New Drug Class Employs Novel Mechanism for Migraine Treatment and Prevention

The U.S. Food and Drug Administration (FDA) has recently approved members of a new class of drugs specifically designed to treat migraine by targeting calcitonin gene-related peptide (CGRP), a substance that is elevated in blood serum during migraine attacks. Designed to decrease the number of migraine attacks, the new class of migraine drugs is metabolized differently and has fewer adverse reactions observed in clinical trials, as well as fewer warnings and precautions, compared to other approved migraine therapeutics. The three new FDA-approved drugs are Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), and Emgality (galcanezumab-gnlm).

A migraine can cause severe, debilitating, and persistent pain that can last for hours or days. Migraine symptoms may also include nausea, vomiting, and extreme sensitivity to light and sound, with some migraine sufferers reporting visual disturbances, called an aura, such as light flashes, spots, or vision loss.

Although several therapeutics are available to stop migraine attacks after they are already underway and some drugs include migraine prevention among several approved indications, the new class of CGRP-targeted drugs is the first to be specifically designed for the preventive treatment of migraine, marking a significant new era of migraine therapeutics.

Understanding the Role of CGRP and the Trigeminal Pain System in Migraine

Migraine is a neurovascular disorder associated with dysfunction of the cerebral nerve cells and blood vessels. Although scientists initially believed that migraine attacks originated in the cerebral blood vessels, more recent research suggests that migraine probably results from primary dysfunction in the brainstem centers that regulate vascular tone and pain sensation. The migraine attack often begins when triggers, such as stress, certain foods, or hormonal changes, set off dysfunctional reactions in the brain, causing excessive relaxation or dilation of cranial blood vessels.

These dilated blood vessels then mechanically activate sensory fibers from the trigeminal nerve located in the vessel wall, which then convey pain impulses to the brainstem and from there to higher brain centers. These impulses prompt the nerve fibers to release vasoactive peptides such as CGRP, which intensify dilation of the cranial blood vessels and cause “neurogenic” inflammation. This chain of events results in increased leakiness of blood vessels and the release of toxic compounds from mast cells, a type of white blood cell found in connective tissue. These events further increase the activation of the sensory fibers and perpetuate the release of vasoactive peptides, including CGRP. Scientists believe that as the migraine attack progresses, the brainstem and spinal cord centers that are the first to receive the pain impulses from the trigeminal nerves amplify the headache pain and increase sensitivity to environmental and other stimuli affecting visual and auditory sensation.

How the New Drug Class Uses CGRP-Targeted Monoclonal Antibodies to Prevent Migraine

In the new class of migraine therapeutics, the primary mechanism of action is the blocking of the effects of CGRP. These specialized monoclonal antibodies that are designed to treat migraine are cloned subclasses of immunoglobulin G (IgG), the most common type of antibody circulating in the blood, and are designed to have little potential to interact with other drugs. They act as antagonists, sometimes called blockers or inhibitors.

In the case of the drug erenumab-aooe, the antagonist selectively targets and binds to the CGRP receptor, blocking CGRP from interacting with the receptor. In contrast, fremanezumab-vfrm and galcanezumab-gnlm block the ability of CGRP to bind to the CGRP receptor.

Previously approved migraine preventive treatments were first approved for other conditions, and were later found to be effective in reducing the frequency of migraine attacks. The mechanism of action for earlier migraine therapeutics is less clear than that of CGRP antagonists, which were developed based on the knowledge that blocking the role of CGRP in the cascade of events that lead to a migraine attack may be an effective mechanism for migraine treatment.

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