR

Ximeng Zheng

Ximeng Zheng is a biotechnology graduate student at the University of Pennsylvania with a background in scientific research and a strong interest in life sciences and healthcare innovation. Her interests center on clinical translation and commercialization, particularly how scientific evidence and market considerations inform investment, business development, and strategic decision-making. She is passionate about translating scientific advances into products and solutions that create real-world impact.

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References

1. Ashina M. Migraine. New England Journal of Medicine. 2020;383:1866–1876. doi:10.1056/NEJMra1915327.

2. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies: successful translation from bench to clinic. Nature Reviews Neurology. 2018;14:338–350. doi:10.1038/s41582-018-0003-1.

3. Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54–61. doi:10.1046/j.1468-2982.2002.00310.x.

4. Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. New England Journal of Medicine. 2004;350:1104–1110. doi:10.1056/NEJMoa030505.

5. US National Library of Medicine, DailyMed. Aimovig (erenumab-aooe) current prescribing information.

6. US National Library of Medicine, DailyMed. Ajovy (fremanezumab-vfrm) current prescribing information.

7. US National Library of Medicine, DailyMed. Emgality (galcanezumab-gnlm) current prescribing information.

8. US National Library of Medicine, DailyMed. Vyepti (eptinezumab-jjmr) current prescribing information.

9. US National Library of Medicine. Ubrelvy (ubrogepant) prescribing information. Updated June 2025.

10. US National Library of Medicine. Nurtec ODT (rimegepant) prescribing information. Updated June 2026.

11. US National Library of Medicine. Qulipta (atogepant) prescribing information. Updated September 2025.

12. US Food and Drug Administration. Zavzpret (zavegepant) prescribing information. Revised 2025.

13. Charles AC, Digre KB, Goadsby PJ, Robbins MS, Hershey A; American Headache Society. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: an American Headache Society position statement update. Headache. 2024;64(4):333–341. doi:10.1111/head.14692.

14. Forbes RB, McCarron M, Cardwell CR. Efficacy and contextual (placebo) effects of CGRP antibodies for migraine: systematic review and meta-analysis. Headache. 2020;60(8):1542–1557. doi:10.1111/head.13907.

15. Basedau H, Ornello R, De Matteis E, et al. Placebo and nocebo in the treatment of migraine: how much does real-world effectiveness depend on contextual effects? Cephalalgia. 2023;43(12). doi:10.1177/03331024231218392.

16. Bruijn NRA, Huessler EM, MaassenVanDenBrink A, et al. Placebo response in acute and prophylactic treatment of migraine: a systematic review and meta-analysis covering 36 years of research. Neurologic Clinics. 2026;44(1):23–45. doi:10.1016/j.ncl.2025.08.011.

17. Barbanti P, Aurilia C, Egeo G, et al. Late response to anti-CGRP monoclonal antibodies in migraine: a multicenter prospective observational study. Neurology. 2023;101(11):482–488. doi:10.1212/WNL.0000000000207292.

18. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(1):16–25. doi:10.1093/brain/awn307.

19. Al-Karagholi MAM, Zhuang ZA, Beich S, Ashina H, Ashina M. PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial. Journal of Headache and Pain. 2025;26:79. doi:10.1186/s10194-025-02022-2.

20. Ashina H, Christensen RH, Hay DL, et al. Pituitary adenylate cyclase-activating polypeptide signalling as a therapeutic target in migraine. Nature Reviews Neurology. 2024;20(11):660–670. doi:10.1038/s41582-024-01011-4.

21. Ashina M, Doležil D, Bonner JH, et al. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia. 2021;41(1):33–44. doi:10.1177/0333102420970889.

22. Ashina M, Phul R, Khodaie M, Löf E, Florea I. A monoclonal antibody to PACAP for migraine prevention. New England Journal of Medicine. 2024;391:800–809. doi:10.1056/NEJMoa2314577.

23. Ailani J, Phul R, Florea I, et al. Bocunebart (anti-PACAP monoclonal antibody Lu AG09222) in adults with migraine and prior preventive treatment failures: Phase 2 program outcomes. European Journal of Neurology. 2026;33(S1):7–8. Article LB_09. doi:10.1111/ene.70677.; H. Lundbeck A/S. Lundbeck presents positive Phase IIb data for bocunebart in migraine prevention at the AHS congress. June 4, 2026.

24. H. Lundbeck A/S. Financial report for the period January 1 to June 30, 2026. Bocunebart expected to progress into Phase 3 by the end of 2026.

25. Pfizer. Fourth-quarter and full-year 2025 earnings release.

26. AbbVie. Full-year and fourth-quarter 2025 financial results. February 4, 2026.

27. Pfizer. Pfizer completes acquisition of Biohaven Pharmaceuticals. October 3, 2022.