Role of CGRP in migraine

CGRP is a small peptide found in the brain and other parts of the body that works as a neurotransmitter.^1,2 Many people with migraine overexpress this molecule, and drugs that block its action have been found to be effective migraine treatments.¹ Indeed, monoclonal antibodies that bind to CGRP or its receptor and small molecules called gepants that compete with CGRP for binding to its receptor are very effective at treating or preventing migraine in a substantial number of individuals.³ Triptans also impact the CGRP pathway by reducing the amount of CGRP released from specific nerves.²

CGRP is a small peptide that can play a big role in migraine 

Efficacy of blocking the CGRP pathway

Despite its recognized role in the pathophysiology of migraine, not all people with migraine respond to CGRP inhibition.³ Indeed, there is considerable heterogeneity in response to CGRP inhibition both between individuals and within individuals themselves.^2,3 In clinical trials, about half of people with episodic migraine demonstrated a ≥50% reduction in migraine frequency after 3 months, a third had a reduction of ≥75%, and about one-fifth had a 100% reduction.^4-7 However, Dr. Goadsby pointed out that about a quarter of individuals have a limited or no benefit from CGRP antagonists, “so we have to do more.” 

CGRP blockers have been ‘game changers’ for some people with migraine but they are not effective for everyone

One of the important benefits of CGRP blockers is that they have very few adverse events,² so the people who benefit from this treatment strategy tend to have a response without paying a penalty in terms of safety. Although CGRP is widely distributed throughout the body (e.g., in the brain, hair follicles, and gastrointestinal tract), the incidence of adverse events due to its blockade is relatively low.² Injection site reactions and constipation are the most common side effects,^4,5 but these effects infrequently led to study withdrawal suggesting that they are seldom treatment-limiting.⁷ Dr. Goadsby concluded that CGRP blockers are effective in many patients and well tolerated in most.

Migraine pathophysiology is complex

The observed lack of complete response to CGRP inhibition in some people with migraine and absence of response in others suggests that CGRP is not important in everyone’s migraine – or in all migraines within an individual.² But Dr. Goadsby posited that other factors may also contribute to the incomplete response to CGRP inhibition including pharmacokinetic issues (i.e., delivering the drug to the intended target), and the evolving biochemistry of migraine attacks over time (i.e., other peptides could become more prominent in migraine attacks once CGRP is inhibited). This complexity in migraine presentation and biochemistry between and within individuals makes it important for clinicians to apply an individualized approach to migraine management that can be tailored to a given patient, and to different migraines experienced by the same patient. To this end, Dr. Goadsby believes in the value of having a well-equipped toolbox with enough tools to deal with the range of migraine attacks, as well as biomarkers to help identify which tools are needed to get the job done. 

Additional tools are needed in the ‘migraine toolbox’

Other peptides on the migraine treatment horizon

The bench to bedside success of CGRP antagonists has injected new enthusiasm into migraine research. Today, there is increasing scientific attention focused on other peptides involved in migraine pathophysiology that could be potential targets for treatment. One such peptide is pituitary adenylate cyclase-activating polypeptide (PACAP), a small peptide that is released from nerves in areas of the brain that are known to be involved in migraine.^8,9 Early clinical trial evidence suggests that monoclonal antibodies that target PACAP can effectively reduce the frequency of migraine attacks.^8,9 Similar to the CGRP blockers, PACAP inhibitors appear to be well tolerated with a low incidence of adverse effects.⁹ However, Dr. Goadsby cautioned that it remains ‘early days’ in PACAP development, and more studies are needed to better understand the role of PACAP in migraine pathophysiology and the role of these agents in migraine treatment and prevention.

PACAP inhibitors are showing promising results in early clinical trials 

Early observations also suggest that PACAP inhibitors not only influence migraine attack frequency and pain intensity, but they also have an effect on premonitory or prodromal symptoms, the harbingers of an imminent migraine attack.¹⁰ This suggests that they could be particularly attractive options for migraine prevention. Similarly, CGRP antagonists have demonstrated benefit in the prodromal phase of migraine attacks, which makes them effective preventive agents.^10,11 Dr. Goadsby is hopeful based on the data he has seen so far that PACAP inhibitors will also be good preventive agents. Moreover, people who do not respond adequately to CGRP inhibition might respond to PACAP treatments, or an approach that targets both peptides could be effective for patients with a more heterogeneous migraine biology.⁹

Several other targets are being investigated for migraine treatment and prevention

Other novel targets in migraine pathophysiology that are being investigated include glutamate, an excitatory neurotransmitter; protease-activated receptor 2 (PAR2), an inflammatory mediator; delta opioid agonists; and orexin, which is involved in pain and sleep cycles.¹² Dr. Goadsby acknowledged the great work that has been done by biochemists in identifying new targets for migraine treatment that led to the development of the anti-CGRP antibodies and gepants, and he anticipates that they will continue to identify new targets in the future. “The CGRP story has lifted the field to understand that yes, we can do it – it’s a story of hope, of delivery, and of promise.”