emerging targets in migraine

REVIEW ARTICLE

Emerging Targets in Migraine

Jan Hoffmann Peter J. Goadsby

Published online: 8 December 2013

Springer International Publishing Switzerland 2013

Abstract Migraine is a common and highly disabling

neurological disorder. Despite the complexity of its path-

ophysiology, substantial advances have been achieved over

the past 20 years in its understanding, as well as the

development of pharmacological treatment options. The

development of serotonin 5-HT1B/1D receptor agonists

(triptans) substantially improved the acute treatment of

migraine attacks. However, many migraineurs do not

respond satisfactorily to triptans and cardiovascular co-

morbidities limit their use in a significant number of

patients. As migraine is increasingly considered to be a

disorder of the brain, and preclinical and clinical data

indicate that the observed vasodilation is merely an epi-

phenomenon, research has recently focused on the devel-

opment of neurally acting compounds that lack

vasoconstrictor properties. This review highlights the most

important pharmacological targets for which compounds

have been developed that are highly likely to enter or have

already advanced into clinical trials for the acute and

preventive treatment of migraine. In this context, preclin-

ical and clinical data on compounds acting on calcitonin

gene-related peptide or its receptor, the 5-HT1F receptor,

nitric oxide synthase, and acid-sensing ion channel block-

ers are discussed.

1 Introduction

Migraine is one of the most common and disabling neu-

rological disorders and its economic impact ranges among

the highest of all neurological diseases [15]. Still, public

awareness of this socioeconomic burden is small and

research funding is limited compared to other neurological

research areas. However, significant advances in the acute

and prophylactic treatment of migraine have been achieved

over the past 20 years. The serotonin 5-HT1B/1D agonists

(triptans) have revolutionized the acute treatment of

migraine attacks and changed the lives of millions of mi-

graineurs worldwide [6]. Preventive treatment options for

episodic and chronic migraine have also been substantially

expanded with new drugs such as topiramate [79] and

onabotulinum toxin A [1012]. Nevertheless, none of the

preventive drugs available are migraine specific and all

available pharmacological approaches, acute or preventive,

are only effective in a limited number of migraineurs. In

addition, the lack of individual predictability for the effi-

cacy of a specific compound complicates treatment and

patient compliance. Therefore, despite multiple available

pharmacological treatment options, there is a significant

need for novel therapeutic drugs for the acute and pre-

ventive treatment of migraine [13]. This review focuses on

the most relevant new pharmacological targets.

2 Calcitonin Gene-Related Peptide (CGRP) Receptor

Antagonists (Gepants)

Calcitonin gene-related peptide (CGRP) is a vasoactive

neuropeptide located on unmyelinated C-fibers and thinly

myelinated Ad-fibers of the trigeminal nerve system. It canbe found in peripheral parts of the trigeminal system, such

J. Hoffmann P. J. Goadsby (&)Headache Group, Department of Neurology, University of

California, San Francisco, 1701 Divisadero St, San Francisco,

CA 94115, USA

e-mail: [email protected]

CNS Drugs (2014) 28:1117

DOI 10.1007/s40263-013-0126-2

as the trigeminal ganglion [14, 15] or the perivascular

nerve fibers surrounding meningeal blood vessels [16], as

well as on its central parts such as the trigeminovascular

complex (TCC), thalamus, and hypothalamus [17, 18].

Interestingly, it is also located on inhibitory structures such

as the periaqueductal gray (PAG) [17]. Due to its potent

vasodilator properties [19], it was initially postulated that

this effect was relevant for its role in migraine patho-

physiology [20]. However, it became clear that migraine is

mainly a disorder of the brain rather than of peripheral

structures, such as the meninges or its blood vessels [21

23], and preclinical studies have been conducted that

demonstrated the ability of CGRP to modulate neuronal

activity in the TCC [24]. Further experimental data indicate

its involvement in the transmission of pain signals from the

TCC to higher brain regions such as the thalamus and

cortex [23].

From a clinical perspective, the causal relationship

between migraine and CGRP became evident after a series

of clinical studies demonstrated that CGRP concentrations

are elevated during spontaneous migraine attacks and

return to baseline levels after sumatriptan treatment [25

27]. Further studies showed that CGRP infusion in mi-

graineurs is able to trigger migraine without aura [28]. The

relevance of CGRP was finally confirmed in a proof-of-

concept trial that demonstrated clinical efficacy of the

CGRP receptor antagonist BIBN4096BS (olcegepant) in

the acute treatment of migraine [29]. However, its exact

site of action, peripheral or central, has not yet been elu-

cidated. In this context, it also remains to be clarified to

what extent CGRP receptor antagonists are able to cross

the bloodbrain barrier, and whether the bloodbrain bar-

rier remains intact during a migraine attack.

Research efforts then focused on the development of

compounds that allow oral administration. As a result

several gepants were developed and multiple clinical

trials tested their efficacy. The first orally available CGRP

receptor antagonist, telcagepant (MK-0974), was proven to

be effective in the acute treatment of migraine [3032].

Clinical trials demonstrated efficacy for 2-h pain relief, 2-h

pain freedom, as well as sustained pain freedom for 224

and 248 h [31, 32]. In addition to being effective in pain

relief, it was effective in alleviating associated symptoms

such as nausea, photophobia, and phonophobia.

BI44370TA is another orally available CGRP receptor

antagonist that was found to be effective when tested in a

phase II trial [33]. Unfortunately, despite being generally

well-tolerated, these promising results were hampered after

some patients in a trial investigating the potential of tel-

cagepant as a preventive showed significant increases in

liver transaminases [34]. Although these patients had

received telcagepant twice daily and the enzyme elevations

were not observed in the trials for the acute treatment of

migraine, further research on the compound was terminated

[34]. Research efforts on a second CGRP receptor antag-

onist, MK-3207, that was characterized by a higher bio-

availability and potency was also terminated [35, 36].

Although it is not clear if the observed liver toxicity is a

class effect or specifically tied to both MK-compounds,

Boehringer Ingelheim also stopped further development on

BI44370TA. However, Bristol-Myers Squibb initially

developed the CGRP receptor antagonist BMS846372,

which was further modified to increase aqueous solubility

leading to the development of BMS-927711, and has now

been demonstrated to be effective in acute migraine [37].

3 Monoclonal Antibodies Against CGRP or its

Receptor

Targeting CGRP [38] or elements of its receptor [39] with

monoclonal antibodies has drawn much attention as a

potential new pharmacological approach for the acute and

prophylactic treatment of migraine. In principle, disruption

of CGRP function in this way may have a similar beneficial

effect on migraine as that observed with CGRP receptor

antagonists. Compared with CGRP receptor antagonists,

preclinical studies revealed a slower onset of action and a

far longer half-life, which in theory suggest utility in pre-

vention [38]. Initial preclinical studies addressing safety

concerns for the use of monoclonal CGRP antibodies

indicate that these molecules do not seem to affect heart

rate and arterial blood pressure [38]. However, based on

these data, a clear statement on its safety in patients with

significant vascular pathology is currently not possible.

Therefore, despite these promising results, further studies

are needed to clarify the safety of these compounds.

Preclinical studies using a monoclonal antibody against

a C-terminal epitope of human a-CGRP (muMab7E9) wereconducted on two established in vivo rat blood flow models

known to be predictive of clinical efficacy to elucidate a

potential effect in the treatment of migraine [40]. Intrave-

nous administration of the anti-CGRP antibody inhibited

electrically induced vasodilation of the skin or the middle

meningeal artery (MMA), a mechanism that is mainly

based on the neurogenic release of CGRP from sensory

afferents [38]. The extent of the observed inhibition was

similar to that observed in preclinical studies using CGRP

receptor antagonists. The antibody was characterized by a

slow onset as treatment effect after a single dose of anti-

CGRP antibody was achieved 12 h after administration

and lasted for at least 7 days.

Another potent selective human monoclonal antibody

against CGRP developed by Eli Lilly and Company,

LY2951742, impedes CGRP from binding to its receptor.

Preclinical studies with subcutaneously administered

12 J. Hoffmann, P. J. Goadsby

LY2951742 demonstrated its ability to prevent capsaicin-

induced increase of dermal blood flow in rats, non-human

primates, and healthy human volunteers [41]. The results of

a safety, tolerability, and pharmacokinetic study of single,

escalating subcutaneous doses of LY2951742 have not yet

become available (NCT01337596). Currently, a phase II

randomized, double-blind, placebo-controlled trial in mi-

graineurs with or without aura is in progress to assess the

efficacy and safety of LY2951742 (150 mg) in the pre-

vention of migraine during 3 months of treatment

(NCT01625988).

Amgen developed a selective human monoclonal anti-

body, AA95, against the human CGRP receptor which was

tested in a preclinical study using an in vivo model of

capsaicin-induced increase of dermal blood flow in cyno-

molgus monkey. Intravenous administration of AA95

induced a dose-dependent inhibition of capsaicin-induced

increase of dermal blood flow that lasted up to 7 days [39].

Taken together, interfering in CGRP function with selec-

tive monoclonal antibodies appears to be a promising

pharmacological approach for the treatment of migraine.

However, further studies on efficacy and safety are needed

to clarify its potential for clinical use.

4 Serotonin 5-HT1F Receptor Agonists (Ditans)

The effect of triptans is based on agonism at the 5-HT1B/1Dreceptors, and certainly some triptans act at the 5-HT1Freceptor. The 5-HT1B and 5-HT1D receptors are located on

meningeal arteries and peripheral trigeminal neurons,

respectively [42]. However, in a migraine context, 5-HT1Freceptors are found in the trigeminocervical complex

(TCC), as are the 5-HT1B and 5-HT1D receptors, and in the

trigeminal ganglion [42]. In experimental in vivo models of

migraine, activation of 5-HT1F receptors inhibits neuronal

activity in the TCC of the rat [43]. Initially, the peripheral

component of triptans action was believed to be the crucial

element of their mechanism. However, as experimental and

clinical evidence indicates more and more that migraine is

mainly a disorder of the brain [21], research efforts have

expanded to the central 5-HT effects. The vascular com-

ponent is now considered to be more an accompanying

epiphenomenon than a causal mechanism of migraine [21,

22], with therapeutic indications coming from non-steroi-

dal anti-inflammatory drugs (NSAIDs) [4446] and CGRP

receptor antagonists [29, 30, 32, 33], which are effective in

migraine treatment and do not significantly constrict

meningeal blood vessels. This is further supported by the

fact that sumatriptan-induced pain relief does not correlate

with the induced vasoconstriction [47]. Moreover, silde-

nafil is able to induce migraine without any change in the

diameter of the middle cerebral artery [48]. As a result,

5-HT1F receptor antagonists (ditans) were developed as

they have no vasoconstrictor actions.

The first neurally active, indole-based, selective 5-HT1Freceptor agonist that was investigated in a randomized,

double-blind, placebo-controlled, parallel-design clinical

trial, LY334370, proved to be effective for the acute

treatment of migraine attacks [49]. The primary endpoint,

sustained response rate at 2 h, which was defined as a

reduction in migraine headache from moderate or severe to

mild or none at 2 h after dosing, without worsening within

24 h or the use of rescue medication, was reached by the

group taking 60 mg (n = 30) and 200 mg (n = 21) [49].

Unfortunately, adverse events were frequent, with asthenia,

dizziness, and somnolence being the most common ones

reported [49]. Due to compound-specific safety concerns in

animals, clinical development was stopped [50]. However,

based on these results the centrally acting 5-HT1F receptor

agonist lasmiditan (COL-144, LY573144), with a novel

pyridinoyl-piperidine structure that is characterized by a

higher receptor selectivity, has been developed [51]. In a

clinical trial using a prospective, randomized, double-blind,

placebo-controlled design with group-sequential adaptive-

treatment assignment, intravenously administered lasmid-

itan proved to be effective for the acute treatment of

migraine attacks at doses above 20 mg [50]. Adverse

events were reported by 65 % of the subjects treated with

lasmiditan (n = 88) compared with 45 % in the placebo

group (n = 42) [50]. Efficacy of an oral formulation of

lasmiditan was demonstrated in a phase II randomized,

double-blind, parallel-group, dose-ranging study involving

391 patients. The primary endpoint, dose response for

headache relief at 2 h, was achieved for 50, 100, 200, and

400 mg [52]. The efficacy in comparison with triptans and

its safety in patient groups that cannot use triptans due to

their vasoconstrictive properties, such as patients with a

history of stroke or myocardial infarction, will finally

define the future of this pharmacological mechanism in the

treatment of acute migraine attacks.

5 Nitric Oxide Synthase Inhibitors

Nitric oxide (NO) is involved in many physiological pro-

cesses. Its most important property is the ability to induce

vasodilation including cerebral and extracerebral arteries.

Beside its vascular properties, NO is able to modulate

neuronal activity in several regions of the CNS, including

the PAG [53] as well as neurons of the TCC that receive

meningeal input [54]. Furthermore, experimental data

indicate an involvement of NO in the establishment of

central sensitization [55], which is believed to be the

pathophysiological correlate of migraine-associated allo-

dynia [56, 57]. Interestingly, in animal models the systemic

Emerging Targets in Migraine 13

[54, 58] as well as the microiontophoretic administration of

NO synthase (NOS) inhibitors [59] into the TCC reduce

neuronal activity in the TCC.

From a clinical perspective, the relationship between NO

and migraine has a long history. The observation that

workers in explosives factories had a significantly higher

incidence of migraine led to the suspicion that glyceryl

trinitrate (GTN), an NO-donor, was the responsible molecule

for the attack induction. This idea was confirmed by a clinical

study demonstrating that intravenous administration of GTN

in migraineurs reliably induces migraine attacks without

aura [60, 61]. Years later, Afridi et al. [62] showed that GTN

not only induces the migraine attack itself, but also the pre-

ceding premonitory symptoms, which were identical to those

reported in spontaneous migraine attacks [63] thereby

highlighting the neuronal effects of NO.

Based on these observations, several NOS inhibitors

were developed and investigated in clinical trials. In prin-

ciple, all three NOS isoforms, the neuronal (nNOS),

endothelial (eNOS), and inducible (iNOS) NOS isoforms,

could represent a potential pharmacological target. How-

ever, since in the context of migraine pathophysiology the

neuronal effects of NO appear to prevail, the search for

therapeutic compounds quickly shifted from non-specific

NOS inhibitors to those that target only specific isoforms

that have more influence on NO production at the neuronal

level, namely nNOS and iNOS. However, the first com-

pound tested for the treatment of acute migraine attacks

was the non-specific NOS inhibitor L-NG methylarginine

hydrochloride (L-NMMA) [64]. Despite encouraging

response rates of 67 % in the L-NMMA group compared

with 14 % in the placebo group, the results have to be

interpreted with caution as the study suffered from some

methodological shortcomings [65]. Poor oral absorption

and an associated increase in systemic blood pressure as a

result of eNOS inhibition made this compound unsuitable

for clinical use [66]. More recently, the iNOS inhibitor

GW274150 was tested for the acute [67] and preventive

[68, 69] treatment of migraine. Despite the high efficacy of

GW274150 in iNOS inhibition [70, 71], both well-designed

trials were negative. Initial results with a novel nNOS-

triptan combination drug NXN-188 suggest that more

needs to be understood to exploit this direction. However,

preclinical results are encouraging as in experimental

migraine models NXN-188 inhibits CGRP release [72].

6 Acid-Sensing Ion Channel Blockers

Acid-Sensing Ion Channels (ASICs) are a family of cation

channels gated by extracellular protons [73]. They are

located in the peripheral and central nervous system and

are expressed on sensory neurons of the cranial meninges

as well as the trigeminal, vagal, and dorsal root ganglion

[73]. The ASIC1a subunit is mainly found in the CNS and

the ASIC3 subunit is largely located in the peripheral

nervous system [73]. ASICs act as a sensor to decreased

extracellular pH, which occurs during inflammatory pain in

the periphery or central electrical events, such as cortical

spreading depression (CSD), which is believed to be the

pathophysiological correlate of migraine aura [74].

Therefore, they act as chemo-electric transducers. Due to

their function and anatomical location, ASICs are of

increasing interest as a potential therapeutic target for the

treatment of migraine.

In a series of preclinical in vivo studies and a small

sample of patients with refractory migraine with prolonged

aura, Holland et al. [75] investigated the effect of the

potassium-sparing diuretic amiloride, the first blocker of

ASICs to be described. In the experimental in vivo models

of migraine, the authors demonstrated that intravenous

amiloride 10 mg/kg significantly inhibited needle prick-

induced CSDs. In transgenic mice with a deletion of the

ASIC1-producing ACCN2 gene, the effect of amiloride was

not observed. Taken together, the data suggest a potential

therapeutic effect on migraine aura. Furthermore, amiloride

inhibited neurogenic vasodilation of the MMA and stimu-

lus-induced neuronal activity in the TCC, indicating an

inhibitory effect on nociceptive processing within the tri-

geminal system and suggesting a pain-relieving effect in

migraine.

In the small open-label pilot study on seven migraineurs

suffering from refractory migraine with persistent aura, the

intravenous administration of amiloride 1020 mg/kg/day

significantly reduced headache severity and the frequency

of aura in four patients during the observation period of

624 months [75]. In conclusion, preclinical and clinical

data strongly suggest a possible therapeutic effect on

migraine and migraine aura, highlighting the need for

randomized placebo-controlled clinical trials.

7 Conclusions

Despite the evident relief and increase in quality of life that

triptans have brought to many migraineurs, there is still a

substantial need for novel pharmacological strategies for

the treatment of migraine. Among the broad range of

pharmacological targets currently under investigation,

CGRP and its receptor, the 5-HT1F receptor, NOS, and

ASICs are among the targets that have the potential for

clinical efficacy and are likely to enter or have already

entered clinical trials. While clinical trials on CGRP

receptor antagonists demonstrated their clinical efficacy,

two advanced compounds have been hampered by liver

toxicity issues. In contrast, antibodies against CGRP or its


receptor may offer similar beneficial effects combined with

a long-lasting effect that may reduce the risk of recurrence

headache. Trials on 5-HT1F receptor agonists have shown

clinical efficacy and their development is awaited with

interest. Clinical efficacy could not be demonstrated for the

acute and prophylactic treatment of migraine by iNOS

inhibitors, and nNOS is now likely to be explored. In

contrast, ASIC blockers may offer a completely novel

pharmacological approach and initial positive results from

preclinical studies have been complemented by the prom-

ising results of a small open-label study that suggests

clinical efficacy for migraine and migraine aura. However,

placebo-controlled randomized trials are needed to confirm

these preliminary results.

Acknowledgments JH has received honoraria for editorial workfrom Journal Watch Neurology and travel support from Allergan.

PJG is on Advisory Boards for Allergan, Colucid, MAP pharma-

ceuticals, Merck, Sharpe and Dohme, eNeura, Neuraxon, Autonomic

Technologies Inc., Boston Scientific, Electrocore, Eli-Lilly, Med-

tronic, Linde Industrial Gases, Arteaus, AlderBio, and Bristol-Myers

Squibb. He has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix,

Impax, and Dr.Reddys, and has been compensated for expert legal

testimony. He has grant support from Allergan, Amgen, MAP phar-

maceuticals, and Merck, Sharpe and Dohme. He has received hono-

raria for editorial work from Journal Watch Neurology and for

developing educational materials and teaching for the American

Headache Society.

JH and PJG have received no funding for writing this review.

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Emerging Targets in MigraineAbstractIntroductionCalcitonin Gene-Related Peptide (CGRP) Receptor Antagonists (Gepants)Monoclonal Antibodies Against CGRP or its ReceptorSerotonin 5-HT1F Receptor Agonists (Ditans)Nitric Oxide Synthase InhibitorsAcid-Sensing Ion Channel BlockersConclusionsAcknowledgmentsReferences

emerging targets in migraine

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