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.

Non‐Responders to Treatment With Antibodies to the CGRP‐Receptor May Profit From a Switch of Antibody Class

“…1 The findings are from open-label treatment, which is inherently prone to bias and we are, naturally, not able to indicate response rates or advising this specific switch. 1 The findings are from open-label treatment, which is inherently prone to bias and we are, naturally, not able to indicate response rates or advising this specific switch.…”

“…1 The clinical trials investigating the different antibodies found little clinical differences regarding efficacy and safety between them, 2 and hence different modes of action of the different antibody classes are not widely discussed. Their pharmacological mode of action is under extensive investigation, and mainly peripheral sites of action are thought to be relevant.…”

A potent fluorescent calcitonin gene‐related peptide analogue enables visualization of receptor internalization

“…This family also includes calcitonin (CT), adrenomedullin (AM), adrenomedullin 2 (AM2), and amylin. CGRP is a vasodilator, plays an important role in neurogenic inflammation, and thus has gained considerable interest for the treatment of migraine . Three antibodies against either CGRP or a CGRP receptor (erenumab, fremanezumab, and galcanezumab) have recently been approved for the treatment of migraine .…”

No Gastrointestinal Dysmotility in Transgenic Mouse Models of Migraine

“…Oral salicylate administered during migraine attacks resulted in lower serum drug levels, compared to administration either between attacks 15 or during attacks pretreated with prokinetic agents (eg, metoclopramide), though this study was limited by failure to use subjects as their own controls. 24 In some 25,26 but not all 27 human studies, CGRP is elevated in jugular venous blood. [17][18][19] Slower rates of gastric emptying have also been correlated with greater headache severity in migraine.…”