Curr Neurol Neurosci Rep (2015) 15:25
DOI 10.1007/s11910-015-0547-z
HEADACHE (RB HALKER, SECTION EDITOR)
CGRP Mechanism Antagonists and Migraine Management
Nazia Karsan & Peter J. Goadsby
# Springer Science+Business Media New York 2015
Abstract 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 vas-
cular 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 trigem-
inal 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 mi-
graine therapeutics. We discuss several recent trials, highlight-
ing the evidence base behind these novel drugs, and their po-
tential future contribution to migraine management.
Keywords Migraine . Calcitonin gene-related peptide
(CGRP) . Migraine management . CGRP antagonists .
Mechanisms of migraine . Monoclonal antibodies
Introduction
CGRP is a 37 amino acid neuropeptide derived from the gene
encoding calcitonin first identified almost 30 years ago [1]. It
is found as two isoforms; α-CGRP is found within the
This article is part of the Topical Collection on Headache
N. Karsan
Headache Group, Department of Basic and Clinical Neuroscience,
Institute of Psychiatry, Psychology and Neuroscience,
King’s College London, London, UK
P. J. Goadsby (*)
NIHR-Wellcome Trust Clinical Research Facility, Wellcome
Foundation Building, King’s College Hospital, London SE5 9PJ, UK
e-mail: peter.goadsby@kcl.ac.uk
peripheral nervous system, and β-CGRP is found predominantly
in the enteric nervous system [2]. CGRP is widely expressed
within the nervous system, both centrally and peripherally at sites
that have been implicated in migraine [3••]. Within the central
nervous system, it is widely found within cell bodies in the hy-
pothalamus, the cerebellum and the brainstem, and immunohis-
tochemistry has shown that it is mainly produced in ventral and
dorsal root neurons [4]. Immunocytochemistry has shown that
up to 50 % of trigeminal neurons produce CGRP in the trigem-
inal system, at trigeminal nerve endings, in the trigeminal gan-
glion and in higher-order neurons and glia [5]. Peripherally,
CGRP mediates vasodilatation via smooth muscle cell receptors;
while centrally, it acts on second- and third-order neurons to
mediate the transmission of pain and in the brainstem where it
is involved in regulatory mechanisms [6].
It has been shown that stimulation of the trigeminal gangli-
on in humans causes release of both CGRP and substance P
[7]; the latter seems to play no role in migraine. When pain-
producing durovascular structures are stimulated in cat, only
CGRP is released into the cranial circulation [8]. In humans
during acute severe migraine, CGRP and not substance P is
elevated in the cranial circulation [9], and this release is re-
versed after successful treatment with sumatriptan [10].
CGRP is also elevated in humans with chronic migraine
[11]. In turn, intravenous administration of CGRP triggers
migraine [12]. Taken together these and other data have driven
development of CGRP mechanism-based therapies compris-
ing the receptor antagonist and monoclonal antibodies to ei-
ther the peptide or the receptor.
This review will focus on the recent updates and the evi-
dence base behind CGRP mechanism-based migraine man-
agement and explore some of the limiting factors surrounding
current use of these drugs.
Mechanisms of Pain in Migraine
Migraine involves activations in the brainstem, demonstrated
with positron emission tomography (PET), and seen during a
25 Page 2 of 9
spontaneous migraine attack that persist despite effective
headache treatment with a triptan [13, 14]. Moreover, recent
work has shown brainstem areas, the dorsolateral pons and
periaqueductal grey matter, as well as the region of the hypo-
thalamus, are active in the premonitory phase of migraine
prior to pain onset [15]. It is likely that changes in brain vas-
culature and cellular functions are mediated through brainstem
and forebrain dysfunction, and the involvement of both as-
cending nociceptive input and descending inhibitory path-
ways contributes to the heterogeneity in symptomatology in
migraine [16••].
CGRP in the Trigeminovascular System
CGRP is a very potent long-acting endogenous vasodilatator. In
the 1980s, Edvinsson and colleagues showed that CGRP-
containing nerve fibres are present within the walls of intracranial
vessels [17]. Despite the expression of several neuropeptides
within trigeminal neurons, studies during acute migraine using
radioimmunoassays have only been positive for two peptides,
CGRP, the subject of our current review, and pituitary adenylate
cyclase activating peptide (PACAP) [18–20].
CGRP is distributed within the central and peripheral ner-
vous systems and often co-localizes with other neuropeptides,
including substance P in C-fibres [21, 22]. Neurons in the
trigeminal ganglion project to the trigeminal nucleus caudalis
and C1/C2 dorsal horn: the trigeminocervical complex (TCC),
where CGRP acts on second-order neurons to activate
quintothalamic pathways [23]. The role of the brainstem and
TCC in migraine pathophysiology is well established, and the
brainstem nuclei are known to be integral anatomical areas of
involvement during a migraine attack [16••]. CGRP may
therefore be involved in migraine at both a central and periph-
eral level. Brainstem stimulation activates the trigeminovascular
system and causes peripheral CGRP release. Brainstem activa-
tion probably also plays a role in central sensitization and its
clinical manifestation of allodynia [16••].
The rise in CGRP levels during acute migraine, the fall in
levels during effective treatment of an attack and the ability of
CGRP infusion to trigger a migraine in migraineurs alone
alludes to the role of CGRP in migraine neurobiology.
CGRP seems integral to the clinical expression of migraine
process at several sites and has led to the investigation and
development of anti-CGRP drugs for the treatment of
migraine.
The CGRP Receptor
The CGRP receptor is a heterotrimer and has seven transmem-
brane domains. The calcitonin receptor-like receptor (CLR) is
accompanied by a small single transmembrane protein called
Curr Neurol Neurosci Rep (2015) 15:25
receptor activity-modifying protein (RAMP1) which forms
the CGRP-specific ligand binding site and the CGRP receptor
(Fig. 1). A small intracellular protein component, called re-
ceptor component protein (RCP), links the receptor to the
intracellular signaling pathway, which works through G pro-
teins and adenylate cyclase, causing raised cAMP levels [24].
Localisation of CGRP Receptors in the Nervous System
Pain improvement could, in principle, be achieved by periph-
eral or central blockade of CGRP effects. Acute treatment of
migraine would require therapeutic agents to treat the associat-
ed neurological symptoms that clearly originate within the brain
[14, 15, 25]. The distribution of CGRP within the nervous
system has been well mapped. Almost all vascular beds are
supplied by CGRP-containing fibres, and the intracranial
CGRP fibres originate in the trigeminal ganglion [26]. The
trigeminal ganglion contains neurons of which 50 % express
CGRP [27]. CGRP acts on higher-order neurons to transmit
pain signals to the brainstem, and studies have shown CGRP-
positive fibres in the TCC [26, 28]. Within the trigeminal gan-
glion, CGRP coexpresses with substance P and 5HT1B/1D re-
ceptors [29]. The cerebellum is also an important site for mod-
ulation of cortical inputs, and CGRP is expressed in the cere-
bellum and Purkinje cells [30, 31]. Brighina and colleagues
showed in 2009 that a loss of cerebellar inhibition is observed
in migraine with aura [32]. The cerebellum has also been shown
in PET studies to be active during acute migraine [33]. Several
immunohistochemical studies have shown that CGRP has a
functional role within the cerebellum and that CGRP antago-
nists may mediate some of their action on the cerebellum [34].
Fig. 1 CGRP receptor complex. The calcitonin gene-related peptide
(CGRP) receptor is made up of the calcitonin-like receptor (CLR), a seven
transmembrane Gs protein coupled structure that is the product of the
CALCRL gene, and the appropriate receptor activity-modifying protein
(RAMP1). When CLR is localized with RAMP2 or RAMP2, the receptor is
activated by adrenomedullin. RCP is the receptor component protein that
is important for signaling. Courtesy of Dr Philip Holland, Headache
Group, King’s College London
Curr Neurol Neurosci Rep (2015) 15:25
It is postulated that the CGRP neuron density in these areas,
which are important in migraine pathophysiology, both within
and outside of mediating the painful features, could correlate
with CGRP mediating some of the non-headache features of
migraine in these areas, such as visual symptoms in the supe-
rior colliculi and phonophobia in the inferior colliculi [35].
Additionally, functional studies and some of the anti-CGRP
clinical trials have alluded to the increased density of CGRP
neurons in the cranial vasculature compared to the coronary
vasculature, which would explain their lack of reported car-
diovascular side effects [36].
Drug Targets for CGRP
Drug targets against CGRP can be designed in various ways.
Competition for a binding pocket or cleft produced by
RAMP1 and the CLR is the best explored mechanism, either
by small molecule or recently by a monoclonal antibody [4].
Free CGRP can also be targeted using monoclonal antibodies
that can neutralize CGRP activity [37].
Small Molecule CGRP Receptor Antagonists
Six CGRP receptor antagonists have been developed, and
each of the five with public data have demonstrated clinical
efficacy in acute migraine. The class has acquired the stem
name—gepants.
Olcegepant (BIBN4096)
The first CGRP receptor antagonist developed was
olcegepant (BIBN4096) [38]. It showed clinical effec-
tiveness when intravenously administered during acute
migraine [39]. It acts specifically on the RAMP1 extra-
cellular region and directly competes for the binding
site of the endogenous ligand CGRP, inhibiting physio-
logical and cellular effects of CGRP [40].
Initially tested in marmoset and rat models measuring the
effect of the drug on facial blood flow, it was found to have
blocking activity at the peripheral vascular level and regard-
less whether the animal was stimulated centrally in the
brainstem at the trigeminal nucleus caudalis or peripherally
at the trigeminal ganglion [38, 41].
In a phase IIa human clinical trial, clinical efficacy was
achieved which was dose responsive, and the 2.5-mg dose
led to a response rate of two thirds compared to a quarter with
placebo, and this result was statistically significant. The drug
has poor oral bioavailability and therefore required intrave-
nous administration. Doses up to 10 mg did not seem to in-
duce cardiovascular side effects [39]. The drug was quick
acting, with effect starting 30 mins after administration, with
Page 3 of 9 25
ongoing improvement over a few hours. One fifth of those
treated developed adverse effects, and the agent lacked the
vasoconstrictive effects of triptans and hence did not have
the same cardiovascular effects. The main side effect reported
was paraesthesias, particularly in women [39]. A separate
study looked at the effects of the drug on cerebral blood flow
and found that there were no drug effects on global or regional
cerebral blood flow [42]. There were difficulties formulating
an oral preparation because of poor oral bioavailability; there-
fore, the drug was discontinued.
Telcagepant (MK 0974)
The first orally available CGRP receptor antagonist was
telcagepant, and this was also shown to be effective in acute
migraine [43]. A phase II clinical trial tested the drug against
rizatriptan and placebo and at 600 mg doses achieved similar
efficacy to rizatriptan (67.5 vs 69.5 %). Tolerability was better
than rizatriptan and comparable to placebo. A large phase III
randomized trial followed, testing the smaller doses against
zolmitriptan in 1380 patients and found that 300 mg
telcagepant had similar effects at 2 hours as zolmitriptan
5 mg. Tolerability was again comparable to placebo and better
than the zolmitriptan [44]. Relatively high plasma concentra-
tions were required to alleviate migraine headaches, and this
was thought to be due to the high protein binding of the drug
leading to limited access to peripheral receptors or limited
access to central receptors because of poor blood-brain barrier
penetration [44].
Concerns were raised regarding liver toxicity because of
raised liver enzymes observed in migraine prevention and
menstrual migraine studies, and the drug was therefore
discontinued [45]. Unlike triptans, telcagepant does not cause
cerebral or coronary vasoconstriction, hence reducing the side
effect profile [36, 46].
There have now been six positive phase III trials in
telcagepant reported [44, 46–50]. These have all shown a sim-
ilar side effect profile to placebo. The concern regarding liver
function abnormalities has led to discontinuation of drug
development.
MK-3207
Another CGRP receptor antagonist, MK-3207, was
found to be more potent than telcagepant and was tested
in a study looking at different doses. The higher doses
of 100 and 200 mg had excellent clinical effect with
pain free rates more than three times that of placebo
and pain relief twice as good as placebo [51].
Concerns were raised around liver toxicity again in
phase I and II trials, and the drug was discontinued.
25 Page 4 of 9 Curr Neurol Neurosci Rep (2015) 15:25

hepatotoxicity concerns

hepatotoxicity concerns
BI 44370

Poor oral bioavailability

Completed phase IIa

Completed phase IIa

Discontinued due to

Discontinued due to
B144370A, a small molecule CGRP receptor antagonist, was

Current status
compared in varying doses to placebo and eletriptan in a phase
II study [52]. Again, a higher dose of 400 mg achieved 2 hour
pain freedom in significantly more patients than in the placebo
and eletriptan groups. The lower doses did not have the same
results, and tolerability was very good. Clinical efficacy and
tolerability of this agent was therefore demonstrated in this

Low number of adverse events-

1.4–9.4 % of treated patients
study, but no further trials have followed [52].

Excellent tolerability, 1–8 %

(depending on dose, up to
reported adverse events

600 mg doses given)

BMS-846372/927711

depending on dose
Reported in 20 %
BMS-846372 is a potent orally active CGRP receptor antag-

Adverse effects

Transaminitis

Transaminitis
onist which has limited aqueous solubility [53]. To increase
solubility, a primary amine was added to the cycloheptane ring
to produce BMS-927711. A recent phase IIb study tested the
agent against placebo and sumatriptan [54]. The drug was
better than placebo, and efficacy was similar to sumatriptan.
The study involved treating one single attack per patient, and

31.3 (zolmitriptan 5 mg)–33.4

in this setting, tolerability was good without significant ad-

35 (sumatriptan 100 mg)

verse events but longer-term data is not available.

34.8 (eletriptan 40 mg)

(rizatriptan 10 mg)
Pain free at 2 h with

MK-1602
triptan (%)

This compound has no reported data as yet [55, 56]. It remains

unclear as to where small molecule CGRP receptor antago-
nists act. They have limited blood-brain barrier permeability,
–

–
although they may well act at areas integral to the migraine
process outside the blood-brain barrier [57]. A PET study
Pain free at 2 h

using telcagepant suggested the central receptor-mediated ef-

(% with drug)

fects were not responsible for clinical efficacy [58]. See

23.8–45.2
Summary of the small molecule CGRP antagonists tested in migraine

Table 1 for data comparison.

31.4
36.2

27.4
44

Monoclonal Antibodies
(% with placebo)
Pain free at 2 h

Monoclonal antibodies have recently increased in use in clin-

ical therapeutics and have shown excellent clinical efficacy in
4.3–10.7

many conditions, including inflammatory bowel and joint dis-

15.3
9.8

8.6

ease, multiple sclerosis and other immune-mediated condi-

2

tions [59].
Humanized monoclonal antibodies have been developed to
counteract the strong immunological reactions that can occur
BI44370 (50 mg, 200 mg, 400 mg)

when animal-produced antibodies are administered to humans

BIBN4096 (olcegepant 2.5 mg)
MK0974 (telcagepant 300 mg)

in chronic use. These agents are therapeutically useful as they

are specific against the receptor they are formulated against
BMS-927711 (75 mg)
comparison purposes

and have a long half-life which means that they can be used in
MK3207 (200 mg)
Drug dose used for

chronic conditions and disease relapse prevention. This leaves

the potential for monthly dosing rather than once or twice
MK-1602

daily dosing as in typical migraine preventive treatment [59].

Table 1

Additionally, these receptor-specific agents are generally ca-

tabolized and excreted through the kidneys or liver but are not
Curr Neurol Neurosci Rep (2015) 15:25
subject to hepatic processing and therefore avoid adverse he-
patic toxicity [44].
The concerns regarding safety of these agents in migraine
largely relate to CGRP inhibition and antibody infusion ef-
fects. Given the vasodilator properties of CGRP, cardiovascu-
lar side effects are of concern. These potentially include
medication-induced hypertension, interactions with anti-
hypertensive drugs and inhibition of stress or ischemia-
related coronary vasodilatation [60••]. Other potential effects
include biological effects within other organ systems, as well
as infusion and administration reactions and immunological
reactions [61]. The long half-life, although allowing for infre-
quent dosing, means that if toxic side effects are encountered,
discontinuation of the drug will not lead to immediate molec-
ular clearance [62].
Several anti-CGRP antibodies have been researched using
animal models in migraine. AA95 prevented the increase in
dermal blood flow in monkey models for up to 7 days [47].
AA32 is another antibody which recognizes the functional
CLR or RAMP type 1 receptor complex. AA32 positive com-
plexes have been identified as being expressed at several sites
within the trigeminovascular system in the monkey and may
therefore be useful for migraine treatment through interference
with CGRP receptor transmission [48].
Monoclonal antibodies to rat alpha-CGRP have also been
investigated and models using measurement of electrical stim-
ulation to induce vasodilatation in the skin or middle menin-
geal artery (MMA) have been used [63]. These studies
showed that with a slower onset of action compared to the
CGRP antagonists, these antibodies were able to inhibit skin
vasodilatation or MMA diameter for up to 1 week post dose.
There are currently four monoclonal antibodies being ac-
tively developed for the preventive treatment of episodic or
chronic migraine in humans (Table 2).
ALD403
ALD403 is a humanized antibody produced by yeast cells for
prevention in episodic migraine. In a phase I study, two dif-
ferent formulations were administered subcutaneously and in-
travenously with 12-week follow-up comparing administra-
tion in healthy volunteers and subsequently comparing the
Table 2 Summary of the monoclonal antibodies being developed for use in migraine
ALD403 (Alder LY2951742 (Arteaus
Biopharmaceuticals) Therapeutics; now Eli Lilly)
Type of antibody Humanized Humanized
Type of migraine Episodic Episodic
Administration IV SC
Dosing in phase II trials Once only Twice a month
Page 5 of 9 25
agent against sumatriptan and placebo [64]. A proof-of-
concept clinical study then tested a single IV dose versus
placebo in episodic migraineurs, aiming to assess safety of a
single intravenous dose with 24-week follow-up, as well as
assess efficacy and pharmacokinetics. In a multi-centre trial of
ALD403, 163 episodic migraineurs were randomized to either
a single infusion of study drug versus placebo (saline infu-
sion). Patients receiving ALD403 had a reduction of 5.6 mi-
graine days from months 1 to 2 compared with 4.6 days for
placebo and a greater 50, 75 and 100 % responder rate for
migraine days at week 12 [65]. It also showed no significant
difference in adverse events between a treated group and pla-
cebo group at a 1000-mg dose [65].
LY2951742
This is a humanized antibody which binds CGRP and is being
developed for prevention in episodic migraine. The agent has
been shown to prevent capsaicin-induced dermal blood flow
increases in rats, nonhuman primates and in healthy human
volunteers. Intravenous and subcutaneous doses have been
tested in phase I and phase II trials [66].
A phase IIa double-blinded placebo-controlled trial in epi-
sodic migraine gave 150 mg of LY2951742 subcutaneously
and compared it with placebo administered every alternate
week for 12 weeks with 12 weeks subsequent follow-up.
The aim was to assess mean change in baseline number of
headache days in 28 days [66]. Secondary endpoints included
mean change from baseline in number of headache days and
proportion of responders (greater than 50 % reduction in head-
ache days over 28-day period). There was a significant differ-
ence in headache days in the treated group versus the placebo
group with 62.5 % decrease in headache days at week 12
compared to 42.3 % with placebo. There were more adverse
events in the treatment group but the data provide preliminary
evidence for this agent [66].
AMG334
AMG334 is a fully human antibody which is being developed
for prevention of episodic and chronic migraine. This agent
targets the CGRP receptor rather than the free molecule [67].
AMG334 (Amgen) LBR-101 (Labrys Biologics—
recently purchased by Teva, 2014)
Human antibody with Fully humanized
CGRP receptor
Episodic/chronic Episodic/chronic
SC SC
Once a month Once a month
25 Page 6 of 9
Phase I studies have tested the safety and tolerability of the
agent, and in one completed study, healthy and migraine sub-
jects were given single ascending doses of the agent intrave-
nously or subcutaneously [68]. A further phase I study is test-
ing multiple doses in healthy and migraine subjects; all ad-
ministered subcutaneously [69]. An ongoing open-label study
is looking at the safety of the agent in prevention in chronic
migraine [70].
LBR-101
LBR-101 is a fully humanized CGRP peptide monoclonal
antibody [71]. It is specifically being developed for the pre-
ventative treatment of chronic migraine, as well as episodic
migraine in two phase II studies [72, 73]. It has been studied in
rats and cynomolgus monkeys and has been very well toler-
ated, 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. The maximum plasma concentration
was reached soon after completion of a 1-h infusion. The
half-life is 44–48 days, and therefore there is the option of
monthly dosing and there are plans to begin a phase IIb trial
[71]. At present, safety concerns have not been raised, and
tolerability appears to be good across doses. No cardiovascu-
lar or hepatic side effects have been noted.
A double-blind, placebo-controlled, single-dose, dose-
escalation study looked at the agent at varying doses, includ-
ing a 2000-mg supratherapeutic dose, in women with a 168-
day follow-up period. Repetitive cardiological screening with
telemetry pre, during and post infusion and subsequent serial
ECGs up to 3 months post dose were conducted. No effects
were seen in the 31 subjects [71, 75].
The Future
The well-established correlation between CGRP and migraine
headache has paved the way for the research into anti-CGRP
agents for the treatment of migraine. The human data suggest
cluster headache would also be a target [76]. Importantly,
none of the clinical trials conducted using CGRP mechanism
antagonists have demonstrated any vasoconstrictor adverse
effects, and all of them have been positive in terms of clinical
efficacy.
The future with regard to the use of CGRP mechanism
antagonists in migraine treatment is promising. If developed
further, the small molecule CGRP receptor antagonists will be
useful for the treatment of acute migraine, and the monoclonal
antibodies will be formulated for the preventive treatment of
chronic migraine and episodic migraine. Triptans are the
Curr Neurol Neurosci Rep (2015) 15:25
currently preferred treatment for acute migraine amongst
headache specialists. They do, however, have the drawback
of often limited response, recurrent headache requiring repeat
doses or alternative analgesia [77] and cardiovascular liability
[78]. Small molecule CGRP receptor antagonists could be
helpful by achieving a better clinical result, and they have
the potential to be used more often than triptans for recurrent
or frequent migraine. The better tolerability of the small
molecule CGRP receptor antagonists may also enable
their more widespread use in comparison to the triptans
which have adverse effects precluding their use in some
patient groups.
Up to 39 % of patients with episodic migraine will need
preventive medication [79]. Current preventives were not de-
signed for migraine, help at best half of any patient group and
are ridden with side effects. The potential infrequent adminis-
tration, long half-lives and excellent tolerability of the mono-
clonal antibodies being developed may counteract some of
these issues [37].
Conclusions
CGRP is now a well-studied peptide which is expressed cen-
trally and peripherally within the nervous system at sites
which have been shown to be integral to the migraine process.
Several agents, both of the small molecule CGRP receptor
antagonist class and the monoclonal antibody class, are being
studied and developed for both the treatment of acute and
chronic migraine. Given the encouraging results, the future
is likely to bring at least some of these treatments into our
clinical practice in managing patients with migraine. The
tolerability and clinical efficacy of these agents has been
a breakthrough in migraine therapeutics, where since
discovery of triptans, there have been no outstanding
developments in the management of this disabling con-
dition. Hopefully, targeting CGRP will help in manag-
ing this condition and contribute to the betterment of
the quality of lives of affected individuals.
Compliance with Ethics Guidelines
Conflict of Interest Nazia Karsan declares no conflict of interest.
Peter J. Goadsby reports grants and personal fees from Allergan, grants
and personal fees from eNeura, personal fees from Autonomic
Technologies Inc, grants and personal fees from Amgen, personal fees from
BristolMyerSquibb, personal fees from AlderBio, personal fees from Pfizer,
personal fees from Zogenix, personal fees from Nevrocorp, personal fees
from Impax, personal fees from DrReddy, personal fees from Zosano,
personal fees from Colucid, personal fees from Eli Lilly, personal fees from
Medtronic, personal fees from Avanir, personal fees from Gore, personal
fees from Ethicon, personal fees from Heptares, personal fees from
Nupathe, personal fees from Ajinomoto and personal fees from Teva out-
side the submitted work. Amgen, AlderBio, Lilly and Teva are currently
developing CGRP antibodies as CGRP preventive agents.
Curr Neurol Neurosci Rep (2015) 15:25
Human and Animal Rights and Informed Consent This article does
not contain any new studies with human or animal subjects performed by
any of the authors, although such studies are reviewed and have been
performed by the authors.
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