Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP

Bigal, Marcelo E.; Walter, Sarah; Bronson, Michele; Alibhoy, Abbas; Escandón, Rafael

doi:10.1177/0333102414527646

Cited by 56 publications

(43 citation statements)

References 36 publications

(49 reference statements)

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“…In patients with migraine, no cardiovascular adverse events were observed in five, relatively small and short-lasting, Phase II clinical trials with four different antibodies directed against CGRP or its receptor [16,17,[38][39][40]. The issue of cardiovascular safety was specifically addressed in two small studies, one in 31 healthy women [41] and another in 56 cynomolgus monkeys [42]. Although no cardiovascular events were noted, these studies were evidently too small and did not address the real issue, namely: what happens in (cardiovascularly compromised) subjects in whom the CGRP system is blocked and who were accidentally struck by mild cardiac or cerebral ischemia?…”

mentioning

confidence: 99%

Wiping Out CGRP: Potential Cardiovascular Risks

MaassenVanDenBrink

Meijer

Villalón³

et al. 2016

Trends in Pharmacological Sciences

199

161

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mentioning

confidence: 99%

Wiping Out CGRP: Potential Cardiovascular Risks

MaassenVanDenBrink

Meijer

Villalón³

et al. 2016

Trends in Pharmacological Sciences

199

161

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“…Thus, antagonizing its effects raises concerns with possible cardiovascular risks such as medication-induced hypertension and inhibition of cardio-protective mechanisms during ischemia [96]. Two independent studies in monkeys found no electrocardiogram or hemodynamic changes from long-term inhibition of CGRP with LBR-101 [97,98]. The drug was well tolerated and, thus far, no relevant cardiovascular effects have been reported [10].…”

Section: Cgrp Monoclonal Antibodies (Mabs)mentioning

confidence: 99%

Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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Migraine is a highly prevalent headache disease that typically affects patients during their most productive years. Despite significant progress in understanding the underlying pathophysiology of this disorder, its treatment so far continues to depend on drugs that, in their majority, were not specifically designed for this purpose. The neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack. It is not surprising that drugs designed to specifically block its action are gaining remarkable attention from researchers in the field with, at least so far, a safe risk profile. In this article, we highlight the evolution from older traditional treatments to the innovative CGRP target drugs that are revolutionizing the way to approach this debilitating neurological disease. We provide a brief introduction on pathophysiology of migraine and details on the characteristic, function, and localization of CGRP to then focus on CGRP receptor antagonists (CGRP-RAs) and CGRP monoclonal antibodies (CGRP mAbs). Key PointsThe neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack.Targeting CGRP as a specific therapeutic tool for migraine may offer similar or even better efficacy than currently available treatments without the vasoconstrictive risk factors.Further studies are necessary to determine the exact role of CGRP receptor antagonists and CGRP monoclonal antibodies in migraine with aura, allodynia, and photophobia.

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“…As already reported, however, preclinical studies in monkeys and rats demonstrate that anti-CGRP mAbs, administered in a way to determine a long-term inhibition of CGRP, do not cause significant electrocardiogram or hemodynamic changes [12,85,87,93] and their administration in humans-both healthy subjects and patients-at wide ranges of dosage does not produce relevant cardiovascular side effects or laboratory abnormalities [86]. No other off-target impairment, such as the liver toxicity observed with GCRP antagonists, has so far been recorded.…”

Section: Critical Considerations and Conclusionmentioning

confidence: 59%

“…The excellent safety profile of LBR-101 was also confirmed by a subsequent double-blind, placebo-controlled study by the same authors [87]. Cardiovascular and hemodynamic parameters (blood pressure, heart rate, and ECGs) were evaluated in 31 healthy women of over 40 years of age-thus a population at increased risk of cardiovascular events-who were administered LBR-101 at doses up to 2000 mg.…”

Section: Ald403 (Table 2)mentioning

confidence: 80%

Anti-CGRP monoclonal antibodies in migraine: current perspectives

et al. 2016

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Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration. Monoclonal antibodies against CGRP (LY2951742, ALD-403, and LBR-101/TEV-48125) or its receptor (AMG334) were subsequently developed. As reviewed in this study, numerous phase 1 and 2 trials and preliminary results of phase 3 trials have shown a good safety/tolerability profile and efficacy in migraine prevention, especially in high frequent episodic and chronic forms. Being macromolecules, these mAbs are not suitable for oral administration; however, their intravenous or subcutaneous delivery can be performed at relatively low frequency-every month or even quarterly-which enhances patients' compliance. Although not all migraineurs respond to this treatment, and longer administration periods will be needed to assess long-term effects, the results so far obtained are extraordinarily promising. The future introduction of mAbs on the market will probably represent a turning point for prevention similar to that represented by triptans for abortive treatment in migraine.

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Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP

Abstract: Sustained CGRP inhibition was not associated with hemodynamic or ECG changes in a population at an increased age risk for cardiovascular events.

Cited by 56 publications

References 36 publications

Wiping Out CGRP: Potential Cardiovascular Risks

Wiping Out CGRP: Potential Cardiovascular Risks

Targeting CGRP: A New Era for Migraine Treatment

Anti-CGRP monoclonal antibodies in migraine: current perspectives

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