Peptide Antagonist of CGRP Receptor for 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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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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Results of migraine treatment depending on its menstrual association

Medical Council ◽

10.21518/2079-701x-2021-12-426-432 ◽

2021 ◽

pp. 426-432

Author(s):

E. A. Kiryanova ◽

N. A. Kovalchuk ◽

G. R. Tabeeva

Keyword(s):

Hormonal Therapy ◽

Medication Overuse ◽

Medication Overuse Headache ◽

Preventive Therapy ◽

Menstrual Migraine ◽

Migraine Treatment ◽

Cgrp Receptor ◽

Treatment Results ◽

Group 2 ◽

Group 1

Introduction. Menstrual migraine attacks are considered more intense, prolonged, and resistant to treatment than non-menstrual ones. Currently, effect of preventive therapy on the course of menstrual-associated migraine has not been well studied; there are isolated studies on the beneficial effect of hormonal therapy on these attacks.The aim of the study was to compare the treatment results in the groups of menstrual-associated and non-menstrual migraine.Materials and methods. This comparative study included 91 patients aged 18 to 48 years (mean age 33,82 ± 8.4) with migraine and menstrual cycle. Depending on the menstrual association of migraine attacks, the patients were divided into 2 groups: group 1 – 54 patients (mean age 36.07 ± 7.37 years) with menstrual-associated migraine (MAM); group 2 – 37 patients (mean age 30.46 ± 8.81 years) with non-menstrual migraine (NMM).Results. Patients with MAM had more migraine days per month, more often received therapy associated with medication-overuse headache (MOH), more often had experience with triptans in comparison with NMM patients. After the treatment, the number of days with migraine per month in the MAM group remained more than in the NMM group: 8 or more days per month were noted in 36.4%, while among NMM patients – 10.8%. The transition to the new therapy with monoclonal antibodies to the CGRP receptor / ligand was positively assessed by 42.9% of MAM patients and 8.1% of NMM patients. Increased duration of hormonal therapy was characterized by a decrease in the number of days with migraines per month (cor = -0,28).Conclusion. In the MAM group, more severe diseases and frequent formation of MOH are observed, as well as a higher resistance to therapy than in NMM. In general, the use of standard therapy regimens for MAM is less effective than for NMM.

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Central effects of erenumab in migraine patients

Neurology ◽

10.1212/wnl.0000000000010740 ◽

2020 ◽

Vol 95 (20) ◽

pp. e2794-e2802 ◽

Cited By ~ 1

Author(s):

Christian Ziegeler ◽

Jan Mehnert ◽

Katharina Asmussen ◽

Arne May

Keyword(s):

Middle Temporal Gyrus ◽

Migraine Treatment ◽

Cgrp Receptor ◽

Central Effects ◽

Lingual Gyrus ◽

Fmri Study ◽

Calcitonin Gene ◽

Central Mode ◽

The Right ◽

Hypothalamic Activation

ObjectiveTo determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab.MethodsWe conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg.ResultsComparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only (t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53–40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor.InterpretationThese findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed.

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