CGRP inhibitors

Calcitonin gene-related peptide (CGRP) inhibitors block the effect of CGRP, which is a small protein that is highly prevalent in the sensory nerves that supply the head and the neck. CGRP is involved in pain transmission and levels increase during a migraine attack. It may also play a causative role in the induction of migraine attacks. CGRP inhibitors are used to manage migraines.

There are two types of CGRP inhibitors – monoclonal antibodies and CGRP receptor antagonists (gepants).

Monoclonal antibodies target either CGRP or the CGRP receptor and are used for migraine prevention. A monoclonal antibody is a collection of identical proteins that have been developed to only target one substance in the body. They are given by injection subcutaneously (under the skin), to avoid degradation by the stomach. Because they are large molecules, they take longer to start working and work in the lining of the brain rather than in the brain itself. They also tend to have few drug interactions and are unlikely to cause liver or kidney damage. The following monoclonal antibody CGRP inhibitors have been approved:

• Aimovig (erenumab-aooe): Approved May 17, 2018
• Ajovy (fremanezumab): Approved Sept 14, 2018
• Emgality (galcanezumab-gnlm): Approved Sept 27, 2018
• Vyepti (eptinezumab-jjmr): Approved Feb 21, 2020.

Gepants are small molecule drugs which block the CGRP receptor and are effective at both relieving migraines and preventing them. Unlike monoclonal antibodies, gepants rapidly penetrate the brain so work quickly; however, they are metabolized in the liver so there is a higher potential for interactions and possibly liver damage. The following have been approved to date:

• Ubrelvy (ubrogepant): Approved Dec 23, 2019
• Nurtec ODT (rimegepant sulfate): Approved Feb 27, 2020.
• Qulipta (atogepant):  Approved Sept 28, 2021
• Zavzpret (zavegepant) (intranasal/oral): Approved March 10, 2023.

CGRP inhibitors were the first drugs to be specifically developed for migraine prevention. All other migraine preventive agents were originally developed for other conditions (such as high blood pressure), and then found later by chance to have an effect in migraine. Triptans were developed to treat migraine attacks, although some have been used off-label as preventive agents, dosed continuously twice daily during the menstrual window, to treat menstrual migraines.