A new frontier in migraine treatment: CGRP inhibitors

By Shoshana Lipson

Opening up treatment options

Approximately 40 million people in the United States live with migraine, a complex neurological disease that has a wide range of incapacitating symptoms. There is no cure for this stigmatized and misunderstood disease that affects more Americans than diabetes and asthma combined, and is the second leading cause of global disability[SL1] . Despite these staggering statistics, it has been decades since any breakthroughs have been made in the area of headache medicine.

Preventive treatment options have been used off-label from other disease states, such as antidepressants, beta blockers, and anti-seizure medications. However, in 2018 a new frontier in migraine preventive treatment was forged with the FDA approval of three CGRP inhibitors. CGRP (Calcitonin Gene Related Peptide) is a neurotransmitter (chemical messenger) that everyone naturally produces. Those who have migraine disease have elevated levels of CGRP during an attack, while someone with chronic migraine has chronically elevated levels of CGRP.

This breakthrough in the understanding of migraine sparked an interest in this new class of medications referred to as CGRP inhibitors. These medications were specifically designed to inhibit or divert the activity of CGRP in the body in the hopes of preventing attacks or reducing their frequency and severity.

On the market

As of April 1, 2019, three CGRP inhibitor medications have been approved by the FDA: AimovigTM, AjovyTM, and EmgalityTM. Monoclonal antibodies (mABs), are used to bind to proteins, parts of a protein (peptide), or their receptors.

CGRP Inhibitor Medications – FDA Approved as of April 1, 2019


Brand Name

Biologic Name





Autoinjector pen used to deliver one or two 70 mg doses monthly via subcutaneous injection

Eli Lilly



Autoinjector pen used to deliver “loading” dose of 240 mg via subcutaneous injections, then one injection of 120mg monthly




Pre-filled syringe used to deliver 225 mg via subcutaneous injection monthly or three 225 mg injections quarterly

How do CGRP inhibitors work?

When CGRP binds to specific receptors it can trigger a migraine attack. There are two different ways in which CGRP inhibitors work to prevent this from occurring. AimovigTM inhibits CGRP by attaching itself to the pain receptors so that CGRP cannot attach. AjovyTM and EmgalityTM inhibit CGRP by attaching to the peptide so that it no longer fits in the receptor.

To illustrate the difference, the analogy of a parking lot may help. Cars (peptides) park in a lot that have multiple parking spaces (pain receptors). Normally a driver can find a parking space and easily park, until a CGRP inhibitor is thrown into the mix. Aimovig attaches to the parking space, making it impossible for a car to fit in the space. On the other hand, AjovyTM and EmgalityTM attach to the car making it larger and no longer able to fit into a parking space. This difference in mechanisms could explain why some find relief with one CGRP inhibitor and not the other.

Standing out from the crowd

This new frontier in migraine treatment is exciting for many reasons.

·       The clinical trial results were extremely positive; in general, 50% of people experienced around 50% relief, and 10-12% “super-responders” experienced 75-100% relief.

·       It is important to be cautiously optimistic when starting on a CGRP inhibitor. On average one-third of patients will not see any improvement.

·       The FDA identified only a few side effects that were statistically significant enough to include on the warning labels: constipation (AimovigTM only), injection site reaction, and allergic response.

·       There are several more CGRP inhibitor medications currently under development in various phases of clinical trials. This surge of new research offers hope for more advancements in the near future.

·       Finally, the existence of medications designed specifically for migraine has sparked a much-needed new interest in headache disorders within the medical profession.

In the pipeline

The discovery of CGRP inhibitors is only the beginning in the quest to unravel the mysteries of the brain. In the coming year it is anticipated that up to six additional FDA applications will be submitted. Some of these new submissions are medications referred to as ‘gepants,’ which are small molecule CGRP inhibitors. The current CGRP inhibitors are taken as a preventive measure, several in the pipeline are being developed for both preventive and abortive measures, as well as for those who have cluster headache disease. The table below outlines what’s in the pipeline.

CGRP Inhibitors in the Clinical Pipeline









Applied to FDA

February 2019

Quarterly IV infusion

Eli Lilly


Preventive for

Episodic Cluster

Applied to FDA March 2019

with priority review

Subcutaneous injection




Applied to FDA March 2019

Oral tablet




& Abortive

Expected FDA application

2Q 2019 with priority review

Oral, dissolvable tablet




In phase 3 trial

FDA application expected 2019

Oral tablet




& Abortive

Starting phase 2/3 trials


Real world outcomes

One of the greatest challenges since the rollout of CGRP inhibitors has been capturing real world outcomes. Potential clinical trial volunteers were excluded from participating if they had certain health issues or were using certain medications.  To maintain scientific protocol, clinical trials did not study the interactions between CGRP inhibitors and other treatments commonly used by those with migraine, such as Botox, antidepressants, and cardiovascular medications. Since it is still early in studying the effects of CGRP inhibitors in the real world, it remains to be seen if more serious side effects will be reported.

If you have experienced adverse side effects to one of the CGRP inhibitor medications, please consider making an online report to the FDA: fda.gov/safety/medwatch

Tying it together

Those who haven’t had a positive reaction to a CGRP inhibitor are often devastated, resulting in going through the grieving process of failure and lost hope all over again. Not everyone knows there are multiple other drugs targeted specifically for those living with not just migraine, but also other headache and cluster diseases. Knowing there are other options that will be available in the near future is a reminder that even if we feel as though we’ve tried everything, there are other treatments that will be available in the next one to three years. Now is definitely the time to stay informed, advocate for access, and most of all, realize there is still hope.


CGRP Support and Community Group: facebook.com/groups/CGRPandMigraine

Migraine Meanderings: migrainemeanderings.com