Calcitonin Gene-Related Peptide in Migraine Prevention

Preliminary Results on Drugs That Target CGRP and Its Receptor

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Can an Antibody to CGRP Prevent Migraines?. Ingram Publishing/Vetta/Getty Images

Calcitonin gene-related peptide (CGRP), a protein produced by some nerve cells in both the central nervous system and peripheral nervous system, is believed to play a vital role in migraines. Not only has this protein found to be elevated during migraine attacks, but the alleviation of migraine pain with a migraine medication called a triptan has coincided with the normalization of CGRP levels in the bloodstream.

During a migraine attack, it's possible that certain migraine triggers stimulate blood vessels around the brain to dilate, or widen. These dilated cranial blood vessels then activate trigeminal sensory nerve fibers. Once activated, the trigeminal nerve fibers send a pain response to the brain – which prompts the release of various proteins, like CGRP.

CGRP then triggers further dilatation of the cranial blood vessels and something called "neurogenic inflammation". As the migraine attacks progress, the brainstem becomes sensitized. This leads to a vicious cycle of head pain and an increased sensitivity to one's environment.

What Do Preliminary Studies on CGRP Show?

Phase II studies - studies done on a small number of patients to determine the benefit and potential side effects of the drug - so far are promising suggesting that CGRP antibodies both prevent migraines and are well-tolerated. 

In one study, 217 participants who experience 4 to14 migraines a month, were blindly randomized to receive beneath the skin injections twice weekly of either a drug called LY2951742 or placebo – a sugar or water injection – for a total of 12 weeks.

(LY2951742 is an antibody to calcitonin gene-related peptide (CGRP) – this means it binds to CGRP and blocks or inactivates it).

Results suggested that participants who received LY2951742 had a significant decrease in the number of their migraine headache days when compared to placebo. Good news too is that this drug was found to be safe and tolerated well by the subjects.

That being said adverse effects included:

  • injection site pain
  • abdominal pain
  • upper respiratory tract infection (e.g. bronchitis)

Another drug called ALD403 – also a calcitonin gene-related peptide antibody – was tested in 163 participants who experience 5 to 14 migraines a month. One-half of the subjects blindly received a 1000mg intravenous (through the vein) dose of the drug, while the other half received a placebo. The subjects were followed for 6 months.

During weeks 5 to 8, the participants who received the drugs saw a 66 percent reduction in the number of days they suffered from a migraine versus 52 percent for those who received placebo.

Also, at 12 weeks, 16 percent of the patients who received the drug were completely migraine-free versus zero of those who received the placebo.

Finally, another drug, administered beneath the skin (subcutaneous injection) called AMG 334 - an antibody that binds to the CGRP receptor (the docking site of CGRP) - was recently found to prevent migraines as well.

Like the other two drugs, AMG 334 was well tolerated. The most common adverse effects were:

  • cold symptoms
  • fatigue
  • headache or migraine (go figure - very small, 3 percent versus 1 percent in the placebo group)
  • nausea
  • upper respiratory tract infection (e.g. bronchitis).

The Bottom Line

These are certainly exciting results for the migraine community. Nevertheless, a larger phase III study - studies that are larger and verify the claims of phase II studies - needs to be done before these drugs will be made available to patients. 

Sources:

Bigal ME, Walter S, Rapoport AM. Calcitonin gene-reported peptide (CGRP) and migraine current understanding and state of development. Headache. 2013;53(8):1230-44.

Durham PL. Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache. 2006;46(Suppl 1):S3-S8.

Goadsby PJ, & Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993 Jan;33(1):48-56.

Initial Results for ALD403, A New Investigational Medicine for Migraine Prevention. (n.d.). In American Headache Society. Retrieved May 18th, 2014.

Sun H et al. Safety and efficacy of AMG 334 for prevention of an episodic migraine: a randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382-90.

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