Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial

Dodick, David W.; Goadsby, Peter J.; Silberstein, Stephen D.; Lipton, Richard B.; Olesen, Jes; Ashina, Messoud; Wilks, Kerri; Kudrow, David; Kroll, Robin; Kohrman, Bruce; Bargar, Robert R.; Hirman, Joe; Smith, Jeff

doi:10.1016/s1474-4422(14)70209-1

Cited by 347 publications

(319 citation statements)

References 28 publications

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“…ALD403 has a rapid onset of action, and 26 % of patients had no migraines in the first month following a single intravenous dose of 1000 mg, which also provided lasting efficacy to 6 months [92]. Most adverse events, including upper respiratory and urinary tract infection, fatigue, back pain, nausea/vomiting, and arthralgia were transient and deemed to be unrelated to study drug [93].…”

Section: Cgrp Monoclonal Antibodies (Mabs)mentioning

confidence: 99%

“…Controversy exists about whether CGRP-RAs penetrate the BBB and whether that would be relevant to their mode of action [75,93]. Measures of CGRP-RA cerebrospinal fluid (CSF) levels in rhesus monkeys demonstrate that these molecules can penetrate the brain even in small quantities.…”

Section: Blood-brain Barriermentioning

confidence: 99%

“…Antibodies consist of larger size molecules that are even less likely to cross the BBB. Recent positive clinical trials with two CGRP mAbs, LY2951742 and ALD403, indicate that efficacy can be achieved via actions at the periphery alone [91,93]. Thus, modulation of CGRP and migraine management may happen outside of the CNS, with the meninges and trigeminal ganglion described as potential sites of action [105].…”

Section: Blood-brain Barriermentioning

confidence: 99%

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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%

Section: Blood-brain Barriermentioning

confidence: 99%

Section: Blood-brain Barriermentioning

confidence: 99%

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Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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“…5,9 Some other drugs are under investigation and the CGRP receptor antagonists (the gepant family drugs), were discontinued although other drugs in this category are still under investigation. [10][11][12][13][14][15][16] However, there are some medically intractable headaches or unsatisfactory patient management or medications are poorly tolerated, therefore, additional treatment options might be helpful.…”

mentioning

confidence: 99%

Neuromodulation and Non-Pharmacological Treatment of Migraine

Samsam¹

2016

Neuro Open J

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“…35 Although these drugs are still in clinical trials, LY2951742 and ALD-403 have both shown to decrease the mean migraine days per month from baseline compared to placebo group. 36,37 The LY2951742 is a humanized mAb against CGRP with a half-life of 28 days and was given subcutaneously (150 mg once every 2 weeks for 12 weeks) to migraine patients. Migraine days decreased from 4-14 days per month.…”

mentioning

confidence: 99%

Targeting Calcitonin Gene-Related Peptide and its Receptor by Monoclonal Antibody, New Developments in the Prevention of Migraine

Samsam

2015

Neuro Open J.

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CitationMigraine is a chronic headache disorder with an unknown pathophysiology. Research in the past decade has shown that to be a brain disorder, a dismodulation of sensory processing affecting vascular tone and pain 1-3 but since the exact pathomechanism of migraine is not very well known, its treatment is also difficult. Current drugs recommended by the "European Federation of Neurological Societies (EFNS)" used in the treatment of migraine include the triptan family drugs that are serotonin (5-HT 1B/D ) receptor agonists, and the Non-Steroid Anti-Inflammatory Drugs (NSAIDs). 4 Several other drugs such as anti-epileptic drugs, beta-blockers, and calcium channel blockers are also recommended in the treatment of migraine. 4 Although glutamic acid is one of the main neurotransmitters in the sensory system, various neuropeptides have been implicated in pain but among them, Calcitonin Gene Related Peptide (CGRP) is the only one neuropeptide that was found elevated in the blood of migraine patients 5-7 and CGRP administration induces migraine-like attack in migraine patients. 8 Therefore, several studies in the last decade focused on drugs to block the CGRP receptor 9-11 or the effect of CGRP itself by antibodies against it 10-12 although, it is not clear if the site of action of these drugs is peripheral or central. 13 Nevertheless, triptan family drugs are currently some of the best and most potent compounds in the treatment of migraine, 4,14 but not all patients respond to them and search for other drugs that lack vasoconstrictive activity has continued. The discovery of CGRP-receptor antagonist drugs, 15 the so called "gepant family drugs" such as telcegepant and olcegepant, and BI 44370 TA were the main events in migraine research in the last decade. [16][17][18][19][20][21] Unfortunately, these drugs were discontinued due to their side effects such as hepatotoxicity although they were able to treat migraine effectively. Nevertheless, some newer drugs in this category including MK-3207, 22,23 BMS-846372 24,25 and MK-1602 26 are still under investigation, see 10 for a brief review. Nevertheless, research in the treatment of migraine did not stop here and search for other drugs being able to block CGRP or its receptor continued.CGRP receptor is a hetero-oligomeric complex that has a peculiar structure and consists of a component, called the "Calcitonin receptor-like receptor (CLR)" which is a transmembrane Gs protein-coupled receptor, and an accessory protein component known as the "Receptor Activity-Modifying Protein 1 (RAMP1)" for the transport of CLR to the plasma membrane, and another component known as "Receptor Component Protein (RCP)" that is important for signaling pathway by determining the G-protein to which the receptor should be coupled with. 10,27,28 In recent years, monoclonal Antibodies (mAbs) against CGRP or its receptor have been developed and are the newest anti-migraine drugs in clinical trials.

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Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial

Cited by 347 publications

References 28 publications

Targeting CGRP: A New Era for Migraine Treatment

Targeting CGRP: A New Era for Migraine Treatment

Neuromodulation and Non-Pharmacological Treatment of Migraine

Targeting Calcitonin Gene-Related Peptide and its Receptor by Monoclonal Antibody, New Developments in the Prevention of Migraine

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