image_pdfimage_print
FIRST IN CLASS MIGRAINE APPROVAL

Last month 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 6 months. This is a big breakthrough that will have significant impact on the quality of life for migraine suffers who have not been able to find other forms of relief.

In this WEEKLY, we’ll review the science behind migraines and explain how Amgen’s new drug works.

ATTACK OF THE MIGRAINE

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 prodome, aura, or postdome phases.

  • Prodome 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 the severe pain attacks. Visual distortions are the most common symptom, with sensory or motor disturbances potentially occurring as well.
  • Postdome happens after the actual headache and includes symptoms such as lingering pain and cognitive difficulties.
THE SCIENCE BEHIND THE EPISODE

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 is 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, increases levels of serotonin 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 accumulation of glutamate in synapses may be a trigger.
THIS JUST IN

The hot new kid on the block is calcitonin gene related peptide (CGRP) inhibitors. CGRP spikes during migraine attacks and is thought to play a role in the brain pathways that process pain. The exact molecular mechanism of how the CGRP spike is related to migraine onset is not yet fully understood, but CGRP is thought to sensitize nerves in the face, neck, and jaw, as well as alongside blood vessels surrounding the brain. A 2002 study provided strong evidence of a key role for CGRP in driving migraines. Injecting volunteers who were migraine-prone with the CGRP peptide induced a migraine within hours; injecting volunteers who were not migraine-prone resulted in a mild headache at worst. These studies helped to form the scientific basis for Amgen’s new monoclonal antibody (mAb) drug that blocks activation of the CGRP receptor. The antibody binds the receptor but does not activate it, and in so doing, prevents CGRP from activating the receptor.

Amgen may have garnered the first CGRP inhibitor approval, but several other companies are also working on drugs that target CGRP.  Eli Lilly (Indianapolis, IN) and Teva (Petah Tikva, Israel) both have filed for regulatory approval of mAb inhibitors directed at CGRP itself; Alder Pharmaceuticals (South Bothell, WA) has a CGRP-directed mAb in Phase III clinical testing. The idea is for the mAb to “mop up” CGRP before it reaches the receptor and triggers a migraine. Allergan (Dublin, Ireland) has a small molecule inhibitor of the CGRP receptor in Phase III clinical testing.

COCKTAIL FODDER: A HEADACHE OF THE PAST

We sometimes blame migraines on the stress of modern living. In some cases, stress is a trigger, but the 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.

emily burke
Emily Burke, PhD

Author

Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and ISIS Pharmaceuticals. As a PhD molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings worldwide. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.

Share This