CGRP – a target for acute therapy in migraine: Clinical data

Abstract

Background

A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine.

Findings

Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint. Gepants also improved migraine associated symptoms, such as nausea, photophobia and phonophobia. Two of the class have had their development stopped because of hepatotoxicity, which is emerging as being due to metabolites. Gepants have a good tolerability and can be safely used in patients with stable cardiovascular disease.

Conclusion

Exciting results have been obtained targeting the calcitonin gene-related peptide pathway to abort acute migraine attacks, thus reinforcing the relevance of mechanism-based treatments specific for migraine.

Keywords

Calcitonin gene-related peptide gepants migraine acute treatment

Introduction

It is now clear that migraine is not simply a disease of recurrent pain attacks, but a more complex and multifaceted brain disorder that comprises four different phases: Premonitory (prodrome), aura, headache and postdrome phases (1). Over the last decades, our understanding of migraine pathophysiology has shifted from the classic “vascular theory” to the “neural theory” (2,3). There is ample evidence that in predisposed migraine patients the activation of different cortical, subcortical and brainstem regions and the subsequent release of key neuropeptides can contribute to the onset of the disease (4). A better understanding of the mechanisms underlying the migraine attack has paved the way for the development of migraine-specific treatments. Although triptans are currently the best available acute antimigraine medicines (5,6), there are many promising, novel therapeutic targets that have been explored during the last years. This article will focus the attention on the calcitonin-gene related peptide (CGRP), highlighting the evidence behind its involvement in migraine pathophysiology and the potential future role of CGRP-targeted drugs as acute migraine treatments.

The role of CGRP in the migraine attack

The discovery that CGRP, a 37 amino acid neuropeptide with a potent cerebrovascular dilatator activity (8), is widely expressed in central and peripheral nervous system regions involved in nociception (9 –11), has promoted interest in its involvement in primary headaches. To exert its function, CGRP binds a seven transmembrane G-protein coupled receptor, the calcitonin-like receptor (CLR), and a single transmembrane protein, the receptor activity-modifying protein 1 (RAMP1). CGRP can also activate the amylin receptor 1, which is formed by the calcitonin receptor (CT) and RAMP1 (12).

It was shown some time ago that activation of the trigeminovascular system in humans and experimental animals resulted in stimulus-locked increases in CGRP in the cranial circulation (13 –15). Shortly afterwards, it was demonstrated (16) that CGRP, and not substance P, was elevated in the cranial circulation of migraineurs during acute migraine attacks, thus suggesting its involvement in migraine pathophysiology. Sumatriptan was shown to normalize cranial CGRP levels in migraine patients with treatment of the acute attack (17). Subsequent studies showed that the administration of CGRP to migraine patients with and without aura can trigger a migraine attack phenotypically similar to their usual ones (18,19). Furthermore, it has been shown that effective antimigraine treatments, like triptans, can normalize salivary CGRP levels and this normalization was associated with the resolution of the migraine headache (20).

CGRP’s role in migraine pathogenesis has been further supported by the demonstration that brain regions with a key role in migraine generation, including the trigeminocervical complex, brainstem, thalamus and hypothalamus, can express CGRP and its receptors (21 –25). Moreover, there is ample evidence that beyond its vascular role, CGRP also has a neuronal modulatory activity. Recent experimental studies revealed that CGRP can modulate the transmission of pain information at the level of the spinal cord (26), brainstem (27,28), thalamus (29) and trigeminal system (22), contributing in this way to central sensitization (30), and hence, perhaps, to allodynia and hyperalgesia that are often experienced by migraine patients. The activation of CGRP receptors seems also to be involved in the development of light hypersensitivity (31), which is one of the main symptoms that, along with the pain, defines a migraine attack.

Is targeting the CGRP pathway a valuable strategy to treat the acute migraine attack?

Based on the background outlined supporting a key role of CGRP in migraine, new antimigraine drugs targeting the CGRP receptor have been developed. The gepants, small molecule CGRP receptor antagonists with a molecular weight ranging from 534 to 869 g/mol, have been widely investigated as acute antimigraine drugs over the last two decades (32,33). Pain freedom at 2 hours, along with no headache recurrence within 24 hours and no adverse events (AEs), are the main endpoints that define the effectiveness of acute migraine treatments (34,35). Triptans, serotonin 5-HT_1B/1D receptor agonists (36), which are currently the most effective acute antimigraine therapy that is available, have a response rate at 2 hours of around 30–40%, but a third of those patients who respond might experience headache recurrence within 24 hours (37). A major issue related to the intake of triptans is their contraindication in patients with significant cerebral and cardiovascular disease (38).

Randomized double-blind placebo-controlled trials (RCTs) have shown that CGRP receptor antagonists are superior to placebo in reducing the pain intensity of the acute migraine attack, as are triptans, but with a better tolerability and a safer profile (33). Moreover, encouraging indications of reduced headache recurrence were seen, and certainly patients’ functional disability was reduced (33)

A summary of the main RCTs that assessed the efficacy and tolerability of the gepants is reported in Table 1.

Table 1.

A summary of the main findings demonstrating CGRP receptor antagonists’ clinical efficacy and tolerability.

Drug name	Molecular weight (g/mol)	Dose* (mg)	Route of administration	Outcomes						Side effects
Drug name	Molecular weight (g/mol)	Dose* (mg)	Route of administration	Pain freedom rate at 2 hours (%)			Sustained response rate over 24 hours (%)			Most frequent adverse events (rate, %)	Clinical trial phase	Reference
Verum	Placebo	Triptan	Verum	Placebo	Triptans	Verum
Olcegepant (BIBN 4096BS)	869	2.5	Intravenous	14/32 (44)	1/41 (2)	–	15/32 (47)	6/41 (15)	–	Paresthesia (25)	Phase II	(42)
Telcagepant (MK-0974)	566	300	Oral	17/38 (45)	16/115 (14)	11/34 (33)^‡	15/38 (40)	13/115 (11)	6/34 (18)	Dry mouth (4–10) Dizziness (5–9) Somnolence (4–9) Nausea (4–9)	Phase II	(46,47,51)
				95/353 (27)	33/343 (10)	107/342 2(31)§	71/351 1(20)	17/343 (5)	62/341 (18)	Fatigue (0–5)	Phase III
MK-3207	557	200	Oral	21/58 (36)	13/133 (10)	–	17/58 (30)	10/133 (8)	–	Dizziness (3) Nausea (3)	Phase II	(55)
										Fatigue (3)
BI44370TA	634	400	Oral	20/73 (27)	6/70 (9)	24/69 (35)^¶	15/73 (21)	5/70 (7)	15/69 (22)	Influenza (3) Fatigue (1)	Phase II	(57)
										Diarrhoea (1)
Rimegepant (BMS-927711)	534	150	Oral	28/85 (33)	31/203 (15)	35/100 (35)^†	24/85 (28)	15/203 (7)	26/100 (26)	Nausea (3) Dizziness (2)	Phase II	(58)
Ubrogepant (MK-1602)	549	100	Oral	26/102 (25)	10/112 (9)	–	22/102 2(22)	7/113 (6)	–	Nausea (7) Dizziness (6)	Phase II	(59)
										Dry mouth (5)
										Somnolence (4)
										Fatigue (3)
		100	Oral	94/448 (21)	55/456 (12)	–	n/a	n/a	n/a	n/a	Phase III	NCT02828020
		50		80/423 (19)

Reported are those doses that achieved the greatest therapeutic effect or the selected dose for the adaptive design.

‡

rizatriptan; §zolmitriptan; ^¶eletriptan; ^†sumatriptan

Olcegepant (BIBN4096BS)

Olcegepant was the first selective nonpeptide CGRP receptor antagonist developed with the purpose of treating the acute migraine attack. Experimental and preclinical studies in animals and humans demonstrated that olcegepant could potently reverse CGRP-mediated cerebrovascular dilation and headache (40,41). A phase II, proof of concept, double-blind, RCT performed in 126 migraine patients showed superiority of intravenous olcegepant (0.25–10 mg) over placebo in treating the acute migraine attack (overall response rate: 60% olcegepant group vs. 27% placebo group, p < 0.001) (42). Promising results were obtained also in relation to the 2-hour pain free response rate, sustained response over a period of 24 hours and improvement in associated symptoms such as nausea, photophobia and phonophobia. Comparing intravenous sumatriptan 2 mg given over 10 minutes, the pain free rate was 71% (43) without a placebo control, while for olcegepant the pain free rate at 30 minutes was 17% on 10 mg intravenous, although only two patients contributed data due to the adaptive dose design (42). When compared to subcutaneous sumatriptan 6 mg, the pain free therapeutic gain at 30 minutes was 35% (44). There is no subcutaneous formulation of a gepant, so that comparisons with triptans are probably best made using the oral formulations.

The overall rate of AEs was 20% in the group of patients treated with CGRP antagonist, and mild paresthesia was the most frequent event that was reported (42).

Despite its efficacy and good tolerability (45), olcegepant was not developed because of formulation issues.

Telcagepant (MK-0974)

An initial phase II, dose-defining, RCT demonstrated that telcagepant, a highly potent and selective oral CGRP receptor antagonist, was well tolerated and more effective than placebo in the 2-hour pain relief response (46). Later large phase III RCTs confirmed a higher superiority of telcagepant over placebo in the 2-hour and sustained pain freedom, as well as in reducing patients’ functional disability (47,48). Moreover, it has been demonstrated that telcagepant 300 mg was as effective as rizatriptan 10 mg (2 hours pain-freedom rate: 45.2% telcagepant 300 mg, 33.4% rizatriptan 10 mg, 14.3% placebo) (46), as well as zolmitriptan 5 mg (2 hours pain-freedom rate: 26.9% telcagepant 300 mg, 31.3% zolmitriptan 5 mg, 9.6% placebo) (47), and its therapeutic advantage remained constant over different migraine attacks (49). Taking all the data together, the mean therapeutic gain for the 2-hour pain freedom for the RCTs of telcagepant 300 mg was lower than seen with triptans (50), consistent with other transmitters being important in some patients.

A further long-term phase III study revealed promising results in terms of safety (51). In a group of 1068 migraine patients, 19.820 attacks were treated with telcagepant 300 mg and 10.981 with rizatriptan 10 mg over 18 months. Compared to the triptan group, the group of patients taking telcagepant experienced fewer drug-related AEs (difference: −15.6%, 95% CI: −22.2, −9.0), and the most common were dry mouth, nausea, dizziness and somnolence. In addition, conversely to triptans, telcagepant has been demonstrated to be safe in migraine patients with concomitant stable coronary disease (52).

Although the intermittent administration of telcagepant did not reveal liver toxicity, an RCT where patients received telcagepant twice daily for up to three months as preventive was terminated early due to elevated symptomatic transaminase levels (53). Similar abnormalities were seen in a later short-term trial assessing the efficacy of daily telcagepant in menstrually-related migraine (54). Despite its apparent safety when used intermittently, these findings raised concerns about telcagepant’s safety when daily administrated, and led to discontinuation of its development.

MK-3207

Hewitt and colleague (55) reported on MK-3207, an orally bioavailable, potent CGRP receptor antagonist (56). It had a dose-response trend for all the primary and secondary efficacy endpoints, with a greater benefit over placebo obtained with the 200 mg dose, thus suggesting that better results might be obtained with a further increase of the MK-3207 dose. However, similarly to telcagepant, MK-3207 development was stopped due to concerns regarding hepatotoxicity.

BI44370TA

A phase II, proof-of-concept, RCT of BI44370TA has shown that, compared to the placebo group, a higher number of patients who treated their migraine attack with oral BI44370TA 400 mg were pain free after 2 hours (27.4% patients for BI44370TA 400 mg vs. 8.6% for placebo, p < 0.005). The effect was comparable to that obtained after eletriptan 40 mg was administrated (34.8% patients) (57). BI44370TA was well tolerated, with no treatment-related serious AEs reported. One patient had increased liver enzymes 5 days after the BI44370TA administration, and given the patient’s medical history was positive for alcohol consumption and cholecystitis, no firm causative conclusion could be drawn. BI44370TA is currently not being developed.

Rimegepant (BMS-927711)

A phase II trial has shown that increasing doses of oral rimegepant (75 mg, 150 mg, and 300 mg) were superior to placebo with respect to several efficacy endpoints (58). The pain-free rates at 2 hours for rimegepant ranged from 29.7% to 32.9% with a 15.3% placebo rate (p < 0.002). The efficacy of rimegepant was comparable to sumatriptan 100 mg (sumatriptan 100 mg pain-free rate at 2 hours was 35%), although this study was also dose-adaptive, so any comparison with parallel group studies is limited. Rimegepant was well tolerated with no treatment-related serious AEs. It is currently in phase III (NCT03235479).

Ubrogepant (MK-1602)

With the hope of reducing the hepatoxicity associated with telcagepant and MK-3207, a novel, chemically distinct, oral CGRP receptor antagonist was developed. Results from a phase II trial have demonstrated that ubrogepant 100 mg was significantly superior to placebo for the 2-hour pain freedom primary endpoint (25.5% ubrogepant 100 mg vs. 8.9% placebo, p = 0.003), with no related serious AEs and, especially, no liver toxicity (59). The most frequent side effects reported by patients treated with the CGRP receptor antagonist were dizziness and nausea, even though these events were generally mild and self-limited. Two phase III, double-blind, placebo-controlled studies (NCT02828020 and NCT02867709) have been completed recently and a phase III, open-label, long-term safety trial (NCT02873221) is ongoing in order to confirm the potentiality of ubrogepant in the acute treatment of migraine and evaluate its long-term safety and tolerability.

Gepants overall

The sites of action of gepants are still a matter of debate. At first, a direct antagonist effect in cranial arteries was proposed (60,61). However, numerous pre-clinical studies have shown that gepants modulate nociceptive trigeminovascular transmission acting at the level of different central sites, such as the brainstem (22), thalamus (29), hypothalamus (62) and cerebellum (63). A recent positron emission tomography (PET) study (64) using a blood-brain barrier penetrant tracer ([^11C]MK-4232) that selectively binds to CGRP receptors demonstrated that a high dose of telcagepant replaced the tracer in the central nervous system. However, when a clinically relevant dose of the CGRP receptor antagonist was administrated, the tracer uptake in the brain did not decrease, thus suggesting a low central availability of the gepant. Compared to in vitro results, very high doses of CGRP receptor antagonists are necessary in clinic to achieve an anti-migraine effect in vivo, possibly due to a low penetration of the blood-brain barrier and high protein binding (65). This evidence has led to an ongoing discussion regarding a central versus a peripheral mechanism of action of CGRP receptor antagonists.

Concerns about a limited efficacy of CGRP receptor antagonists compared to triptans have been raised (50,66,67). There are two issues. First, this is not a question of potency, since pain free in a triptan study is identical to pain free in a gepant study for any individual who is rendered pain free. Rather, it is an issue of population potential for a response, which seems, in the round, about 5% less for gepants. Whether this is true from attack to attack in individuals is unclear. It is certainly consistent with other transmitters, such as pituitary adenylate cyclase activating polypeptide (PACAP), being important in some patients (68,69) and with the general notions of the complexity of migraine pathobiology. Secondly, the gepants represent a valid alternative to use in those patients with cardiovascular pathologies and in whom triptans are contraindicated (70). The value proposition in clinical practice is simple; the pathophysiological implications remain complex. Even though CGRP is one of the most potent endogenous vasodilators and has a protective effect during coronary and cerebral ischemia (71), many studies have demonstrated that CGRP receptor antagonists do not have a direct vasoconstrictor activity (72,73) and are well tolerated in patients with stable cardiovascular diseases (70,74). This may relate to the cardioprotective effects of other related vasodilator peptides, such as adrenomedullin (75), whose mechanisms are not targeted and protective effects not impaired by gepants. Seeing gepants in isolation from other cardioprotective mechanisms is at best jejune.

Although only minimal AEs have been reported after using CGRP receptor antagonists intermittently, the severe events resulting from the chronic intake of telcagepant (53) have raised concerns regarding gepants’ frequent use and their long-term safety.

Based on the promising results achieved by previous phase II and phase III studies, novel anti-CGRP receptor compounds have been recently developed and investigated. New derivatives of telcagepant, MK-2918, have been explored (76) and an intranasal anti-CGRP receptor antagonist has been developed (BMS742413) (77). Future RCTs are needed in order to assess their efficacy and tolerability.

Conclusion

We are currently living an era when new mechanism-based acute and preventive treatments specific for migraine have been developed. The promising results obtained using the gepants, CGRP receptor antagonists, to abort the acute migraine attack strengthen the relevance of such therapeutic strategy. Remarkably, all the studied gepants have been shown to be effective and well tolerated, thus suggesting that they might represent a reasonable alternative to triptans, especially in those patients who are non-responders, experience headache recurrence, or in whom triptans are contraindicated or not tolerated. In the future, large comparative RCTs in patients who are triptans-naïve, triptan non-responders or responders are warranted. Additionally, further long-term studies are needed in order to confirm the cardiovascular safety of gepants and evaluate whether their recurrent use might be associated with medication overuse problems.

Clinical implications

CGRP receptors are currently the most promising target to abort the acute migraine attack.

Gepants, CGRP receptor antagonists, are significantly superior over placebo in pain freedom at 2 hours, sustained response over 24 hours and in improving migraine associated symptoms.

Gepants are well tolerated and can be safely used in patients with stable cardiovascular diseases.

The exciting results obtained targeting the CGRP pathway reinforce the relevance of mechanism-based treatments specific for migraine.

Footnotes

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Roberta Messina has nothing to disclose. Peter J Goadsby reports grants and personal fees from Allergan, Amgen, and Eli-Lilly and Company; and personal fees from Akita Biomedical, Alder Biopharmaceuticals, Cipla Ltd, Dr Reddy’s Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer Inc, Quest Diagnostics, Scion, Teva Pharmaceuticals, Trigemina Inc., Scion; and personal fees from MedicoLegal work, Journal Watch, Up-to-Date, Massachusetts Medical Society, Oxford University Press; in addition, Dr. Goadsby has a patent magnetic stimulation for headache assigned to eNeura.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Goadsby

Holland

Martins-Oliveira

et al.

Pathophysiology of migraine: A disorder of sensory processing. Physiol Rev 2017; 97: 553–622.

Edvinsson

Goadsby

. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 2010; 6: 573–582.

Charles

. Migraine: A brain state. Curr Opin Neurol 2013; 26: 235–239.

Akerman

Holland

Goadsby

. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 2011; 12: 570–584.

Ferrari

Goadsby

Roon

et al.

Triptans (serotonin, 5-HT1B/1D agonists) in migraine: Detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–658.

Goadsby

Sprenger

. Current practice and future directions in the prevention and acute management of migraine. Lancet Neurol 2010; 9: 285–298.

Brain

Williams

Tippins

et al.

Calcitonin gene-related peptide is a potent vasodilator. Nature 1985; 313: 54–56.

Edvinsson

Fredholm

Hamel

et al.

Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat. Neurosci Lett 1985; 58: 213–217.

Tajti

Uddman

Moller

et al.

Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 1999; 76: 176–183.

10.

Uddman

Edvinsson

Ekblad

et al.

Calcitonin gene-related peptide (CGRP): Perivascular distribution and vasodilatory effects. Regul Pept 1986; 15: 1–23.

11.

Emeson

Hedjran

Yeakley

et al.

Alternative production of calcitonin and CGRP mRNA is regulated at the calcitonin-specific splice acceptor. Nature 1989; 341: 76–80.

12.

Edvinsson

. The trigeminovascular pathway: Role of CGRP and CGRP receptors in migraine. Headache 2017; 57: 47–55.

13.

Goadsby

Edvinsson

Ekman

. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23: 193–196.

14.

Uddman

Edvinsson

Ekman

et al.

Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: Trigeminal origin and co-existence with substance P. Neurosci Lett 1985; 62: 131–136.

15.

Edvinsson

. The journey to establish CGRP as a migraine target: A retrospective view. Headache 2015; 55: 1249–1255.

16.

Goadsby

Edvinsson

Ekman

. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183–187.

17.

Goadsby

Edvinsson

. The trigeminovascular system and migraine: Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48–56.

18.

Lassen

Haderslev

Jacobsen

et al.

CGRP may play a causative role in migraine. Cephalalgia 2002; 22: 54–61.

19.

Hansen

Hauge

Olesen

et al.

Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010; 30: 1179–1186.

20.

Cady

Vause

et al.

Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache 2009; 49: 1258–1266.

21.

Bhatt

Gupta

Ploug

et al.

mRNA distribution of CGRP and its receptor components in the trigeminovascular system and other pain related structures in rat brain, and effect of intracerebroventricular administration of CGRP on Fos expression in the TNC. Neurosci Lett 2014; 559: 99–104.

22.

Storer

Akerman

Goadsby

. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 2004; 142: 1171–1181.

23.

Bower

Eftekhari

Waldvogel

et al.

Mapping the calcitonin receptor in human brain stem. Am J Physiol Regul Integr Comp Physiol 2016; 310: R788–R793.

24.

Edvinsson

Cantera

Jansen-Olesen

et al.

Expression of calcitonin gene-related peptide1 receptor mRNA in human trigeminal ganglia and cerebral arteries. Neurosci Lett 1997; 229: 209–211.

25.

Warfvinge K and Edvinsson L. Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia. 2019; 39: 342–353.

26.

Lundeberg

. Role of calcitonin gene-related peptide and its antagonist on the evoked discharge frequency of wide dynamic range neurons in the dorsal horn of the spinal cord in rats. Regul Pept 2002; 103: 23–27.

27.

Pozo-Rosich

Storer

Charbit

et al.

Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia 2015; 35: 1298–1307.

28.

Asghar

Becerra

Larsson

et al.

Calcitonin gene-related peptide modulates heat nociception in the human brain – an fMRI study in healthy volunteers. PLoS One 2016; 11: e0150334–e0150334.

29.

Summ

Charbit

Andreou

et al.

Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 2010; 133: 2540–2548.

30.

Marquez de Prado

Hammond

Russo

. Genetic enhancement of calcitonin gene-related peptide-induced central sensitization to mechanical stimuli in mice. J Pain 2009; 10: 992–1000.

31.

Russo

Kuburas

Kaiser

et al.

A potential preclinical migraine model: CGRP-sensitized mice. Mol Cell Pharmacol 2009; 1: 264–270.

32.

Hoffmann

Goadsby

. New agents for acute treatment of migraine: CGRP receptor antagonists, iNOS inhibitors. Curr Treat Options Neurol 2012; 14: 50–59.

33.

Goadsby

. Bench to bedside advances in the 21st century for primary headache disorders: Migraine treatments for migraine patients. Brain 2016; 139: 2571–2577.

34.

Dodick

Sandrini

Williams

. Use of the sustained pain-free plus no adverse events endpoint in clinical trials of triptans in acute migraine. CNS Drugs 2007; 21: 73–82.

35.

Tfelt-Hansen

Pascual

Ramadan

et al.

Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia 2012; 32: 6–38.

36.

Goadsby

. The pharmacology of headache. Prog Neurobiol 2000; 62: 509–525.

37.

Ferrari

Roon

Lipton

et al.

Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001; 358: 1668–1675.

38.

Dodick

Lipton

Martin

et al.

Consensus statement: Cardiovascular safety profile of triptans (5-HT agonists) in the acute treatment of migraine. Headache 2004; 44: 414–425.

39.

Russell

King

Smillie

et al.

Calcitonin gene-related peptide: Physiology and pathophysiology. Physiol Rev 2014; 94: 1099–1142.

40.

Moreno

Abounader

Hebert

et al.

Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: Potential implications in acute migraine treatment. Neuropharmacology 2002; 42: 568–576.

41.

Petersen

Lassen

Birk

et al.

BIBN4096BS antagonizes human alpha-calcitonin gene related peptide-induced headache and extracerebral artery dilatation. Clin Pharmacol Ther 2005; 77: 202–213.

42.

Olesen

Diener

Husstedt

et al.

Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004; 350: 1104–1110.

43.

Doenicke

Brand

Perrin

. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet 1988; 1: 1309–1311.

44.

Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med 1991; 325: 316–321.

45.

Iovino

Feifel

Yong

et al.

Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the first selective small molecule calcitonin gene-related peptide receptor antagonist, following single intravenous administration in healthy volunteers. Cephalalgia 2004; 24: 645–656.

46.

Mannix

Fan

et al.

Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 2008; 70: 1304–1312.

47.

Ferrari

Dodick

et al.

Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: A randomised, placebo-controlled, parallel-treatment trial. Lancet 2008; 372: 2115–2123.

48.

Connor

Shapiro

Diener

et al.

Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 2009; 73: 970–977.

49.

Dahlof

Silberstein

et al.

Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia 2010; 30: 1443–1457.

50.

Pascual

. Efficacy of BMS-927711 and other gepants vs triptans: There seem to be other players besides CGRP. Cephalalgia 2014; 34: 1028–1029.

51.

Connor

Aurora

Loeys

Ashina

Jones

Giezek

et al.

Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache 2011; 51: 73–84.

52.

Chaitman

et al.

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache 2012; 52: 224–235.

53.

Connor

Zhang

et al.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 2014; 83: 958–966.

54.

et al.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. Cephalalgia 2016; 36: 148–161.

55.

Hewitt

Aurora

Dodick

et al.

Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia 2011; 31: 712–722.

56.

Salvatore

Moore

Calamari

et al.

Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist. J Pharmacol Exp Ther 2010; 333: 152–160.

57.

Diener

Barbanti

Dahlof

et al.

BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: Results from a phase II study. Cephalalgia 2011; 31: 573–584.

58.

Marcus

Goadsby

Dodick

et al.

BMS-927711 for the acute treatment of migraine: A double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 2014; 34: 114–125.

59.

Voss

Lipton

Dodick

et al.

A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 2016; 36: 887–898.

60.

Petersen

Birk

Doods

et al.

Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat. Br J Pharmacol 2004; 143: 697–704.

61.

Erdling

Sheykhzade

Edvinsson

. Differential inhibitory response to telcagepant on alphaCGRP induced vasorelaxation and intracellular Ca(2+) levels in the perfused and non-perfused isolated rat middle cerebral artery. J Headache Pain 2017; 18: 61–61.

62.

Eftekhari

Gaspar

Roberts

et al.

Localization of CGRP receptor components and receptor binding sites in rhesus monkey brainstem: A detailed study using in situ hybridization, immunofluorescence, and autoradiography. J Comp Neurol 2016; 524: 90–118.

63.

Eftekhari

Salvatore

Gaspar

et al.

Localization of CGRP receptor components, CGRP, and receptor binding sites in human and rhesus cerebellar cortex. Cerebellum 2013; 12: 937–949.

64.

Hostetler

Joshi

Sanabria-Bohorquez

et al.

In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther 2013; 347: 478–486.

65.

Tfelt-Hansen

Olesen

. Possible site of action of CGRP antagonists in migraine. Cephalalgia 2011; 31: 748–750.

66.

Hong

Liu

. Calcitonin gene-related peptide antagonism for acute treatment of migraine: A meta-analysis. Int J Neurosci 2017; 127: 20–27.

67.

Tfelt-Hansen

. Is there an inherent limit to the efficacy of calcitonin gene-related peptide receptor antagonists in the acute treatment of migraine? A comment. J Headache Pain 2009; 10: 389–391.

68.

Zagami

Edvinsson

Goadsby

. Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Transl Neurol 2014; 1: 1036–1040.

69.

Tuka

Helyes

Markovics

et al.

Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia 2013; 33: 1085–1095.

70.

Chan

Vermeersch

de Hoon

et al.

Potential mechanisms of prospective antimigraine drugs: A focus on vascular (side) effects. Pharmacol Ther 2011; 129: 332–351.

71.

Bigal

Walter

Rapoport

. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 2013; 53: 1230–1244.

72.

Chan

Edvinsson

Eftekhari

et al.

Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J Pharmacol Exp Ther 2010; 334: 746–752.

73.

Petersen

Birk

Lassen

et al.

The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers. Cephalalgia 2005; 25: 139–147.

74.

Chaitman

Behm

et al.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina. Clin Pharmacol Ther 2012; 91: 459–466.

75.

Burley

Hamid

Baxter

. Cardioprotective actions of peptide hormones in myocardial ischemia. Heart Fail Rev 2007; 12: 279–291.

76.

Paone

Nguyen

Shaw

et al.

Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: Discovery of MK-2918. Bioorg Med Chem Lett 2011; 21: 2683–2686.

77.

Chaturvedula

Mercer

et al.

Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-y l)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): A potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery. Bioorg Med Chem Lett 2013; 23: 3157–3161.