CGRP-Receptor Antagonism in Migraine Treatment

Abstract Background: The pathophysiology of migraine has been researched incessantly, and it has been suggested that calcitonin gene-related peptide (CGRP) is associated with migraine attacks. CGRP receptor blockers are attracting attention for migraine prevention and treatment of acute episodes, and CGRP receptor antagonists have been shown to be effective in treating acute migraine headaches. This meta-analysis aimed to assess the effect of available CGRP receptor antagonists, focusing on their therapeutic doses for acute migraine treatment.Methods: We performed a systematic search of MEDLINE (from inception to March 2021) and EMBASE (from inception to March 2021) for English publications using the keywords “migraine” and “Calcitonin gene-related peptide,” limited to human studies.Results: Five studies that focused on examining the effects of CGRP receptor antagonists on acute migraine treatment met the eligibility criteria for this meta-analysis. The pooled analysis demonstrated that the CGRP receptor antagonist improved freedom from pain (OR=2.066, 95% confidence interval [CI] 1.766–2.418, I2=0%), absence of bothersome symptoms (OR=1.606, 95% CI=1.408–1.830, I2=0%), pain relief (OR=1.791, 95% CI=1.598–2.008, I2=0%), and freedom from nausea (OR=1.361, 95% CI=1.196–1.548, I2=0%), significantly more than the placebo. Conclusions: CGRP receptor antagonists are effective for acute migraine treatment and are expected to be used clinically as emerging therapeutic agents.

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Peptide Antagonist of CGRP Receptor for Migraine Treatment

Synfacts ◽

10.1055/s-0040-1705917 ◽

2020 ◽

Vol 16 (10) ◽

pp. 1223

Keyword(s):

Migraine Treatment ◽

Cgrp Receptor ◽

Peptide Antagonist

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Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment

Neuropharmacology ◽

10.1016/s0028-3908(02)00008-4 ◽

2002 ◽

Vol 42 (4) ◽

pp. 568-576 ◽

Cited By ~ 65

Author(s):

M.J Moreno ◽

R Abounader ◽

E Hébert ◽

H Doods ◽

E Hamel

Keyword(s):

Receptor Antagonist ◽

Cerebral Arteries ◽

Migraine Treatment ◽

Acute Migraine ◽

Cgrp Receptor ◽

Cgrp Receptor Antagonist ◽

Acute Migraine Treatment

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No additive effect of combining sumatriptan and olcegepant in the GTN mouse model of migraine

Cephalalgia ◽

10.1177/0333102420963857 ◽

2020 ◽

pp. 033310242096385

Author(s):

Charlotte Ernstsen ◽

Sarah L Christensen ◽

Jes Olesen ◽

David M Kristensen

Keyword(s):

Mouse Model ◽

Glyceryl Trinitrate ◽

Additive Effect ◽

Migraine Treatment ◽

High Dose ◽

Cgrp Receptor ◽

Single Drug ◽

Cgrp Receptor Antagonists ◽

Combination Study ◽

Higher Doses

Introduction Despite recent advances in migraine treatment there is a need for therapies with higher clinical efficacy and/or fewer side effects. Triptans (5-HT1B/1D/1F agonists) are essential in the present treatment regime and gepants (CGRP-receptor antagonists) are recognized as effective in acute migraine treatment. Triptans and gepants have different mechanisms of action and here we tested the hypothesis that a combination of these drugs (sumatriptan and olcegepant) would result in an additive effect. Methods Using the validated glyceryl trinitrate mouse model of migraine, we initially tested dose-response relationships of sumatriptan (0.1, 0.3, and 0.6 mg/kg IP) and olcegepant (0.25, 0.50, and 1.0 mg/kg IP) to find suitable high and low doses. Subsequently, we performed a combination study of the two drugs with a low and a high dose. All experiments were vehicle (placebo) controlled and blinded. Results Sumatriptan significantly reduced glyceryl trinitrate-induced allodynia (F(4,54) = 13.51, p < 0.0001) at all doses. Olcegepant also reduced glyceryl trinitrate-induced allodynia (F(4,53) = 16.11, p < 0.0001) with the two higher doses being significantly effective. Combining 0.50 mg/kg olcegepant with 0.1 or 0.6 mg/kg sumatriptan did not have any improved effect compared to either drug alone ( p > 0.50 on all days) in our mouse model. Conclusion Combining olcegepant and sumatriptan did not have an additive effect compared to single-drug treatment in this study. Triptan-gepant combinations will therefore most likely not improve migraine treatment. Nevertheless, further studies are necessary, and combinations should also be examined in patients with migraine.

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CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment

British Journal of Clinical Pharmacology ◽

10.1111/bcp.12618 ◽

2015 ◽

Vol 80 (2) ◽

pp. 193-199 ◽

Cited By ~ 98

Author(s):

Lars Edvinsson

Keyword(s):

Migraine Treatment ◽

Cgrp Receptor ◽

Receptor Antagonists ◽

Cgrp Receptor Antagonists

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Migraine therapeutics differentially modulate the CGRP pathway

Cephalalgia ◽

10.1177/0333102420983282 ◽

2021 ◽

Vol 41 (5) ◽

pp. 499-514

Author(s):

Minoti Bhakta ◽

Trang Vuong ◽

Tetsuya Taura ◽

David S Wilson ◽

Jennifer R Stratton ◽

...

Keyword(s):

Small Molecule ◽

Therapeutic Agents ◽

Camp Signaling ◽

Migraine Treatment ◽

Cgrp Receptor ◽

Calcitonin Gene ◽

Migraine Pathogenesis ◽

Cgrp Receptor Antagonists ◽

Receptor Family

Background The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature. Methods To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays. Results Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses. Conclusion The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.

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