Effects of monoclonal antagonist antibodies on calcitonin gene-related peptide receptor function and trafficking

Manoukian, Raffi; Sun, Hong; Miller, Silke; Shi, Dai; Chan, Brian; Xu, Cen

doi:10.1186/s10194-019-0992-1

Cited by 25 publications

(26 citation statements)

References 41 publications

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“…For example, membrane-bound CGRP receptors are known to internalize into endosomes after CGRP agonist stimulation. 8 , 9 Mechanistic studies in cellular and animal behavior assays have shown that these internalized CGRP receptors can continue to actively drive CGRP-mediated pain signals. 10 Given that the truncated peptide antagonist CGRP (8–37), conjugated to cholesterol for endosome-specific targeting, can suppress CGRP-mediated endosomal signaling and inhibit both cellular signals and animal pain responses, 10 it is possible that a differential ability for small molecules vs mAbs to enter cells and engage endosomal CGRP receptors may be a factor.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, neither receptor-targeted nor ligand-targeted CGRP mAbs are localized with internalized CGRP receptors in the presence of CGRP. 9 This may present a situation during migraine attacks (when CGRP levels are most elevated 11 ) in which the 2 agents have differential access to an endosome-bound CGRP-mediated pain signaling pathway and rimegepant might provide additional benefits to ongoing mAb therapy.…”

Section: Discussionmentioning

confidence: 99%

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Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy

et al. 2020

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ObjectiveTo provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine.MethodsCase reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol.ResultsPatients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events.ConclusionsRimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study.ClinicalTrials.gov identifierNCT03266588.Classification of evidenceThis study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy

et al. 2020

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“…However, the downstream molecular mechanisms following ligand-receptor blockade have not been clearly demonstrated. It's indicated that inactivating CGRP by anti-CGRP antibodies or blocking CGRP access to trigeminal neurons by anti-CGRP receptor antibodies, can interrupt CGRP-induced cAMP accumulation and inhibits CGRP receptor internalization [37].CGRP-related drugs have numerous advantages over existing conventional therapies, as they are designed specifically to act on the trigeminal pain system, along with more specific mechanisms of action and fewer adverse effects. CGRP receptor antagonists, such as ubrogepant and so on, are effective in relieving acute migraine headache, but the underlying liver toxicity restricts their long-term usage [38,39].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – an updated systematic review and meta-analysis

Deng

Nie

et al. 2020

BMC Neurol

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Background: Migraine is one of the most common neurological disorders that leads to disabilities. However, the conventional drug therapy for migraine might be unsatisfactory at times. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibody (CGRP mAb) for the preventive treatment of episodic migraine, and provide high-quality clinical evidence for migraine therapy. Methods: A systematic electronic database search was conducted to identify the potentially relevant studies. Two independent authors performed data extraction and quality appraisal. Mean difference (MD) and risk ratio (RR) were pooled for continuous and dichotomous data, respectively. The significance levels, weighted effect sizes and homogeneity of variance were calculated. Results: Eleven high-quality randomized control trials that collectively included 4402 patients were included in this meta-analysis. Compared to placebo group, CGRP mAb therapy resulted in a reduction of monthly migraine days [weighted mean difference (WMD) = − 1.44, 95% CI = (− 1.68,− 1.19)] and acute migraine-specific medication days [WMD = − 1.28, 95% CI = (− 1.66,− 0.90)], with an improvement in 50% responder rate [RR = 1.51, 95% CI = (1.37,1.66)]. In addition, the adverse events (AEs) and treatment withdrawal rates due to AEs were not significantly different between CGRP mAb and placebo groups. Similar efficacy and safety results were obtained for erenumab, fremanezumab, and galcanezumab in subgroup analysis. Conclusions: The current body of evidence reveals that CGRP mAb is an effective and safe preventive treatment for episodic migraine.

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“…However, the downstream molecular mechanisms following ligand-receptor blockade have not been clearly demonstrated. It's indicated that inactivating CGRP by anti-CGRP antibodies or blocking CGRP access to trigeminal neurons by anti-CGRP receptor antibodies, can interrupt CGRPinduced cAMP accumulation and inhibits CGRP receptor internalization [37] .CGRP-related drugs have numerous advantages over existing conventional therapies, as they are designed specifically to act on the trigeminal pain system, along with more specific mechanisms of action and fewer adverse effects. CGRP receptor antagonists, such as ubrogepant and so on, are effective in relieving acute migraine headache, but the underlying liver toxicity restricts their long-term usage [38,39] .…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – An updated systematic review and meta-analysis

Deng

Nie

et al. 2019

Preprint

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Background: Migraine is one of the most common neurological disorders that leads to disabilities. However, the conventional drug therapy for migraine is unsatisfactory. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibody (CGRP mAb) for the preventive treatment of episodic migraine, and provide high-quality clinical evidence for migraine therapy. Methods: A systematic electronic database search was conducted to identify the potentially relevant studies. Two independent authors performed data extraction and quality appraisal. Mean difference (MD) and risk ratio (RR) were pooled for continuous and dichotomous data, respectively. The significance levels, weighted effect sizes and homogeneity of variance were calculated. Results: Eleven high-quality randomized control trials that collectively included 4402 patients were included in this meta-analysis. Compared to placebo group, CGRP mAb therapy resulted in a reduction of monthly migraine days [weighted mean difference (WMD) = −1.44, 95% CI = (−1.68,−1.19)] and acute migraine-specific medication days [WMD = −1.28, 95% CI = (−1.66,−0.90)], with an improvement in 50% responder rate [RR = 1.51, 95% CI =(1.37,1.66)]. In addition, the adverse events (AEs) and treatment withdrawal rates due to AEs were not significantly different between CGRP mAb and placebo groups. Similar efficacy and safety results were obtained for erenumab, fremanezumab, and galcanezumab in subgroup analysis. Conclusions: The current body of evidence reveals that CGRP mAb is an effective and safe preventive treatment for episodic migraine. Keywords: calcitonin gene-related peptide monoclonal antibody, episodic migraine, efficacy, safety, meta-analysis

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Effects of monoclonal antagonist antibodies on calcitonin gene-related peptide receptor function and trafficking

Cited by 25 publications

References 41 publications

Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy

Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – an updated systematic review and meta-analysis

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – An updated systematic review and meta-analysis

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