CGRP as a new target in prevention and treatment of migraine

Abstract

Calcitonin-gene-related peptide (CGRP), which is released during migraine attacks, has been identified as a possible target for the treatment of migraine. 1 Goadsby PJ Evidence of the involvement of CGRP in migraine and cluster headache: a physiological perspective. in: Poyner D Marshall I Brain S The CGRP family: calcitonin gene-related peptide (CGRP), amylin, and adrenomedullin. Landes Bioscience, Georgetown, Texas2000: 159-165 Google Scholar CGRP is located in sensory nerve endings in cranial blood vessels and is a potent dilator of cerebral arteries. 2 Asghar MS Hansen AE Kapijimpanga T et al. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2014; 75: 1520-1526 Crossref Scopus (105) Google Scholar Its receptors are also found in many brain areas, including the central trigeminal system. 3 Edvinsson L Warfvinge K CGRP receptor antagonism and migraine therapy. Curr Protein Pept Sci. 2013; 14: 386-392 Crossref PubMed Scopus (18) Google Scholar Therefore, CGRP antagonists were developed for the treatment of acute migraine attacks (panel), and they were suggested as a possible treatment for patients with contraindications for triptans, such as those with angina or after myocardial infarction or stroke. However, CGRP antagonists are no longer being developed for the treatment of acute migraine attacks, probably because of the hepatic signal after their long-term use. 10 Ho TW Connor KM Zhang Y et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014; 83: 958-966 Crossref PubMed Scopus (185) Google Scholar CGRP receptor antagonists •Olcegepant: a CGRP antagonist that was effective for acute migraine in a proof-of- concept study 4 Olesen J Diener HC Husstedt IW et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004; 350: 1104-1110 Crossref PubMed Scopus (1018) Google Scholar but, because of poor oral absorption, could only be administered intravenously and was not developed further. •BI 44370 TA: an oral CGRP receptor antagonist that showed, in a placebo-controlled, phase 2b dose-finding study, dose-dependent efficacy in the treatment of acute migraine attacks. 5 Diener HC Barbanti P Dahlof C Reuter U Habeck J Podhorna J BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2010; 31: 573-584 Crossref PubMed Scopus (182) Google Scholar The development of the drug was terminated for unknown reasons. •Telcagepant: a CGRP receptor antagonist was effective in the treatment of acute migraine attacks; 3 Edvinsson L Warfvinge K CGRP receptor antagonism and migraine therapy. Curr Protein Pept Sci. 2013; 14: 386-392 Crossref PubMed Scopus (18) Google Scholar however, in a long-term study in which telcagepant was used daily for 3 months for migraine prevention, some patients showed marked increases of liver enzymes, and the drug development programme was terminated. •MK-3207: The oral CGRP receptor antagonist MK-3207 was assessed for acute treatment of migraine in a multicentre, double-blind, randomised, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimum dose selection. 6 Hewitt DJ Aurora SK Dodick DW et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011; 31: 712-722 Crossref PubMed Scopus (216) Google Scholar We can only speculate that the development was terminated when the liver toxicity of telcagepant became known. •BMS-927711: a potent, selective, competitive oral CGRP receptor antagonist without vasoconstrictor effects. 7 Marcus R Goadsby PJ Dodick D Stock D Manos G Fischer TZ BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014; 34: 114-125 Crossref PubMed Scopus (190) Google Scholar In a randomised, double-blind, placebo-controlled, dose-ranging study, 7 Marcus R Goadsby PJ Dodick D Stock D Manos G Fischer TZ BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014; 34: 114-125 Crossref PubMed Scopus (190) Google Scholar 885 patients were randomly assigned using an adaptive design to six doses of BMS-927711, sumatriptan 100 mg, or placebo. Significantly more patients in the BMS-927711 75 mg, 150 mg, and 300 mg groups and the sumatriptan group were pain free at 2 h after dose versus placebo. 7 Marcus R Goadsby PJ Dodick D Stock D Manos G Fischer TZ BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014; 34: 114-125 Crossref PubMed Scopus (190) Google Scholar Development has halted, but no information as to why has been provided. Antibodies •LY2951742: an anti-CGRP antibody given intravenously; showed preliminary evidence of efficacy in a phase 2 study. 8 Dodick DW Goadsby PJ Spierings EL Scherer JC Sweeney SP Grayzel DS Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014; 13: 885-892 Summary Full Text Full Text PDF PubMed Scopus (291) Google Scholar •ALD403: an anti-CGRP antibody given intravenously; showed preliminary evidence of efficacy in a phase 2 study. 9 Dodick DW Goadsby PJ Silberstein SD et al. for the ALD403 study investigatorsSafety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014; (published online Oct 6.)http://dx.doi.org/10.1016/S1474-4422(14)70209-1 Google Scholar •AMG 334: an anti-CGRP antibody given subcutaneously in an ascending multiple-doses study in healthy participants and patients with migraine (NCT01723514). •LBR-101: an anti-CGRP antibody given subcutaneously in a multicentre randomised, placeb controlled study in patients with high frequency episodic migraine (NCT02025556). CGRP=calcitonin-gene-related peptide. CGRP receptor antagonists •Olcegepant: a CGRP antagonist that was effective for acute migraine in a proof-of- concept study 4 Olesen J Diener HC Husstedt IW et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004; 350: 1104-1110 Crossref PubMed Scopus (1018) Google Scholar but, because of poor oral absorption, could only be administered intravenously and was not developed further. •BI 44370 TA: an oral CGRP receptor antagonist that showed, in a placebo-controlled, phase 2b dose-finding study, dose-dependent efficacy in the treatment of acute migraine attacks. 5 Diener HC Barbanti P Dahlof C Reuter U Habeck J Podhorna J BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2010; 31: 573-584 Crossref PubMed Scopus (182) Google Scholar The development of the drug was terminated for unknown reasons. •Telcagepant: a CGRP receptor antagonist was effective in the treatment of acute migraine attacks; 3 Edvinsson L Warfvinge K CGRP receptor antagonism and migraine therapy. Curr Protein Pept Sci. 2013; 14: 386-392 Crossref PubMed Scopus (18) Google Scholar however, in a long-term study in which telcagepant was used daily for 3 months for migraine prevention, some patients showed marked increases of liver enzymes, and the drug development programme was terminated. •MK-3207: The oral CGRP receptor antagonist MK-3207 was assessed for acute treatment of migraine in a multicentre, double-blind, randomised, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimum dose selection. 6 Hewitt DJ Aurora SK Dodick DW et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011; 31: 712-722 Crossref PubMed Scopus (216) Google Scholar We can only speculate that the development was terminated when the liver toxicity of telcagepant became known. •BMS-927711: a potent, selective, competitive oral CGRP receptor antagonist without vasoconstrictor effects. 7 Marcus R Goadsby PJ Dodick D Stock D Manos G Fischer TZ BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014; 34: 114-125 Crossref PubMed Scopus (190) Google Scholar In a randomised, double-blind, placebo-controlled, dose-ranging study, 7 Marcus R Goadsby PJ Dodick D Stock D Manos G Fischer TZ BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014; 34: 114-125 Crossref PubMed Scopus (190) Google Scholar 885 patients were randomly assigned using an adaptive design to six doses of BMS-927711, sumatriptan 100 mg, or placebo. Significantly more patients in the BMS-927711 75 mg, 150 mg, and 300 mg groups and the sumatriptan group were pain free at 2 h after dose versus placebo. 7 Marcus R Goadsby PJ Dodick D Stock D Manos G Fischer TZ BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014; 34: 114-125 Crossref PubMed Scopus (190) Google Scholar Development has halted, but no information as to why has been provided. Antibodies •LY2951742: an anti-CGRP antibody given intravenously; showed preliminary evidence of efficacy in a phase 2 study. 8 Dodick DW Goadsby PJ Spierings EL Scherer JC Sweeney SP Grayzel DS Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014; 13: 885-892 Summary Full Text Full Text PDF PubMed Scopus (291) Google Scholar •ALD403: an anti-CGRP antibody given intravenously; showed preliminary evidence of efficacy in a phase 2 study. 9 Dodick DW Goadsby PJ Silberstein SD et al. for the ALD403 study investigatorsSafety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014; (published online Oct 6.)http://dx.doi.org/10.1016/S1474-4422(14)70209-1 Google Scholar •AMG 334: an anti-CGRP antibody given subcutaneously in an ascending multiple-doses study in healthy participants and patients with migraine (NCT01723514). •LBR-101: an anti-CGRP antibody given subcutaneously in a multicentre randomised, placeb controlled study in patients with high frequency episodic migraine (NCT02025556). CGRP=calcitonin-gene-related peptide. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trialNo safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days. Full-Text PDF