Decades of research proved CGRP is a key driver of migraine pain, leading to two new drug classes — injectable antibodies and oral gepants — that have transformed migraine treatment.
7+ approved drugsCGRP-targeting therapies include 4 injectable antibodies and 3 oral gepants — all developed from the discovery that this single peptide drives migraine pain
What the researchers found
CGRP (calcitonin gene-related peptide) has been definitively proven as a central driver of migraine through decades of converging evidence: anatomical colocalization with pain-producing meningeal blood vessels, elevated levels during migraine attacks, intravenous CGRP triggering migraines only in migraineurs, and clinical efficacy of drugs blocking CGRP.
Critically, PET imaging studies showed that CGRP receptor antagonists achieved no brain receptor occupancy at effective antimigraine doses — proving the therapeutic action is peripheral, not central. This revolutionized migraine understanding: migraine pain is at least partly peripheral in origin.
Two drug classes have emerged from this science: (1) monoclonal antibodies given by injection that neutralize CGRP peptide (fremanezumab, galcanezumab, eptinezumab) or block its receptor (erenumab) for migraine prevention; and (2) oral small-molecule CGRP receptor antagonists (gepants) for both acute treatment (ubrogepant, rimegepant) and prevention (atogepant). All have shown consistent efficacy in large, multicenter RCTs.
Why it matters
The CGRP migraine story is one of the greatest successes in peptide-based drug development. It took the field from a peptide discovered in sensory nerves to multiple FDA-approved drugs in two different drug classes — all within a few decades. This represents a complete bench-to-bedside arc: peptide biology → disease mechanism → drug target → approved therapeutics. It also fundamentally changed how scientists understand migraine — from a brain disorder to one with a significant peripheral peptide component.
The numbers in context
4 approved anti-CGRP antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) · 3 approved gepants (ubrogepant, rimegepant, atogepant) · PET showed 0 brain receptor occupancy at effective doses · IV CGRP triggers migraine only in migraineurs
How the study worked
Comprehensive narrative review published in Headache, the official journal of the American Headache Society. Chronicles the scientific history of CGRP in migraine from anatomical discovery through translational studies, clinical trials of small molecule antagonists, PET imaging proof-of-mechanism, and the development and approval of anti-CGRP antibodies and gepants.
Who was studied
Not applicable (review covering migraine patients in multiple clinical trials and translational studies)
What this study cannot tell us
Published in 2019, so does not cover the most recent clinical data and real-world experience with anti-CGRP drugs. As a review by key figures in the field, it presents an advocacy perspective for CGRP-based approaches. Long-term safety data for anti-CGRP therapies was still limited at time of publication.
How to read the evidence
Published in Headache by leaders in the field. The review synthesizes evidence from multiple large, multicenter RCTs, PET imaging studies, and translational research. The clinical efficacy of CGRP-targeting drugs is supported by the highest level of evidence — multiple randomized, placebo-controlled trials leading to FDA approval.
When this study was published
Published in 2019. All major anti-CGRP drugs discussed were approved at or around the time of publication. The field has since expanded with additional real-world data and new indications.
The bigger picture
The CGRP-migraine story is a template for how peptide science can transform medicine. A peptide identified through basic neuroscience research became the basis for an entirely new class of drugs that have improved the lives of millions of migraine sufferers. The approach — targeting a specific neuropeptide pathway with both biologics and small molecules — is now being applied to other pain conditions and could serve as a model for future peptide drug development.
Questions still open
- What are the long-term effects of chronically blocking CGRP, given its roles in cardiovascular protection and wound healing?
- Will newer CGRP-targeting approaches (like combination therapies or dual-mechanism drugs) further improve migraine outcomes?
- Can the CGRP drug development model be replicated for other neuropeptide-driven conditions like cluster headache or fibromyalgia?
Common questions
What is CGRP and why does it cause migraines?
What's the difference between anti-CGRP antibodies and gepants?
Read the original research
Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class.
Headache, 59(6), 951-970
Citation
Hargreaves, Richard; Olesen, Jes. (2019). Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class.. Headache, 59(6), 951-970. https://doi.org/10.1111/head.13510