Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine

Bussiere, Jeanine L.; Davies, Rhian; Dean, Charles R.; Xu, Cen; Kim, Kyung Hoon; Vargas, Hugo M.; Chellman, Gary J.; Balasubramanian, Ganesh; Rubio‐Beltrán, Eloísa; MaassenVanDenBrink, Antoinette; Monticello, Thomas M.

doi:10.1016/j.yrtph.2019.05.013

Cited by 36 publications

(33 citation statements)

References 87 publications

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“…However, there was no observed AE signal related to cardiovascular events. Although these clinical trials excluded patients with existing cardiovascular disease, the findings are consistent with dedicated preclinical and clinical studies that collectively showed no evidence for negative vascular effects in the setting of CGRP receptor antagonism with erenumab (21–25). A detailed evaluation of the cardiovascular safety profile of erenumab (related to data pooled from these studies) is the subject of a separate analysis (26).…”

Section: Discussionsupporting

confidence: 76%

Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions

et al. 2019

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Background Efficacy and safety of erenumab have been evaluated in a comprehensive clinical development program resulting in approval for migraine prevention in over 40 countries to date. Methods This integrated safety analysis included four double-blind randomized trials and their extensions (up to three-plus years). Safety endpoints included exposure-adjusted patient incidences of adverse events, serious adverse events, and anti-erenumab antibodies. Results In all, 2375 of the patients randomized across the four studies received at least one dose of erenumab (70 mg or 140 mg), with cumulative exposure of 2641.2 patient-years. Exposure-adjusted adverse event rates during the double-blind treatment phase were similar to placebo, with the exception of injection-site reactions (17.1 vs. 10.8 per 100 patient-years), constipation (7.0 vs. 3.8 per 100 patient-years), and muscle spasm (2.3 vs. 1.2 per 100 patient-years). During the long-term extensions, adverse events reported were similar to those observed during the double-blind treatment phase, and rates of injection site reactions, constipation, and muscle spasm were reported at lower rates than in the double-blind treatment phase. There were two deaths reported, both confounded by pre-existing conditions. Conclusions This pooled safety analysis revealed a favorable and stable adverse event profile over time for erenumab with more than three years of exposure. Trial registration ClinicalTrials.gov NCT01952574, NCT02483585, NCT02456740, NCT02066415, and NCT02174861.

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Section: Discussionsupporting

confidence: 76%

Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions

et al. 2019

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“…Finally, the current considerations in the development of anti-CGRP antibodies are identity, expression pattern, and function of CGRP receptors, which affect the safety and efficacy of these antibodies. Although CGRP is capable of activating multiple receptors, it binds with high affinity to two receptors, the CGRP receptor and Amylin-1 (AMY1) receptor, which are considered more physiological relevance than other receptors and play a central role in the molecular pathophysiology of the trigeminovascular system 38 , 39 . The function of anti-CGRP antibodies may exhibit different profiles in blocking the cross-talk between the peptides and their receptors 40 .…”

Section: Discussionmentioning

confidence: 99%

“…The function of anti-CGRP antibodies may exhibit different profiles in blocking the cross-talk between the peptides and their receptors 40 . For instance, erenumab does not block the AMY1 receptor but only the CGRP receptor 38 . Therefore, further studies are warranted to investigate the therapeutic differences in these anti-CGRP antibodies targeting various CGRP-relevant receptors.…”

Section: Discussionmentioning

confidence: 99%

Optimal treatment strategy of fremanezumab in migraine prevention: a systematic review with network meta-analysis of randomized clinical trials

Huang

Lee

et al. 2020

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Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.

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“…As antibodies are considered to have a BBB permeability of <0.1% (18) and erenumab has been shown to be effective for the prophylactic treatment of migraine (19,20), it is considered that the mechanisms of action of erenumab are peripheral, with one of them being possibly inhibition of the CGRP-mediated vasodilation of the dural arteries (1). While erenumab has no vasoconstrictive properties per se (21), its success as prophylactic treatment may well be (partly) by effectively preventing the vasodilatory responses to CGRP in the HMMA, associated with the onset of migraine attacks. In accordance with this, human provocation studies have shown dilation of the HMMA on the headache side at migraine onset, and headache relief after vasoconstriction of the HMMA by sumatriptan (1,22).…”

Section: Discussionmentioning

confidence: 99%

Characterisation of vasodilatory responses in the presence of the CGRP receptor antibody erenumab in human isolated arteries

et al. 2019

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Background Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine. Methods We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 μM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab. Results Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab. Conclusion Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.

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Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine

Cited by 36 publications

References 87 publications

Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions

Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions

Optimal treatment strategy of fremanezumab in migraine prevention: a systematic review with network meta-analysis of randomized clinical trials

Characterisation of vasodilatory responses in the presence of the CGRP receptor antibody erenumab in human isolated arteries

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