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CGRP and migraine

What is CGRP?

The neuropeptide calcitonin gene-related peptide (CGRP) is a very potent vasodilator which plays a major role in migraine pathophysiology.

It was first identified over 30 years ago and is found as two isoforms, one in the peripheral nervous and central nervous system (α-CGRP) and the other (β-CGRP) mainly in the enteric nervous system surrounding the intestines.1

CGRP and its receptors are currently being targeted for the development of new preventive therapies for migraine.

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What is the evidence that CGRP plays a role in migraine pathophysiology?

There is now much evidence supporting CGRP’s role in migraine. In 1990 a study found that CGRP is released into the external jugular vein during the headache phase of migraine in patients with or without aura.2 Since that time a number of studies have shown that CGRP is released when the trigeminal ganglion is stimulated and during severe migraine attacks. 1 In addition, it has been shown that CGRP administration triggers migraine in patients, and that reversal of a migraine attack with effective triptan treatment normalises the levels of CGRP.1 Recent studies have shown that blood CGRP levels are significantly higher in women with a history of migraine.3

As CGRP seems integral to the clinical expression of migraine, CGRP blockade offers a possible strategy for the treatment of migraine.

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What approaches have been used to target CGRP or its receptor?

A number of small molecule CGRP receptor blockers have been developed that show clinical efficacy in acute migraine. The first CGRP receptor blocker was called olcegepant. It was given intravenously and provided proof of concept that targeting CGRP was an effective migraine strategy. Although the drug showed clinical effectiveness in phase II trials, there were difficulties in producing an orally available formulation and so drug development was discontinued. The first orally available molecule of this class - the ‘gepants’- was called telcagepant but liver toxicity issues resulted in discontinuation. New oral gepants, including rimegepant and MK-1602, are currently undergoing clinical trials. These have not shown liver toxicity to date.

It is hoped that the CGRP receptor blockers may provide an alternative to triptan therapy for acute migraine which has been associated with limited response, adverse effects, and the frequent need for repeat dosing or alternative analgesia.2

Another approach in migraine therapy uses monoclonal antibodies to block CGRP activity. These humanised monoclonal antibodies to CGRP are administered intravenously and have shown potential in preventing migraine attacks.4

What is the potential for therapeutic monoclonal antibody therapy targeting CGRP or its receptor?

Clinicians agree that a therapeutic monoclonal antibody directed against CGRP or the CGRP receptor shows much promise in preventing migraine. Leading international clinical experts have described the tolerability and clinical efficacy of these agents as “a breakthrough in migraine therapeutics, where, since the triptans, there have been no outstanding developments in the management of this disabling condition.”1

Four monoclonal antibodies - erenumab [formerly AMG 334], galcanezumab [formerly LY2951742], fremanezumab [formerly TEV-48125] and eptinezumab [formerly ALD403]) - are in development for the preventive treatment of episodic or chronic migraine. A growing body of evidence from Phase 2 and Phase 3 studies shows encouraging efficacy and safety, and erenumab (Aimovig) received approval for use in the preventive treatment of migraine in adults in the USA in May 2018 and in the EU in July 2018.

Summaries of the clinical trial data are available here.

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References

  1. Karzan N, Goadsby PJ. CGRP mechanism antagonists and migraine management. Curr Neurol Neurosci Rep 2015;15:25.
  2. Goadsby PJ, Edvinsson L, Ekman R. Vasocactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183-187.
  3. Cernuda-Morollon E, Larrosa D, Ramon C, et al. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 2013;81:1191-1196.
  4. Diener H-C, Charles A, Goadsby P, Holle D. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol 2015;14:1010-1022.