What are Disease Modifying Migraine Drugs (DMMDs)?

Migraine is a disabling disease that affects around one billion people globally. Migraines present as severe, debilitating headaches, mostly affecting one side. Headaches are usually accompanied by nausea, vomiting, photophobia (light sensitivity), and phonophobia (sound sensitivity), which may last from 4 hours to 72 hours.

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Migraine is observed more in females than males, with reports estimating that one in five women experience a migraine in their lifetime. Migraine has a strong genetic predisposition, and genetic factors are shown to be involved in the pathogenesis, chronicity, and response to drug therapy in migraine.

What causes migraines?

The trigeminal vascular system plays a key role in the development of migraine. Various internal and external environmental factors trigger hyper excitement and activation of the trigeminal nerves. These nerves then release of neuroinflammatory mediators.

Release of neuroinflammatory mediators results in inflammation, vasodilation, activation of pain receptors, and, ultimately, initiation of pain response. Calcitonin gene-related peptide (CGRP), serotonin, and substance P are the major neuropeptides that are released during a migraine attack. Of these neuropeptides, numerous studies have demonstrated a pivotal role of CGRP in migraine attacks.

CGRP is a neuropeptide made up of 37 amino acids. The peptide is spread in both peripheral and central nervous systems and is expressed in 50% of neurons in the trigeminal ganglia. CGRP levels are found to be elevated during a migraine attack, and its intravenous administration has also shown to provoke migraine.

What are the treatment options for migraine?

Persons with migraines are usually under-treated, and there exists significant dissatisfaction with current migraine treatments.

Preventive treatment is also recommended for people who experience frequent migraine headaches. Current preventative treatment options include drugs developed for diseases other than migraine such as hypertension, depression, and epilepsy. These drugs have delays of weeks or even months to develop clinical benefits, which limits their use.

Recently, the first class of disease modifying migraine drugs (DMMDs) has been developed: the CGRP antagonists.

The CGRP antagonists block the CGRP ligand or receptor. CGRP blockers are considered DMMDs because they can act on the pathophysiological mechanism of migraine.

Chief among the DMMDs are humanized antibodies and a fully human antibody. Of these, some are FDA approved, while some await approval.

The humanized antibodies target the CGRP ligand, while fully human antibody binds to the CGRP receptor. Medications containing these antibodies can be self-administered once a month by an autoinjector (as with an insulin pen) at home.

Ditans are another class of DMMDs. Ditans activate the serotonin 5-HT1F receptor (5-HTR1F) and decrease the release of excitatory transmitters and CGRP in the trigeminal nerves. None of the ditans are currently approved for human use; one prospective ditan is currently undergoing phase III clinical trials. Ditans selectively bind to the 5-HTR1F and do not cause the vasoconstriction commonly produced by other migraine drugs such as triptans.

Another therapeutic strategy to tackle migraine involves the use of gepants. Gepants are small drug molecules that block the CGRP receptor. They have the ability to cross the blood-brain barrier, which accounts for their quick mechanism of action.

Gepants have efficacy comparable to triptans and also lack the vasoconstrictor side effects. Several new gepants are being developed and are awaiting approval. Frontrunners among these agents have shown promising results in phase III clinical trials.

The advent of DMMDs represents a valuable novel treatment option for migraine, which may potentially change the treatment paradigm for it. However, cost and access to therapy will be pivotal factors in the paradigm shift.

Further Reading

• All Migraine Content
• What are Migraines?
• Migraine Diagnosis
• Migraine Pathophysiology
• Migraine History