Migraine is a highly prevalent and disabling neurological disease, affecting approximately 12% of adults worldwide. For those living with migraines, the condition can severely impact their quality of life and ability to function. Migraine attacks involve moderate to severe throbbing head pain, often accompanied by nausea, vomiting, photophobia, and phonophobia. Attacks last 4-72 hours when untreated.

The societal costs of migraine are immense. In the United States alone, migraine accounts for over $78 billion annually in direct healthcare costs and lost productivity. Patients with chronic migraines (experiencing headaches 15 or more days per month) are especially disabled, missing on average 5 days of work or school per month.

Current Treatments

Existing treatment options leave many patients dissatisfied. Medications like NSAIDs, triptans (e.g. eletriptan), and ergotamines can provide symptom relief but do not prevent attacks from occurring. Their use is also limited by contraindications and side effects. Prophylactic options like beta blockers, anticonvulsants, and tricyclic antidepressants are not universally effective and many come with troublesome side effects leading to treatment discontinuation.

Botulinum toxin injections have proven effective for chronic migraine but must be administered by a specialist every 3 months. There is a need for new acute and preventive migraine treatments that are easy to use, well-tolerated, and effective for a broad population of patients.

CGRP Receptor Antagonists

Recently, small molecule CGRP receptor antagonists have emerged as a promising new class of therapeutics for migraine prevention and acute treatment. CGRP is a peptide involved in migraine pathogenesis. Within the meninges, CGRP is presumed to stimulate neurogenic inflammation by inducing the secretion of neuronal sensitizing compounds from mast cells. This action subsequently results in exacerbated vasodilation in the dura. This change in neuronal activity in the meninges sets off a feedback system, culminating in peripheral sensitization of pain receptors (nociceptors). By blocking its receptor, CGRP receptor antagonists like Ubrogepant inhibit migraine mechanisms.

Ubrogepant is the first FDA-approved oral CGRP receptor antagonist for acute migraine treatment (for more information about the CGRP market, please check out this article). In phase 3 trials, a single dose of Ubrogepant provided significant headache pain relief at 2 hours compared to placebo, reduced functional disability, and was well tolerated. It lacks drug interactions seen with triptans and may be an option for patients who cannot take or fail triptan therapy. Since then, other drugs targeting CGRP receptor have been approved, such as Rimegepant (oral CGRP antagonist, approved in 2020) and Zavegepant (nasal spray CGRP antagonist, approved in 2023)

The chemical structure of Ubrogepant, CAS RN 1374248-77-7

The innovation of CGRP receptor antagonists like Ubrogepant represents an exciting advancement for migraine patients who struggle to find satisfactory relief. As research continues, there is hope these new mechanisms can transform migraine treatment paradigms and reduce the immense individual and societal burdens of this devastating neurologic disease.

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