Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide

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

doi:10.4161/mabs.29242

Cited by 39 publications

(25 citation statements)

References 36 publications

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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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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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“…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: 86%

“…These show that the long-term inhibition of CGRP by the LBR-101 does not affect cardiovascular and hemodynamic parameters, and the compound is well tolerated, a result of high importance in view of the clinical applicability [85].…”

Section: Ald403 (Table 2)mentioning

confidence: 97%

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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“…It has been studied in rats and cynomolgus monkeys and has been very well tolerated, up to 14 weeks of follow-up. No cardiovascular side effects in the monkey model were noted, and the drug could be given subcutaneously or intravenously [74]. Phase I trials have studied the pharmacokinetics and have looked at doses between 10 and 2000 mg administered as intravenous infusions.…”

Section: Lbr-101mentioning

confidence: 98%

CGRP Mechanism Antagonists and Migraine Management

Karsan

Goadsby

2015

Curr Neurol Neurosci Rep

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Migraine is a complex disorder of the brain that is common and highly disabling. As understanding of the neural pathways has advanced, and it has become clear that the vascular hypothesis does not explain the disorder, new therapeutic avenues have arisen. One such target is calcitonin gene-related peptide (CGRP)-based mechanisms. CGRP is found within the trigeminovascular nociceptive system widely from the trigeminal ganglion to second-order and third-order neurons and in regulatory areas in the brainstem. Studies have shown CGRP is released during severe migraine attacks and the reversal of the attack with effective triptan treatment normalizes those levels. CGRP administration triggers migraine in patients, and CGRP receptor antagonists have been shown to abort migraine. Here, we review the current state of CGRP mechanism antagonist therapy as its research and development is increasing in migraine therapeutics. We discuss several recent trials, highlighting the evidence base behind these novel drugs, and their potential future contribution to migraine management.

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Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide

Cited by 39 publications

References 36 publications

Targeting CGRP: A New Era for Migraine Treatment

Targeting CGRP: A New Era for Migraine Treatment

Anti-CGRP monoclonal antibodies in migraine: current perspectives

CGRP Mechanism Antagonists and Migraine Management

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