Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial

Sun, Hong; Dodick, David W.; Silberstein, Stephen D.; Goadsby, PJ; Reuter, Uwe; Ashina, Messoud; Saper, Joel R.; Cady, Roger; Chon, Yun; Dietrich, Julie; Lenz, Robert

doi:10.1016/s1474-4422(16)00019-3

Cited by 334 publications

(370 citation statements)

References 36 publications

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“…Thus far, the results from the Phase II clinical trials evaluating the efficacy and tolerability of antibodies directed against CGRP or the CGRP receptor are promising [16,17,[38][39][40]. This is potentially good news for patients with migraine or (possibly) cluster headache because specifically designed, effective, and well-tolerated prophylactic agents against these diseases are currently not available.…”

Section: Discussionmentioning

confidence: 99%

“…However, these studies were performed in normal, anesthetized animals without pre-existing or induced ischemia. 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].…”

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confidence: 99%

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Wiping Out CGRP: Potential Cardiovascular Risks

MaassenVanDenBrink

Meijer

Villalón³

et al. 2016

Trends in Pharmacological Sciences

199

161

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Section: Discussionmentioning

confidence: 99%

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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“…It is likely that CGRP does not directly activate trigeminal dural afferents but potentiates the release of nociceptive agents into the perivascular space [31; 46]. Clinical investigations have now demonstrated that small molecule CGRP receptor antagonists (e.g., AMG334 [68]) are also efficacious against migraine [38; 55]; however, development of this therapeutic class remains uncertain due to safety issues. The precise site of action of small molecule CGRP antagonists remains to be confirmed but studies using PET imaging in humans showed poor penetration of telcagepant to the brain at therapeutically effective doses [39].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of (S)-lacosamide in preclinical models of cephalic pain

Moutal

Eyde

Telemi

et al. 2016

PR9

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Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have suboptimal efficacy, and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective, but small molecule antagonists have not been advanced because of toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel “druggable” target for inhibiting CGRP release and for potential relevance for treatment of migraine pain. Collapsin response mediator protein 2 has been demonstrated to regulate N-type voltage-gated Ca2+ channel activity and Ca2+-dependent CGRP release in sensory neurons. The coexpression of CRMP2 with N-type voltage-gated Ca2+ channel and CGRP in trigeminal ganglia (TGs) sensory neurons suggested the possibility of a novel approach to regulate CGRP release in the trigeminal system. Screening protocols surprisingly revealed that (S)-lacosamide ((S)-LCM), an inactive analog of the clinically approved small molecule antiepileptic drug (R)-lacosamide (Vimpat), inhibited CRMP2 phosphorylation by cyclin-dependent kinase 5 in rat TG slices and decreased depolarization-evoked Ca2+ influx in TG cells in culture. (S)-LCM significantly blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat in ex vivo cranial cup preparation. Additionally, cephalic and extracephalic cutaneous allodynia induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators, was inhibited by oral administration of (S)-LCM. The confirmation of CRMP2 as an upstream mediator of CGRP release, together with the brain penetrance of this molecule suggests (S)-LCM as a potential therapy for acute migraine.

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“…LBR101/TEV-48125 (Labys Biologics, Pfizer, USATeva Pharmaceuticals, USA) has been proven to be efficient in migraine prevention [76] and an ongoing phase III clinical trial will be completed by October 2017 [74]. AMG 334 (Amgen, USA-Novartis) is the only mAb that targets the CGRP receptors [77]. A phase III trial was started in 2015 and will end in March 2017 [74].…”

Section: Calcitonin Gene-related Peptide (Cgrp)mentioning

confidence: 99%

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

Lukács

Tajti

Fülöp

et al. 2017

CMC

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Abstract:Background: Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms. Objective: To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation. Method: A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published in January 2017. Results: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant result compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC 1 ), and kynurenic acid (KYNA) analogues. Conclusion: Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis.

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Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 334 publications

References 36 publications

Wiping Out CGRP: Potential Cardiovascular Risks

Wiping Out CGRP: Potential Cardiovascular Risks

Efficacy of (S)-lacosamide in preclinical models of cephalic pain

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

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