Calcitonin gene-related peptide-targeting drugs for migraine: how pharmacology might inform treatment decisions

Al-Hassany, Linda; Goadsby, PJ; Danser, A.H. Jan; MaassenVanDenBrink, Antoinette

doi:10.1016/s1474-4422(21)00409-9

Cited by 75 publications

(77 citation statements)

References 89 publications

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“…Considerations to support the switch from one CGRP-mAb to another, include differences in the mechanism of action (action on the ligand or on the receptor), difference in administration schedule (monthly versus quarterly) and to a lesser extent difference in formulations (subcutaneous versus intravenous) Eptinezumab is the only CGRP mAb available in an intravenous formulation. From a pharmacological perspective, eptinezumab only requires hours (theoretically even only minutes, given its intravenous administration) to reach its maximum serum concentrations, which is as fast as the gepants, but considerably faster than the other antibodies, which require up to 1 week to reach their maximum levels [ 61 ]. So far, there are no RCTs which addressed whether switching between different CGRP-mAbs may offer benefits to non-responder individuals with migraine.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, CGRP has an important role in the regulation of uteroplacental circulation; its levels are increased during physiological pregnancy and decreased in pre-eclampsia [ 67 ]. Concerns in the use of those drugs in women of childbearing potential are related also to the long (around 1 month) half-life of the CGRP-mAbs that implies that these drugs can only be considered as eliminated from the circulation 6 months after stopping [ 61 ]. Information about the potential risk related to an unplanned pregnancy are to be discussed with female individuals with migraine of childbearing potential.…”

Section: Resultsmentioning

confidence: 99%

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European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

et al. 2022

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Background A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments. Methods The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. Results We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives. Conclusion Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

et al. 2022

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“…The clinical experience with these 4 next-generation CGRP signal-blocking drugs has been largely in line with DILIsym predictions for these compounds. Rimegepant, ubrogepant, and atogepant have all demonstrated clinical efficacy and safety ( Al-Hassany et al , 2022 ) and have since been approved by the FDA for the treatment of migraine (acute for ubrogepant, preventive for atogepant, and dual-therapy acute and preventive for rimegepant). Meanwhile, clinical trial results for zavegepant which continues to advance in clinical trials for the acute (nasal) and preventive (oral) treatment of migraine without a liver safety signal ( Al-Hassany et al , 2022 ; Goadsby et al , 2020 ; Moreno-Ajona et al , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Two of the first-generation small molecules in the CGRP receptor antagonist class, telcagepant and MK-3207, failed during late-stage clinical trials due to liver injury ( Hewitt et al , 2011 ; Ho et al , 2016 ). Several next-generation drugs have been developed since the failure of telcagepant and MK-3207; 3 compounds, rimegepant (Nurtec ODT), ubrogepant (Ubrelvy), and atogepant (Qulipta), have been approved by the FDA for the treatment of migraine ( Al-Hassany et al , 2022 ).…”

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confidence: 99%

Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling

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Howell

et al. 2022

Toxicological Sciences

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Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, while four next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant’s failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all five compounds and thus to compare the four next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically-based pharmacokinetic (PBPK) models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the four next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the four compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and non-hepatotoxic molecules within the same class.

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“…Therapeutic strategies to damper CGRP signaling include monoclonal antibodies directed against CGRP (fremanezumab, galcanezumab, eptinezumab), or the CGRP receptor (erenumab), and gepants which are small molecule antagonists of the CGRP receptor (rimegepant, ubrogepant, atogepant) [ 2 , 9 ]. CGRP-targeting drugs are considered to be effective and generally safe but there are still uncertainties [ 2 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Calcitonin gene-related peptide-targeting drugs and Raynaud’s phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database

et al. 2022

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Background Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud’s phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud’s phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®). Methods We queried all reports of Raynaud’s phenomenon involving a CGRP-targeting drug. We sought disproportionate reporting of Raynaud’s phenomenon with these drugs. For this purpose, we relied on the calculation of the Information Component (IC). A positive lower end of the 95% confidence interval (CI) of the IC defines a statistically significant association. As migraine patients are prone to Raynaud’s phenomenon, we also calculated the IC of Raynaud’s phenomenon with CGRP-targeting drugs compared to 5HT1B/D agonists (triptans), and beta-blockers used in the treatment of migraine. Results Overall, 99 reports of Raynaud’s phenomenon involving CGRP-targeting drugs have been yielded in VigiBase®. The most reported CGRP-targeting drug was erenumab, with 56 reports (56.6%). The median time to onset was 84 days. No fatality was notified, but one patient suffered from gangrene and extremity necrosis. As a whole, CGRP-targeting drugs were significantly associated with Raynaud’s phenomenon, with an IC of 3.3 (95%CI: 3.0–3.5). There was a disproportionate reporting of Raynaud’s phenomenon with CGRP-targeting drugs compared to triptans (IC 0.4; 95%CI: 0.1–0.6) and to beta-blockers (IC 0.5; 95%CI: 0.2–0.7) as well. Conclusions There is a significant disproportionality signal of Raynaud’s phenomenon with CGRP-targeting. This signal stands out when CGRP-targeting drugs are compared to other drugs used in patients with migraine. This study is limited by missing data in pharmacovigilance reports. CGRP-targeting drugs may be subject to Weber effect and reporting bias. Nonetheless, CGRP blockade might be the last straw that disrupts the physiological balance of vascular response in patients at-risk of Raynaud’s phenomenon. Pending further data regarding vascular safety of CGRP-targeting drugs, caution is warranted in these patients.

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Calcitonin gene-related peptide-targeting drugs for migraine: how pharmacology might inform treatment decisions

Cited by 75 publications

References 89 publications

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling

Calcitonin gene-related peptide-targeting drugs and Raynaud’s phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database

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