CGRP – a target for acute therapy in migraine: Clinical data

Abstract

Background A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine. Findings Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint. Gepants also improved migraine associated symptoms, such as nausea, photophobia and phonophobia. Two of the class have had their development stopped because of hepatotoxicity, which is emerging as being due to metabolites. Gepants have a good tolerability and can be safely used in patients with stable cardiovascular disease. Conclusion Exciting results have been obtained targeting the calcitonin gene-related peptide pathway to abort acute migraine attacks, thus reinforcing the relevance of mechanism-based treatments specific for migraine.

NO up-regulates migraine-related CGRP via activation of an Akt/GSK-3β/NF-κB signaling cascade in trigeminal ganglion neurons

“…There are at least three this kind of neuropeptides that have been identified so far, including substance P (SP), calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Although these neuropeptides share a common property of powerful vasodilation as well as all have been found within the trigeminal afferents innervating the meninges, CGRP is the only one that has been proven as a therapeutic target for the treatment of migraine to date [2,9,10]. In this context, the CGRP-targeted therapies, including monoclonal antibodies against CGRP receptor (e.g., Erenumab/AMG 334, Galcanezumab/LY2951742, Fremanezumab/TEV-48125, and Eptinezumab/ALD403), have been either approved or investigated in ongoing phase III clinical trials for the prevention and acute treatment of migraine [11,12].…”

Migraine treatment: the doors for the future are open, but with caution and prudence

“…Monoclonal antibodies represent an interesting way to treat migraine. Because of their peculiar characteristics of restricted tissue penetrance, very long half-life and highly selective affinity for the CGRP or its receptor, they have become the center of the upcoming arsenal against the suffering imposed by migraine, although CGRP nerve endings are extraluminal in most tissues, which may impair and limit their efficacy 4,5 . Erenumab was recently approved for the preventive treatment of migraine.…”

“…Different molecules can indeed antagonize CGRP or its receptor. Over the last few decades, potential agents for the acute treatment of migraine acting on the CGRP receptor have been studied 4,5,7,8 . Although true efficacy was demonstrated with several antagonists, toxicity, especially hepatotoxicity, has impeded their approval, and resulted in the interruption of the release of upcoming medications such as telcagepant 8,9 .…”

Pharmacotherapy of the most frequent headaches in adults

“…Čitava nova klasa lekova, antagonista receptora za peptid sličan kalcitoninu (CGRP), sa zbirnim nazivom gepanti je u III fazi kliničkih ispitivanja. Ovi lekovi nemaju vazokonstriktorni efekat, a za sada je pokazano da su efikasniji od placeba, kao i da nisu manje efikasni u poređenju sa triptanima (8). Selektivni agonista serotoninskih 1F (5-HT 1F ) receptora -lasmiditan je slične efikasnosti kao triptani i takođe bez vazokonstriktornih potencijala.…”