Migraine affects over a billion people and is a leading cause of disability. The past decade's therapeutic revolution — targeting the CGRP pathway — has matured, and the field is now beginning to move "beyond CGRP."
CGRP pathway therapies
Atogepant, an oral CGRP-receptor antagonist, reduces monthly migraine days by roughly 4 days versus about 2.5 with placebo in prevention, with constipation and nausea the main side effects. The injectable CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and the intravenous eptinezumab) prevent both episodic and chronic migraine, with about half of patients achieving a 50% reduction in attacks; tolerability is good, with injection-site reactions and constipation most common. Combining onabotulinumtoxinA with a CGRP antibody is an effective, if costly, option for highly resistant chronic migraine.
Gepants and ditans
The gepants (ubrogepant, rimegepant, atogepant, and the nasal zavegepant) serve both acute and preventive roles, with a favorable cardiovascular profile compared with triptans and no major hepatic or vascular safety signals. Lasmiditan, a 5-HT1F agonist, treats acute migraine without vasoconstriction, though its CNS effects (dizziness, somnolence, driving impairment) require counseling.
Beyond CGRP: PACAP inhibition
The most important new mechanism is inhibition of PACAP (pituitary adenylate cyclase-activating polypeptide). The antibody Lu AG09222 (bocunebart) showed proof of concept in a Phase 2 trial (a single infusion cut monthly migraine days by roughly 2 days versus placebo in patients who had failed multiple preventives), and a subsequent Phase 2b trial in prior-treatment-failure patients met its primary endpoint, with Phase 3 planning under way. It remains investigational, but PACAP is the leading candidate to become the second antibody target — after CGRP — for migraine prevention, and may help CGRP-refractory patients.
Neuromodulation
Non-invasive devices — transcutaneous supraorbital neurostimulation and single-pulse transcranial magnetic stimulation among them — are approved for acute and preventive use in selected patients, generally well tolerated aside from local discomfort.
| Therapy | Indication | Efficacy | Notes |
|---|---|---|---|
| Atogepant | Prevention | ~4 fewer migraine days/mo | Oral, well tolerated |
| CGRP antibodies | Prevention | ~50% achieve 50% reduction | Episodic and chronic |
| Gepants | Acute/preventive | Significant reduction | Favorable vs triptans |
| Lasmiditan | Acute | Headache freedom | No vasoconstriction; CNS effects |
| PACAP inhibitor (bocunebart) | Prevention | ~2 fewer migraine days/mo (Phase 2) | Investigational; advancing to Phase 3 |
| Neuromodulation | Acute/preventive | Device-dependent | Non-invasive, adjunctive |
Further reading: Atogepant (Ailani et al., NEJM 2021); PACAP antibody HOPE trial (Ashina et al., NEJM 2024) and Phase 2b PROCEED (2026); gepant and CGRP-antibody reviews (2022–2025).