In May 2018, the FDA approved Amgen’s (Thousand Oaks, CA) new migraine drug Aimovig, the first drug shown to prevent the onset of migraines. The drug significantly reduces the number of migraine days in difficult-to-treat (those that have failed 2 to 4 prior treatments) patient populations. In some patients dubbed “super responders,” migraines occurrence went from several times/month to no occurrence for six months. This is a big breakthrough that will significantly impact the quality of life for migraine sufferers who have not been able to find other forms of relief.

This article will review the science behind migraines and explain how Amgen’s new drug works.

As many as 36 million Americans suffer from migraines—about 12% of the population. More than just a headache, migraines often include symptoms like intense pain, nausea, and extreme sensitivity to light or noise. They can last anywhere from a few hours to days on end. Episodes may be as frequent as several times a month or as infrequent as a few times a year.

There are three distinct parts of a migraine episode; however, not all migraine sufferers experience these phases with the same intensity. Each set of symptoms is unique to the individual and can include prodrome, aura, or postdrome phases.

• Prodrome occurs in the hours or days before a migraine attack. It includes mood disturbances, stiff muscles, and sensitivity to smells or noise.
• Aura is the period just before severe pain attacks. Visual distortions are the most common symptom, with sensory or motor disturbances potentially occurring.
• Postdrome happens after the actual headache and includes symptoms such as lingering pain and cognitive difficulties.

While the exact cause is largely unknown, there are a few theories:

• Brain Stem Changes: Research by the Mayo Clinic (Rochester, MN) suggests migraines derive from changes in the brain stem and its interaction with the trigeminal nerve. The trigeminal nerve supplies feeling to the face and are considered a pain-associated pathway in migraine attacks.
• Lowered Serotonin Levels: Another area of active research involves the neurotransmitter serotonin. Serotonin is most often associated with mood— antidepressants such as Eli Lilly’s (New York, NY) Prozac increase serotonin levels in the brain. This neurotransmitter is also implicated in migraine pain pathways, with levels dropping during an attack.
• Hormonal Link: Migraines are more common in women than men, so a hormonal link may be tied to the causality. There is often a reduction in symptoms after menopause.
• Glutamate Accumulation: In recent years, a few gene variations that appear to increase the risk of developing migraines have been identified through genome-wide association studies. Two of these genes result in increased levels of the neurotransmitter glutamate, suggesting that the accumulation of glutamate in synapses may be a trigger.

While calcitonin gene-related peptide (CGRP) inhibitors once held the spotlight as the promising new approach to migraine treatment, the landscape of migraine research has evolved. CGRP, known to spike during migraine attacks, plays a role in the brain pathways that process pain. Its exact molecular mechanism in relation to migraine onset remains a topic of research. CGRP is believed to sensitize nerves in the face, neck, and jaw, as well as alongside blood vessels surrounding the brain.

A pivotal study in 2002 showcased the significance of CGRP in migraines. When migraine-prone volunteers were injected with the CGRP peptide, they experienced a migraine within hours. In contrast, those not prone to migraines only reported a mild headache. This research laid the groundwork for Amgen’s monoclonal antibody (mAb) drug that blocks the activation of the CGRP receptor. The antibody binds to the receptor without activating it, thereby preventing CGRP from triggering the receptor. However, as recent research suggests, not all patients respond to CGRP(-receptor) therapies. The scientific community is now exploring alternative targets beyond CGRP, aiming to provide comprehensive solutions for all migraine sufferers.

The FDA has initially approved four mAbs targeting the CGRP peptide or its receptor for the prophylactic treatment of migraine. These mAbs include Erenumab, co-developed by Novartis (Basel, Switzerland) and Amgen (Thousand Oaks, CA), Fremanezumab, licensed by Teva (Petah Tikva, Israel), Galcanezumab developed by Eli Lilly (Indianapolis, IN) and Eptinezumab (ALD403) developed by Lundbeck Seattle BioPharmaceuticals (Bothel, Washington). In December 2019, the FDA approved Ubrelvy, manufactured by Allergan (Dublin, Ireland), as a potent, orally-administered CGRP receptor antagonist for the acute treatment of migraine with or without aura in adults. Ubrelvy is not a mAb but works similarly to the monoclonal antibody medications by blocking the CGRP receptor.

We sometimes blame migraines on the stress of modern living. Stress is sometimes a trigger, but headaches are hardly a modern phenomenon. Descriptions consistent with migraines are found in the ancient Egyptian medical text Ebers Papyrus, dating from 1550 B.C., as well as Hippocratic texts dating from 200 BC.

The approval of Amgen’s migraine drug, Aimovig, marks a significant milestone in migraine treatment. This first-in-class drug offers hope to those who have struggled with migraines and failed previous therapies. Aimovig’s ability to reduce migraine days, particularly in challenging cases, demonstrates its potential to enhance the quality of life for migraine sufferers. The science behind migraines is complex, involving brain stem changes, serotonin levels, hormonal links, and neurotransmitter imbalances. The recent focus on calcitonin gene-related peptide (CGRP) inhibitors represents a promising avenue. These inhibitors aim to prevent the activation of the CGRP receptor, offering a potential solution for migraine prevention. With the FDA’s approval of various monoclonal antibody (mAb) drugs targeting the CGRP pathway, including Aimovig, Erenumab, Fremanezumab, Galcanezumab, and Eptinezumab, the landscape of migraine treatment is evolving. This groundbreaking approach promises a brighter future for those affected by migraines.

1. WHAT IS THE SIGNIFICANCE OF AIMOVIG’S APPROVAL IN MIGRAINE TREATMENT?

Aimovig’s approval by the FDA is groundbreaking as it is the first drug designed to prevent the onset of migraines. This offers new hope to patients who have previously struggled to find effective relief.

2. HOW DOES THE SCIENCE BEHIND MIGRAINES SUGGEST THE ROLE OF SEROTONIN?

Serotonin, a neurotransmitter associated with mood regulation, is also implicated in migraine pain pathways. Antidepressants that increase serotonin levels, such as Prozac, have been found to influence migraine occurrences.

3. CAN YOU EXPLAIN THE ROLE OF CALCITONIN GENE-RELATED PEPTIDE (CGRP) IN MIGRAINES?

CGRP spikes during migraine attacks and is believed to sensitize nerves in the face, neck, and jaw, as well as blood vessels surrounding the brain. Blocking CGRP activation using monoclonal antibody drugs offers a promising avenue for migraine prevention.

4. HOW ARE THE FDA-APPROVED MONOCLONAL ANTIBODY (MAB) DRUGS TARGETING CGRP USED FOR MIGRAINE TREATMENT?

These mAb drugs, including Aimovig, Erenumab, Fremanezumab, Galcanezumab, and Eptinezumab, aim to inhibit the CGRP pathway by targeting either the peptide itself or its receptor. They offer a new approach to preventing migraines.

5. ARE THERE HISTORICAL REFERENCES TO MIGRAINES?

Yes, descriptions consistent with migraines have been found in ancient medical texts like the Ebers Papyrus from 1550 B.C. and Hippocratic texts dating back to 200 BC, highlighting that migraines have been a concern for centuries.