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CGRP as the target of new migraine therapies — successful translation from bench to clinic

Abstract

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

Key points

  • Multiple studies have confirmed that release of calcitonin gene-related peptide (CGRP) is increased during acute migraine attacks.

  • In the trigeminal ganglion, CGRP is expressed in C-fibres and its receptor is expressed in Aδ-fibres; these types of fibres are involved in different aspects of pain perception.

  • The trigeminal ganglion is central to the trigeminovascular reflex, which is triggered to protect against vasoconstriction; triggering of this system in patients with migraine leads to the perception of pain.

  • The trigeminal ganglion and dura are not behind the blood–brain barrier; therefore, they are likely to be the targets of gepants and antibodies in migraine treatment.

  • CGRP receptor antagonists, anti-CGRP antibodies and anti-CGRP receptor antibodies have proved effective for migraine pain relief, strongly supporting the hypothesis that CGRP has a major role in migraine pathophysiology.

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Fig. 1: Timeline of the key events in the development of drugs that target CGRP for migraine therapy.
Fig. 2: Components of CGRP transmission and sites of action for CGRP-related migraine therapies.
Fig. 3: Clinical data that demonstrate that CGRP has an important role in migraine headache and its treatment.
Fig. 4: CGRP and CGRP receptors in the trigeminovascular system.
Fig. 5: Proposed involvement of the trigeminal ganglion in migraine headache and mode of action of CGRP-targeted therapies.

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Nature Reviews Neurology thanks H.-C. Diener, A. Rapoport, A. Russo and C. M. Villalón for their contribution to the peer review of this work.

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All authors researched data for the article, made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission. L.E. and D.N.K. wrote the manuscript.

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Edvinsson, L., Haanes, K.A., Warfvinge, K. et al. CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat Rev Neurol 14, 338–350 (2018). https://doi.org/10.1038/s41582-018-0003-1

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