HEADACHE CURRENTS
Headache Currents
Calcitonin Gene-Related Peptide Modulators – The History
and Renaissance of a New Migraine Drug Class
Richard Hargreaves, PhD; Jes Olesen, MD
Several lines of evidence pointed to an important role for
CGRP in migraine. These included the anatomic colocalization
of CGRP and its receptor in sensory fibers innervating pain-
producing meningeal blood vessels, its release by trigeminal
stimulation, the observation of elevated CGRP in the cranial
circulation during migraine with normalization concomitant
with headache relief by sumatriptan, and translational studies
with intravenous (IV) CGRP that evoked migraine only in
migraineurs. The development of small molecule CGRP receptor
antagonists (CGRP-RAs) that showed clinical antimigraine
efficacy acutely and prophylactically in randomized placebo-
controlled clinical trials subsequently gave definitive
pharmacological proof of the importance of CGRP in migraine.
More recently, CGRP target engagement imaging studies using a
CGRP receptor PET ligand [11C]MK-4232 demonstrated that
there was no brain CGRP receptor occupancy at clinically
effective antimigraine doses of telcagepant, a prototypic
CGRP-RA. Taken together, these data indicated that (1) the
therapeutic site of action of the CGRP-RAs was peripheral not
central; (2) that IV CGRP had most likely evoked migraine
through an action at sites outside the blood-brain barrier; and
(3) that migraine pain was therefore, at least in part, peripheral in
origin. The evolution of CGRP migraine science gave impetus to
the development of peripherally acting drugs that could modulate
CGRP chronically to prevent frequent episodic and chronic
migraine. Large molecule biologic antibody (mAb) approaches
that are given subcutaneously to neutralize circulating CGRP
peptide (fremanezumab, galcanezumab) or block CGRP receptors
(erenumab) have shown consistent efficacy and tolerability in
multicenter migraine prevention trials and are now approved for
clinical use. Eptinezumab, a CGRP neutralizing antibody given
IV, shows promise in late stage clinical development. Recently,
orally administered next-generation small molecule CGRP-RAs
have been shown to have safety and efficacy in acute treatment
(ubrogepant and rimegepant) and prevention (atogepant) of
migraine, giving additional CGRP-based therapeutic options for
migraine patients.
From the Center for Pain and the Brain, Harvard Medical School and Department
of Anesthesia, Boston Children’s Hospita, Boston, MA USA (R. Hargreaves); Danish
Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark
(J. Olesen).
Address all correspondence to R. Hargreaves, Center for Pain and the Brain Boston
Children's Hospital, Department of Anesthesia, Critical Care and Pain Medicine c/o
1 Autumn Street, Boston MA 02115 USA, email: richard.hargreaves@childrens.harvard.edu.
Accepted for publication March 12, 2019.
Headache
© 2019 American Headache Society
1
Key words: calcitonin gene-related peptide, CGRP receptor antagonist,
CGRP neutralizing antibody, CGRP receptor antibody,
migraine treatment, migraine prevention
INTRODUCTION
Calcitonin gene-related peptide (CGRP) is a 37-amino acid
peptide that belongs to a family of peptides that also includes
calcitonin (CT), adrenomedullin (AM), and amylin (AMY).
Two forms of CGRP are present in humans, αCGRP, produced
by alternate splicing of the CT gene,1 and βCGRP, which has
a separate genetic origin.2 CGRP is widely expressed in the
peripheral and central nervous systems, with αCGRP being
highly expressed in sensory neurons, and βCGRP in the enteric
nervous system.3
The CGRP receptor is a member of the family B G-protein-
coupled receptors and comprises a multimeric complex made
up of the 7 transmembrane GPCR designated CT receptor-like
receptor (CLR) domains together with a single transmem-
brane protein designated receptor activity modifying protein 1
(RAMP1). RAMP1 is itself a member of a family of proteins
that includes RAMP2 and RAMP3.4 The RAMPs differ in their
extracellular N-terminus but share a common transmembrane
alpha-helical structure and intracellular domain. CLR is able to
partner with each of these RAMPs and the interaction with a
specific RAMP yields ligand specificity. CLR with RAMP1 gives
the CGRP receptor but with RAMP2 or RAMP3 produces adre­
nomedullin AM1 and AM2 receptors, respectively. RAMPs can
also form heteromers with the CT receptor, which alone binds
calcitonin preferentially but when linked to RAMP1, RAMP2,
and RAMP3 forms the amylin receptors AMY1, AMY2, and
AMY3, respectively.5-7 Table 1 and Figure 1 summarize the com­
position, agonist, and antagonist pharmacology of the calcitonin
family of receptors.8 It is noteworthy that CGRP is a potent
agonist at the CGRP receptor that is made up of CLR with
RAMP1, and also the AMY1 receptor that is made up of CTR
with RAMP1.9 The converse is not, however, true, as amylin is
only a weak activator of the CGRP receptor.10,11
The mechanism of CGRP binding to its receptor is thought
to be represented by a 2-domain model. In this model, the
C-terminal region of CGRP first binds with high affinity to
the extracellular N-terminal regions of CLR and RAMP1
Conflict of Interest: Richard Hargreaves declares that the views expressed in this review are
his own and not those of his current employer and that he was a former employee of Merck
and a paid consultant for Labrys on fremanuzemab. Jes Olesen declares no conflicts.
2 | Headache | Month 2019
Headache Currents

Table 1.—The Calcitonin Family of Receptors

Agonist Peptide Receptor GPCR-RAMP Complex Agonist Potency

Calcitonin gene-related peptide CGRP CLR + RAMP1 CGRP > AM ≥ AMY > CT
Adrenomedullin (AM) AM1 CLR + RAMP2 AM > CGRP > AMY > CT
AM2 CLR + RAMP3 AM > CGRP > AMY > CT
Calcitonin (CT) CTR CTR (no associated RAMP) CT > AMY = CGRP > AM
Amylin (AMY) AMY1 CTR + RAMP1 AMY ≥ CGRP > CT > AM
AMY2 CTR + RAMP2 Not well defined
AMY3 CTR + RAMP3 AMY > CGRP > AM
CLR = calcitonin receptor-like receptor; CTR = calcitonin receptor; RAMP = receptor activity modifying protein.
Adapted from Moore and Salvatore.8

Fig. 1.—Agonist and CGRP modulator pharmacology at CGRP and amylin receptors (adapted from Hay10). 1: CGRP peptide neutralizing
antibody; 2: CGRP receptor blocking antibody; 3: CGRP small molecule receptor antagonist. The boldness of the lines indicates the
potency of the agonist interactions with the CLR and CTR receptor subtypes.

forming an affinity trap that increases the local concentrations
of CGRP to allow the N-terminal of CGRP to interact with
the juxta-membrane region of CLR and trigger the accumu-
lation of cAMP. The binding of CGRP to the AMY1 receptor
(CTR + RAMP1) is thought to be a similar affinity trap mech-
anism due to the contribution of a common set of amino acids
shared between CLR and CTR together with a common inter-
action with RAMP1 residue tryptophan 84.9,12-15
The role of CGRP in the pathogenesis of migraine and its his-
tory as an antimigraine drug target have been reviewed recently.16
CGRP containing sensory nerve fibers and CGRP receptors
are widely distributed peripherally and centrally throughout
the trigeminovascular system, where they play an important
role in its sensory physiology and pharmacology.17,18 CGRP
is a potent vasodilator19,20 and mediator of pain signal transmis­
sion when trigeminal sensory nerve fibers are activated. In addi-
tion to being involved in the mechanisms of migraine headache
pain, it has been hypothesized that prolonged activation of tri-
geminal pathways by CGRP could contribute to sensitization
of central second order sensory neurons21 and, potentially, the
transformation of episodic migraine into chronic migraine for
which there are fewer treatment options.
Preclinical biochemical studies of the clinically effective acute
antimigraine serotonin (5-HT) agonists revealed their effec-
tiveness in suppressing trigeminovascular CGRP release. The
ergots and the 5-HT1B/5-HT1D receptor agonists (triptans) at-
tenuated elevated levels of CGRP evoked by electrical stimula-
tion of the trigeminal ganglion and superior sagittal sinus.22-24
3 | Headache | Month 2019
Subsequent pharmacological experiments25,26 proved that the
triptans inhibited CGRP release in the meninges through an
action at prejunctional 5-HT1D receptors on trigeminal sen-
sory nerve terminals,26-28 supporting direct modulation of
CGRP as a potentially useful antimigraine mechanism. These
triptan-led preclinical studies fueled a deeper understanding
of migraine pain pathways and the initiation of novel antimi-
graine drug discovery programs targeted at CGRP and its
receptor.29-32
Translational biochemical studies of CGRP in migraine
showed that its concentration increased in external jugular
venous blood during a migraine attack compared to non-
­ complete blockade both of CGRP and AMY1 receptors.11
migraine controls. Moreover, similar to the findings in pre-
clinical biochemical experiments in vivo, CGRP was reduced
concomitant with migraine headache relief by sumatriptan,
supporting a potential role in migraine headache pain.23,33,34
The big question arising from these biochemical studies was,
however, whether CGRP itself could trigger a migraine attack.
This was solved by the pivotal observation that an intravenous
(IV) infusion of CGRP to migraine patients during a headache
free phase induced not only an immediate moderate headache
but also a delayed headache that completely mimicked their
migraine.35 Interestingly, this IV CGRP infusion induced
headache, but no pain in other body parts (Jes Olesen, personal
communication).
From this provocation experiment it followed (1) that if
CGRP could induce a migraine attack, then antagonizing
CGRP could be a possible treatment for migraine; (2) that mi-
graine pain was at least in part peripheral in origin; and that
(3) therapy may require only a peripherally acting drug since IV
CGRP was unlikely to have penetrated the blood-brain barrier.
However, unrecognized at this time was the fact that the IV
CGRP infusion used to trigger migraine was, at the concen-
trations used, highly likely to have activated AMY1 receptors
as well as CGRP receptors. Amylin, unlike the sensory neuro-
peptide CGRP, is a metabolic hormone and is primarily found
in the β cells of the islets of Langerhans in the pancreas from
where it is released to regulate food intake through central and
peripheral mechanisms and indirectly through efferent vagal
activation to slow gastric emptying and induce satiety.36 In the
trigeminovascular system, unlike CGRP and its receptors, there
is sparse evidence for amylin itself, and the expression of AMY1
receptors is restricted to the trigeminal ganglia and spinal sen-
sory nuclei.11 To date, there have been no experimental medi-
cine provocation studies to determine if amylin, or its analog
pramlintide, which is used clinically in diabetes,36,37 can trigger
migraine.
All successful drug development programs have elements
of serendipity. Crystallography studies have now shown that
small molecule CGRP receptor antagonists (CGRP-RAs)
Headache Currents
bind to CGRP receptors in a hydrophobic pocket formed
by CLR and RAMP 1,38 thereby blocking the initial CGRP
peptide binding event and subsequent receptor activation.
Given the similarity of CGRP peptide binding at the CGRP
(CLR + RAMP1) and AMY1 (CTR + RAMP1) receptors, it is
perhaps not surprising that the small molecule drugs developed
against the CGRP receptor also antagonize CGRP acting at
the AMY1 receptor. Indeed, it is noteworthy that the clinically
effective plasma concentrations of olcegepant the first
CGRP-RA to show activity against migraine in a pivotal IV
proof of concept study (see below) are likely to have produced
Similar to olcegepant, the next-generation oral CGRP-RAs,
although relatively selective for the CGRP receptor, all have
activity against the AMY1 receptor at therapeutic plasma
concentrations (see Table 2). Recently, more detailed phar-
macological studies with olcegepant have also shown that
estimates of CGRP receptor antagonist activity are highly
assay dependent, such that these molecules may be less se-
lective for the CGRP receptor than commonly reported.39
The relevance of AMY1 blocking activity to therapeutic ef-
fectiveness remains unknown, as neither selective AMY1 an-
tagonists nor pure small molecule CGRP-RAs have yet been
synthesized.
Studies in vitro with the CGRP receptor mAb erenumab have
been suggested to support the view that AMY1 antagonism
is unimportant in the antimigraine response. Unfortunately,
however, the activity of erenumab was assessed using calci-
tonin as the agonist in an MCF-7 cell line that has multiple
RAMPs 1, 2, and 3 present alongside CTR.40 This experiment
was really a test of its activity at a calcitonin receptor and cer-
tainly not specifically at AMY1. It is time to do experiments
to probe the activity of erenumab in an appropriate cell line
transfected with the AMY1 receptor using CGRP or amylin as
agonist. Definitive proof of inactivity could, by exclusion, help
resolve the question of CGRP acting at the AMY1 receptor
in migraine and its antagonism in the CGRP-RA therapeutic
response.
SMALL MOLECULE CGRP RECEPTOR
ANTAGONISTS (CGRP-RAs)
Combined evidence from basic science and human experi-
mental research was sufficiently convincing for pharmaceutical
companies to start developing CGRP-RAs. The discovery of
these molecules was, however, difficult because of the com-
plex nature of the peptide agonist binding interaction and the
heterodimeric nature of the receptor. The first non-peptide
CGRP-RA developed and tested in humans was olcegepant
(BIBN4096BS). After IV administration olcegepant proved
4 | Headache | Month 2019
Headache Currents

effective in the acute treatment of migraine attacks and thus

Fold CGRP vs AMY1

­delivered a proof of mechanism for CGRP in migraine and val-

Binding: Functional
Receptor Selectivity

Ligand binding was performed in cells expressing human CGRP or AMY1 receptors using 125I-CGRP or 125I-Amylin, respectively. Functional potency was determined in
327 (functional)
idated the therapeutic concept.41 Subsequently, olcegepant was

238 (binding)
40 binding
also shown clinically to antagonize CGRP-induced headache.42

117:105
120:92
n.a.
Despite this breakthrough clinical result and a leadership
position in the field, olcegepant was not developed further, as
it was limited as an acute antimigraine therapeutic by its phar-
maceutical properties. Olcegepant is a high molecular weight,
high polarity molecule with several H-bond donors that make it
COS-7† HEK-297‡

poorly absorbed after oral administration. This proof of concept

Table 2.—Comparison of the Binding Affinity and Functional Activity of Small Molecule CGRP-RAs at CGRP and Amylin 1 Receptors

Functional cAMP
(CTR + RAMP1)
AMY1 Receptor

for CGRP-RAs in migraine, however, opened the door for sub-

Cell Types

2.4 nM‡
8.4 nM‡
36 nM†

sequent development of optimized oral CGRP-RA therapies.

n.a.

Subsequently, 5 different small molecule oral CGRP receptor

antagonists, telcagepant (MK-0974,43 MK-3207,44 rimegep-
ant (BMS927711),45 BI-44370TA,46 and ubrogepant47, were
developed and shown to be effective acutely against migraine.
Atogepant48 has demonstrated promising activity as a migraine
Binding HEK-293† COS-7‡
(CTR + RAMP1) Ligand

SK-N-MC§ Cell Types

prevention agent.
cells by estimating human CGRP or amylin-stimulated cAMP responses in the presence and absence of antagonist.
AMY1 Receptor

190 nM†

8.2 nM§
0.8 nM‡

1.8 nM§
n.a.

n.a.

CURRENT STATUS OF CGRP-RA PROGRAMS

Data were summarized from review citation 8 or received as a personal communication from Allergan.†

Telcagepant49 has been the most extensively studied small

molecule CGRP-RA, providing deep insights into migraine
pain mechanisms, potential benefits and limitations of CGRP
modulation for the acute treatment of migraine, and effec-
tiveness of the mechanism vs triptans as standards of care.
SK-N-MC† HEK-293‡
Functional cAMP
(CLR + RAMP1)

Telcagepant was also studied for the prevention of episodic mi-

CGRP Receptor

0.026 nM‡

graine using chronic daily dosing50 and the prevention of men-

Cell Types

0.08 nM‡
0.14 nM†
0.11 nM†
0.5 nM‡
0.1 nM‡

strual migraine using 7 days of dosing peri-menstrually.51 Both

of these studies provided proof of concept for CGRP modula-
tion in migraine prevention with efficacy in the chronic study
similar to topiramate (as judged by comparison to a separate
but similarly designed clinical trial),52 but with much improved
CNS tolerability.
(CLR + RAMP1) Ligand
Binding SK-N-MC Cells

Unfortunately, the progress of many small molecule CGRP

CGRP Receptor

receptor antagonists toward registration was halted by safety

0.027 nM

0.015 nM
0.07 nM
0.02 nM
0.05 nM
0.8 nM

concerns over the therapeutic margins to unacceptable

drug-induced liver injury (DILI). Despite their structural
chemical diversity, telcagepant (MK-0974) and MK-3207
showed increases in liver alanine transaminase enzyme (ALT)
levels several times the upper limit of normal and with MK-
3207 delayed liver test abnormalities.44 It should be noted
Rimegepant (BMS-927711)
Olcegepant (BIBN4096BS)

that with telcagepant these hepatotoxic effects were not seen

Atogepant (AGN-241689:
Ubrogepant (MK-1602)†
Telcagepant (MK-0974)
Small Molecule CGRP

during intermittent use for 18 months for the acute treat-

Receptor Antagonist

ment of migraine,53 but only after chronic or intensive use for

­m igraine prevention or menstrual migraine.50,51 Nevertheless,
MK-8031)†

since widespread outpatient use even in the acute setting still

MK-3207

potentially carried DILI risk to patients, its development was

terminated. BI-44370 TA was also discontinued, but there
has been only speculation and no formal report that this was
5 | Headache | Month 2019
Fig. 2.—Evolution of small molecule CGRP RAs highlighting key structural differences (Allergan R&D Day, 2015).
also due to hepatotoxicity. These observations led to ques-
tions over whether the CGRP receptor blocking mechanism
was inherently flawed as a therapeutic approach. However,
the diverse presentation of the liver injury caused by the dif-
ferent CGRP molecules suggested that the DILI effects could
be due to the specific chemistry of each of these molecules
and not a GGRP-RA class effect.
In Merck, despite the setbacks with telcagepant and MK-
3207, there was a strong belief that the liver toxicity was due
to the chemical structure of the molecules and was not related
to the CGRP antagonist mechanism. It was hypothesized that
both these compounds might be capable of metabolic oxida-
tion to produce reactive intermediates, with potential over time
for producing hepatotoxicity. The exact mechanism for this re-
mains, however, unknown.
For telcagepant, oxidative biotransformation of the Western
difluorophenyl was proposed to be related to its ability to label
proteins in hepatocytes. For MK-3207, hepatotoxicity was pos-
tulated to be related to the potential for metabolic activation of
the aniline substructure, or oxidation of the Western portion of
the molecule to liberate a reactive phenyl-glyoxal (see Fig. 2).
The CGRP receptor antagonist drug discovery programs
continued at Merck, seeking to address these potential liabilities
with appropriate structural alterations and intense toxicological
Headache Currents
evaluation of hepatic safety. These efforts yielded the novel
small molecule drug candidates ubrogepant (MK-1602), a can-
didate for acute migraine treatment, and atogepant (MK-8031,
AGN-241689), a differentiated candidate suitable for trials in
migraine prevention. These molecules are quite different from
telcagepant and MK-3207 in structure (see Fig. 2 for compari-
sons), lacking the chemical functionalities postulated to be as-
sociated with the hepatotoxicity.
Ubrogepant completed a Phase 2 dose-finding study in acute
migraine treatment at 1, 10, 25, 50, or 100 mg and confirmed
previous telcagepant data, as it performed equally well in high
and low triptan responders with overall adverse event rates sim-
ilar to placebo.47 These Phase 2 results were recently confirmed
by the Phase 3 ACHIEVE-1 and 2 trial data with ubrogepant.
In ACHIEVE-1, doses of 50 and 100 mg were superior to pla-
cebo in both primary endpoints of pain freedom and absence of
most bothersome symptom (MBS). ACHIEVE-2 tested doses
of 25 and 50 mg and in a modified intention to treat analy-
sis showed that 50 mg was again significant on 2-hour pain
­freedom and absence of MBS, while those on 25 mg met the
2-hour pain freedom criteria. Four cases of cases of ALT eleva-
tions were reported but a blinded panel of liver experts deter-
mined these events were not likely to be related to ubrogepant
treatment.54
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Headache Currents

Clinical Phase 3 data from 2 acute migraine treatment clin-
ical trials with rimegepant have also recently been reported
showing that a 7 mg dose is superior to placebo on the 2-hour
pain-free and MBS endpoints. In these acute studies, there was
no evidence for ALT elevations with rimegepant.55
The concern that drug-induced liver injury may be an intrin-
sic class effect of anti-CGRP approaches, and in particular the
GCRP-RAs, persists,56 especially for chronic use in migraine
prevention as telcagepant hepatotoxicity was seen only after
repetitive and prolonged dosing. It is therefore reassuring for
the mechanism and the CGRP-RAs to see long-term use data
with erenumab (AMG-334) the CGRP receptor blocking an-
tibody57-59 and 12-week Phase 2B/3 data with the CGRP-RA
atogepant showing robust efficacy in migraine prevention
without liver safety signals. Importantly, atogepant was studied
over a wide dose range (10 mg QD, 30 mg QD, 30 mg BID,
60 mg QD, and 60 mg BID) with once and twice daily admin-
istration.54 Finally of interest, during a recent portfolio priori-
tization exercise, Heptares had rights to their intranasal small
molecule CGRP-RA development program returned to them
by TEVA.60 The hepatic liability of this molecule is currently
unknown, but the intranasal formulation may lower dosing
requirements and avoid first-pass high-level hepatic drug expo-
sures and hepatic metabolism, thereby optimizing its liver safety
margin.
COMPARING CGRP-RAs TO TRIPTANS
IN THE ACUTE TREATMENT OF MIGRAINE
How then does the clinical efficacy of CGRP receptor
antagonists in acute migraine compare to the triptan 5-HT1B/1D
receptor serotonin agonists that are now generic and for many
people have become the current standard of care for the acute
treatment of migraine? Direct comparative randomized clinical
trials of small molecule CGRP antagonists with the triptans
are scarce. Studies to date have compared telcagepant with
rizatriptan 10 mg61 and zolmitriptan 5 mg,62 rimegepant to
sumatriptan,45 and BI-44370 to eletriptan 40 mg46 in acute mi-
graine treatment and shown similar but consistently slightly less
efficacy for the CGRP-RAs on the 2-hour pain-free endpoint
making some investigators question the therapeutic value of the
mechanism.63,64 Others have put forward the counter argument
that assumptions based on a specific symptom at a specific time
point (2-hour headache pain-free) can be uninformative in pre-
dicting the benefit for individual patients who can respond to
both, one, or neither treatment option.65-67 Moreover, conclu-
sions based on efficacy alone, particularly when measured by
a single unidimensional endpoint, undervalue the totality of
a therapeutic profile and thereby the overall potential useful-
ness of a new drug class with novel mechanism of action. The
CGRP-RAs have the potential to help many migraine patients
for whom triptan therapy is not an option because of cardiovas-
cular risk factors, intolerance, or fear of side effects.
WHERE DO THE CGRP-RAs ACT TO TREAT
MIGRAINE?
Two important pharmacodynamic assays were developed to
assess the pharmacology of CGRP receptor antagonism and the
relative roles of peripheral and central CGRP receptors in the
antimigraine therapeutic response to small molecule CGRP
receptor antagonists. The first was the capsaicin-induced der-
mal vasodilation assay (CIDV) in which capsaicin applied to
the intact forearm skin triggers release of CGRP, via activation
of the transient receptor potential cation channel subfamily V
member 1 (TRPV1) receptor on sensory nerve fibers that, in
turn, causes vasodilation through its effects on CGRP recep-
tors on blood vessels. This vasodilator response can be mea-
sured with laser Doppler and its inhibition provides a measure
of CGRP antagonism in the periphery.68-70 The second assay

Baseline (no drug) 140mg (clinical dose) 1120mg (8x clinical dose)

4-10% occupancy 43-58% occupancy

[plasma] 254-859 nM [plasma] 16.3-22.2uM

Fig. 3.—PET images of CGRP receptor binding before and after dosing the CGRP-RA telcagepant at clinically effective and
supratherapeutic antimigraine doses (adapted from Hostetler et al73). [11C]MK-4232 averaged PET images (overlaid on MR image)
in human brain at baseline (left panel) and after 140 and 1120 mg telcagepant (center and right panels, respectively). Color scale is in
standardized uptake values (SUV).
7 | Headache | Month 2019
was enabled by the development of a novel positron emission
tomography (PET) imaging tracer, [11C]MK-4232, as a key
pharmacological tool to visualize CGRP receptors in the brain
(see Fig. 3). This tracer, used at concentrations that are spe-
cific for CGRP receptors, was used to determine whether the
CGRP-RA, telcagepant (MK-0974), engaged central CGRP
receptor sites at clinically effective antimigraine doses.71,72
The pharmacodynamic data showed that clinically effective
acute antimigraine doses of telcagepant inhibited the CIDV
response >90% but at the same doses (and at doses nearly 10
time higher), the PET data showed no evidence for pharma-
cologically significant target engagement of central CGRP
receptors by the drug, indicating that the clinical effectiveness
of telcagepant was driven by its extracerebral actions.73,74 These
observations with a CGRP-RA, together with the observation
that the peripherally restricted human αCGRP agonist peptide
given IV can trigger migraine,35 have important implications
for our understanding of migraine neurobiology.
First, they support the view that migraine pain is, at least in
part, peripheral in origin, since CGRP can trigger it, and non-
brain penetrant drugs can relieve it. Second, a key site of action for
the triptans was most likely prevention of neuropeptide release
from sensory nerves in the periphery. Third, preliminary case
reports of [11C]MK-4232 PET studies of the occupancy of cen-
tral CGRP receptors by telcagepant (MK-0974) between and
during migraine attacks showed no evidence for increased oc-
cupancy by telcagepant during an attack, suggesting that the
blood-brain barrier remains intact during migraine and does
not allow peripherally acting drugs to access CNS target sites.75
It remains unknown whether accessing central sites will influ-
ence antimigraine efficacy and safety, as today’s CGRP-RAs as
well as CGRP therapeutic antibodies are essentially excluded
from the brain. Increased brain penetration if maintaining tol-
erability would be an interesting approach for next generation
CGRP-RA programs.
BIOLOGIC APPROACHES TO CGRP
MODULATION
In the late 1980s, immuno-neutralization studies with
CGRP antisera76-78 highlighted the important role of CGRP
in neurogenic inflammation. In the mid-1990s, as his PhD
thesis for Cambridge University, UK, Keith Tan conducted
immuno-blockade studies in vitro and in vivo with an
anti-CGRP monoclonal antibody and its Fab’ fragment
in the Merck Research Laboratories Neuroscience Center,
UK.79 His in vitro experiments first selected antibody can-
didates that could block the neurotransmitter role of CGRP
in vitro80 and these were then subsequently examined in vivo
for their ability to inhibit cutaneous vasodilation evoked
Headache Currents
by CGRP released from sensory nerve fibers as a result of
antidromic stimulation of the hind limb saphenous nerve.81
Conceptually, this preclinical hind limb assay has similar
pharmacology to the neurogenic inflammation assays used in
the context of migraine by David Williamson 25 that showed
the triptans inhibited CGRP release from meningeal sensory
nerves.
Tan’s in vivo studies were the first to show that a Fab’ CGRP
antibody fragment could block vasodilation evoked by sensory
nerve stimulation to a similar extent as the CGRP receptor pep-
tide antagonist CGRP8-37. A full-length CGRP mAb was inac-
tive over the short time course of his experiments.
These findings showed for the first time that CGRP neu-
tralizing approaches could be used to modulate the peripheral
activity of CGRP peptide released from activated sensory
nerves. The lack of activity of the full length CGRP mAb was
likely a pharmacodynamic artifact of the short (30 minutes)
time course of these experiments, giving insufficient time for
the mAb to access and neutralize the high levels of CGRP re-
leased into the synaptic cleft. It is interesting to speculate that
chronic or longer term exposure to the full-length antibody
might have realized pharmacological effects.
CGRP ANTIBODY THERAPEUTICS
(CGRP mAbs)
The initiation of biologic antibody approaches to CGRP
modulation as potential migraine therapeutics was driven
by the early human experimental research that showed that
CGRP, despite not being able to cross the blood-brain barrier,
could nevertheless induce a migraine attack.35 Subsequently
the demonstration that peripherally restricted CGRP-RAs were
clinically efficacious against migraine41 and CGRP-induced
headache42 added impetus to this effort.
Antibody drug administration is invasive, being either subcu-
taneous or intravenous, and as such not well suited to frequent
administration, for example, as acute symptomatic therapies,
where oral small molecules are generally preferred, especially
because speed of onset is important. Antibody drugs, however,
have several important advantages over small molecule drug
candidates, especially in chronic indications: (1) They have
long-circulating plasma half-lives (weeks) compared to small
molecules (hours), leading to monthly/infrequent administra-
tion improving adherence; (2) unlike small molecules, they lack
active toxic metabolites, as they are not degraded in the liver
but broken down to their constituent amino acids; (3) as anti-
bodies are not hepatically metabolized, they have no metabolic
drug-drug interactions; and (4) their exquisite target selectivity
minimizes off-target pharmacology, leading to low toxicity and
relatively benign nonmechanism-based tolerability profiles.
8 | Headache | Month 2019
Headache Currents

Table 3.—Monoclonal Antibodies Against CGRP or the CGRP Receptor Currently in Development

Marketed Name AIMOVIG® EMGALITY® AJOVY® TBD

Generic name Erenumab Galcanezumab Fremanezumab Eptinezumab†
Characteristics Human Humanized Humanized Humanized
Sponsor Amgen/Novartis Lilly Teva Alder
Being studied for Episodic migraine Episodic migraine Episodic migraine Episodic migraine
Chronic migraine Chronic migraine Chronic migraine Chronic migraine
Treatment resistant migraine Episodic cluster Refractory migraine
(hot flashes)
Chronic cluster‡ Episodic cluster
Treatment resistant migraine Chronic cluster‡
Posttraumatic headaches
Dosing Monthly SC 70 or 140 mg Loading dose 240 mg then 120 mg 225 mg Monthly SC Quarterly IV
monthly SC
675 mg Quarterly SC Final doses TBD
Target CGRP receptor CGRP peptide CGRP peptide CGRP peptide
†Produced in yeast.
‡Studies in chronic cluster headache were terminated for inefficacy.

There are currently 3 US FDA-approved CGRP antibodies
that have shown efficacy in the prevention of frequent episodic
and chronic migraine. These are the CGRP receptor anti-
body erenumab (AMG-334: AIMOVIG®: Amgen-Novartis)
and the CGRP ligand neutralizing antibodies galcanezumab
(LY2951742: EMGALITY®: Lilly) and fremanezumab (previ-
ously Rinat RN-307, Labrys LBR-101, TEV-48125: AJOVY®:
Teva). Eptinezumab (ALD-403; Alder) is in Phase 3 develop-
ment (see Table 3 for a comparison). Interestingly, although
published only in patent applications, CGRP ligand neutral-
izing antibodies and their Fab fragments do not appear to be
selective in their binding of αCGRP or βCGRP.82,83
COMPARING THE CGRP ANTIBODIES
CLINICALLY
The CGRP mAbs all have a peripheral site of antimigraine ac-
tion, and so their pharmacokinetic-pharmacodynamic relationship
was modeled translationally for dose predictions using the CIDV
assay in healthy volunteers and migraine patients.84,85 As a class,
the CGRP mAbs have all been shown to be effective in decreasing
the frequency of headaches in individuals with frequent episodic
migraine and chronic migraine as measured by the proportion of
patients improving by at least 50% over a 3-month period. These
studies also showed some patients with an unprecedented drop
of > 75% in their migraine headache days or, amazingly, com-
plete resolution of their migraine headache attacks. We need to
understand these so-called hyperresponders further (see Section
Questions to Ponder?) as well as those who fail to respond to this
mechanism. The clinical profiles of the CGRP-modulating and
receptor antibodies are and will be the subject of a multitude of re-
views and presentations, so we will not attempt to cover them here
but focus instead on similarities between the CGRP neutralizing
antibodies and potential differences from the CGRP receptor an-
tibody. Recent reviews have been provided by several groups.86-91
To date, despite diverse clinical trial designs (see Table 4 for
factors to watch out for) and diverse pharmaceutical character-
istics (formulation, dose, dose route [SC vs IV], dose interval,
and measured attributes) the clinical efficacy profile of the
CGRP biologics seems more similar than different.
Clinical response features probably common to all the anti-
bodies are:
1. Quick onset of effect, separating from placebo within
1 week.
2. Clinically meaningful responses observed after 1 month,
measured by decrease in the consumption of acute medica-
tion, and metrics of quality of life and disability.
3. A subgroup of “super responders” (≥50% improvement and
higher). Analyses vs placebo to support this observation are
necessary, and a few have been reported but not fully pub-
lished as of the time of this review (February 2019).
4. Responses not limited by past failure to other preventive
medications such as topiramate or botulinum toxin type A.
Erenumab showed efficacy in patients who had failed 2 or
more previous prophylactic medications.
5. Safety and tolerability appear generally similar to placebo
except for GI side effects (see Section Safety and Tolerability
of the CGRP Antibodies).
9 | Headache | Month 2019
Headache Currents

Table 4.—Factors to Consider When Comparing Clinical Trials With CGRP Antibodies

Mechanisms CGRP receptor and CGRP peptide neutralizing mAbs

Dosing route Intravenous vs subcutaneous – monthly or quarterly
• How frequent – how many injections to deliver active doses?
Headache definitions Frequent episodic migraine and chronic migraine ICDH-2 or ICDH3
• Migraine days vs headache days
Severity Baseline number of migraine days at entry
• Important for hyperresponder analyses
Study periods Lead in and baseline periods, long-term data
• Potential to affect placebo and drug response, long-term efficacy
Inclusion criteria Baseline headache days
• More or less severe migraine population being treated
• Use of standard preventatives
Exclusion criteria Previous use of anti-CGRP antibodies or Botox – common
• Lack of response to preventatives, limited exposure to opiates, and barbiturates
Concomitant medications Use of rescue and permitted use of other acute and preventative medications
• Clinical trial restrictions vs likely real-life scenarios
Placebo Size and variability of placebo response
• Use of non-placebo adjusted response data to describe trial outcomes
Response Reduction in moderate to severe migraine days
Reduction in migraine hours and most bothersome symptoms
Responder rate
Reduction in use of preventative medications
Hyperresponders Contribution of hyperresponders to overall clinical benefit
• Response data without patients with >75% and 100% reduction in migraine days

Important differences may include: due to receptor turnover-mediated elimination. Moreover, as

Route of administration (IV for eptinezumab and SC for
others).
Dose and dose interval (monthly for all, but also quarterly
SC – fremanezumab – or IV – eptinezumab). It is interesting
to consider the different biologic and drug properties that drive
dose and dose interval for the neutralizing anti-CGRP anti-
bodies in contrast with the anti-CGRP receptor approaches
(see Table 3 for dosing schedules). Overcoming fast systemic
CGRP turnover (and the accumulation of drug-CGRP com-
plex) and potential CGRP spikes during attacks are the main
drivers of the neutralizing approach. Thus, for the CGRP
ligand antibodies, the doses required for efficacy will reflect
the drug concentration needed to give sustained neutraliza-
tion of CGRP, and this will be a product of the clearance
rate or plasma half-life of the antibody. It is noteworthy that
with this neutralizing antibody pharmacology, as exposure
decreases, relative clearance remains constant, so there is a
gradual loss of activity over time, and smooth dose responses.
In contrast, for the CGRP receptor antibody, effective drug
exposures must first overcome nonrelevant CGRP receptor
binding in peripheral tissues (that may vary between individ-
uals perhaps based on body mass), and the clearance of drug
exposure ­decreases, relative receptor mediated clearance (both
migraine relevant and irrelevant) increases, so there is a rapid
loss of activity driving a step function-like dose response pro-
file. Full efficacy therefore requires a dose that can maintain
high plasma concentrations above the turnover rate of the
drug-CGRP receptor complex and this in turn is dependent
on the sustaining plasma half-life of the drug itself. This may
well be why there is no clear dose response for erenumab, since
once the threshold is reached, more drug drives duration but
not efficacy. The turnover rate of the CGRP receptor complex
is currently unknown. Higher doses of erenumab than those
studied to date could, if safe, theoretically give greater effi-
cacy at longer inter-dose intervals than a month, or as shown
by comparing the 70-140 mg dose, also reduce response vari-
ability at the currently studied intervals by ensuring that more
patients reach the efficacy threshold.
Gastrointestinal (GI) side effects. Unlike the CGRP neu-
tralizing mAbs, use of the CGRP receptor blocking antibody
erenumab produces constipation.92 Why might this be so? The
likely explanation lies in differences in the tissue biodistribu-
tion of the CGRP receptor antibody vs the CGRP peptide
neutralizing antibodies at the exposures required to produce
what is essentially an equivalent antimigraine preventative
10 | Headache | Month 2019
Headache Currents

effect (see Fig. 4). This hypothesis is supported by the differ-

ential activity of the CGRP neutralizing antibodies (galcane-
zumab and eptinezumab) vs erenumab, the CGRP receptor
antibody, in the CIDV pharmacodynamic assay that is a mea-
sure of CGRP activity in the peripheral vasculature.84,85 In
this assay, the CGRP neutralizing antibodies appear to block
the CIDV response less than the CGRP receptor antibody
erenumab at exposures that are clinically equi-effective in mi-
graine prevention. The greater sensitivity of the CIDV assay to
antimigraine doses of the CGRP neutralizing antibodies vs the
CGRP receptor antibody suggests: (1) that the antimigraine
site of action of the CGRP antibodies is not in the vasculature,
or the depth of inhibition of the CIDV response associated
with exposures to the clinically effective antimigraine doses of
the neutralizing antibodies and the receptor antibody would
have been similar, and (2) that the higher peripheral blockade
of the CIDV response with the CGRP receptor antibody than
the CGRP peptide neutralizing antibodies at clinically equiv-
alent antimigraine doses reflects a need to drive the CGRP
receptor antibody from the vasculature to its antimigraine site
of action in tissues (most likely within the ganglia or neural
processes of the trigeminal system – see Section Questions to
Ponder?).
What then does this mean for GI function during migraine
and chronic antibody therapy? Trigeminovascular αCGRP
released during migraine will promote migraine through tri-
geminal CGRP receptors, but circulating CGRP can also
­potentially alter GI motility directly at CGRP/amylin receptors
in the GI tract and indirectly via AMY1 receptors in the area
postrema, a chemosensory structure that is outside the blood-
brain barrier. The area postrema is part of the dorsovagal com- Fig. 4.—Antimigraine and GI sites of action of CGRP modulators
plex that also includes the nucleus tractus solitarius, a center at CGRP and amylin receptors. CGRP peptide antibodies are
for integrating distension, mechanosensory and other inputs white and CGRP receptor anti-bodies brown. We hypothesize
from the viscera, and the dorsal motor nucleus of the vagus (1) that CGRP neutralizing antibodies are confined to the
that coordinates motor and secretory drive to the viscera.93 The circulation and trap CGRP peptide, preventing its penetration
­activation of amylin receptors in the area postrema is important to CGRP and amylin receptors in tissues, (2) CGRP receptor
in controlling food intake and maintaining glucose homeosta- antibodies penetrate peripheral tissues and block CGRP
receptors selectively, and (3) small molecule CGRP-RAs enter
sis as it leads to gastric stasis and satiation, thereby reducing
peripheral tissues and central brain areas lacking a blood-brain
feeding.94 This effect appears to be mediated centrally, since an
barrier to interact with both CGRP and AMY1 receptors.
intact vagus nerve and an intact area postrema are required. In Pharmacological selectivity, receptor distribution, and tissue
rats subjected to total subdiaphragmatic vagotomy or surgical penetrance may all contribute to differences in the antimigraine/
ablation of the area postrema, amylin was no longer effective GI therapeutic index of the CGRP modulator drugs.
at inhibiting gastric emptying.95 The amylin analog pramlin-
tide that is used with premeal insulin to control carbohydrate
delivery to the small intestine in the treatment of diabetes96
does so by reducing gastric emptying to induce early meal ter- therapy, suggesting that this migraine symptom may also have
mination.36,97 It is noteworthy that the most prominent side an AMY1 component.98
effect of pramlintide use is nausea, a common symptom in mi- CGRP signaling has also been implicated as a mediator of the
graine, which appears from post hoc analyses of fremanezumab postoperative gastric ileus and inflammation99 that often occurs
trials to be rapidly responsive to CGRP neutralizing antibody with abdominal surgery. Preclinical studies in dogs, rats, and
11 | Headache | Month 2019
mice have shown that the peptide CGRP receptor antagonist
CGRP8-37,100 the CGRP-RA olcegepant,101 and an ­anti-CGRP
antibody improve postoperative gastric emptying.102
The pharmacology of CGRP in GI physiology is complex.
Early studies have used antibodies and reagents with poorly
defined specificity, and many have not recognized the potent
cross-reactivity of CGRP at AMY1 receptors, making inter-
pretation of the findings difficult. Nonetheless, CGRP 103 and
CGRP receptors 104 have been shown to present throughout
the human gastrointestinal tract. Specific CGRP displaceable
binding sites for amylin have also been shown in the stomach
fundus in rodents.105 αCGRP appears to be associated with
­extrinsic sensory afferent innervation, and βCGRP with intrin-
sic enteric and myenteric neurons.106 In the GI tract, CGRP acts
as a s­ ensory transmitter to promote GI motility via the extrin-
sic sensory and intrinsic pathways that mediate the peristaltic
response to muscle stretch and to mucosal simulation, respec-
tively.107 Exogenously administered αCGRP has been shown to
cause diarrhea in mice that was blocked by a CGRP neutral-
izing antibody and the small molecule CGRP-RA o­ lcegepant,
suggesting a potential to treat diarrhea in disease or treatments
that result in elevated CGRP.108,109
Interestingly, a case report of a patient with irritable bowel
syndrome (IBS) and a history of migraine headaches showed
that low-dose triptan medication relieved GI hypermotility
symptoms of IBS, consistent with a role for CGRP in increased
GI motility and the known pharmacology of the triptans
to inhibit sensory (visceral) afferent CGRP release.110 We
acknowledge that this CGRP-hypermotility hypothesis is not
consistent with some early experimental preclinical observa-
tions that CGRP neutralizing antibodies ameliorate ileus in
the small bowel and colon postoperatively,111,112 but this may
reflect the differential involvement of CGRP released from vis-
ceral afferent neurons when activated by nociceptive stimuli or
inflammatory stimuli produced during abdominal surgery vs
the enteric and myenteric CGRP receptors that respond to an
excess of circulating CGRP. It should be noted here that visceral
sensory afferent activation will be associated with the release of
colocalized sensory neuropeptides such as substance P that may
also contribute to any physiological proinflammatory response.
Selective lymphatic deletion of calcitonin receptor-like recep-
tor (CLR), the core subunit of the canonical CGRP receptor
(CLR/RAMP1) and the 2 adrenomedullin receptors (AM1
and AM2), has been shown in mice to exacerbate intestinal in-
flammation and impair lipid absorption after acute mucosal in-
jury.113 In an extension of these studies, the same group recently
showed that this selective deletion of CLR in the lymphatics
resulted in disorganized and reduced mucosal and submuco-
sal innervation and inefficient absorption of dietary fat under
conditions of a high-fat diet. These findings, together with the
Headache Currents
observation that mice with genetic loss of the CGRP corecep-
tor RAMP1 have mucosal and submucosal innervation deficits,
suggest that CRL, and perhaps CGRP receptors in particular,
may play a regulatory role in the neurolymphocrine axis that
regulates intestinal lipid absorption.114 The pathophysiologi-
cal consequences of disrupting this pathway chronically with
drug treatments remains a topic for future monitoring and
investigations.
CGRP neutralizing antibodies act within the vasculature to
trap the CGRP peptide when it is released, thereby preventing
its penetration to activate CGRP receptors in tissues. At ther-
apeutic antimigraine exposures, they are unlikely to sequester
CGRP released within GI tissues and thereby influence GI
­motility directly. In contrast, CGRP neutralizing antibodies
will prevent CGRP released during migraine from reaching
amylin receptors within the area postrema, thereby reducing
gastroparesis. It would be interesting to determine whether the
therapeutic use of the CGRP neutralizing antibodies could help
relieve GI stasis in those migraine patients in which it is a prom-
inent comorbid feature of their headache attacks.115 In contrast
to the neutralizing antibodies, the CGRP receptor antibody ere-
numab (assuming it is inactive at AMY1 receptors; see Section
Introduction above for discussion) is dosed to achieve tissue
penetration to prevent migraine. Erenumab therefore has the
potential to block CGRP receptors in tissues (whether its ­origin
is from visceral sensory afferents or from elevated CGRP in the
circulation), thereby reducing CGRP-mediated GI motility and
peristalsis, and predisposing to constipation in some individ-
uals. The reason for this susceptibility is unknown but could
relate to differences in the status of sensory afferent CGRP tone
between individuals.
The potential GI side effects associated with long-term use
of small molecule CGRP-RAs are difficult to predict as they
will have multiple sites of action at CGRP and amylin re-
ceptors throughout tissues in the gut-brain axis (see Fig. 4).
Additionally, pharmacological characterization of their activ-
ity against neuronal α or enteric βCGRP is sparse, and their
perceived selectivity for CGRP over AMY1 receptors is likely
dependent on the assay systems used, and this has also not been
extensively studied.39 It is possible that the gastroprokinetic and
reduced intestinal motility effects of the CGRP-RAs will off-
set; however, from what we know today from pilot migraine
prevention studies with telcagepant50 and dose ranging Phase
2/3 migraine prevention trials with atogepant,54 constipation
was reported at higher rates than placebo in at least one drug-
treated arm in each trial. Definition of the GI therapeutic index
for CGRP-RAs in migraine prevention awaits dose selection
and completion of more extensive Phase 3 registration trials.
Real-world postmarketing surveillance is now needed to deter-
mine the differential GI profiles of the CGRP modulators and
12 | Headache | Month 2019
perhaps identify patient subsets most at risk of GI dysfunction
to personalize the selection of the best CGRP therapeutic mo-
dality to meet their needs.
SAFETY AND TOLERABILITY OF THE CGRP
ANTIBODIES
The consequences of long-term CGRP system blockade
were previously unknown, but to date all the CGRP antibod-
ies look generally safe and well tolerated. The clinical labs,
ECG, and adverse event profiles are unremarkable. Overall,
the main adverse events were generally mild-moderate and
did not differ significantly from placebo, with the main ob-
servations being injection site reactions with SQ adminis-
tration and constipation with the CGRP receptor antibody.
Happily, to date, there is no evidence for the liver toxicity
liability that was seen with early CGRP-RAs in chronic daily
use. The final profiles, however, await the outcome of lon-
ger term real-world open label studies in greater numbers of
patients.116,117
As noted in the mAb product labels, with all therapeutic
proteins, there is potential for immunogenicity, but the
detection of antidrug antibodies (ADAs) is highly depen-
dent on the sensitivity and specificity of the assay. Moreover,
the observed incidence of antibody (including neutralizing
antibody that could reduce therapeutic response) positivity
varies with assay methodology, sample handling and time
of collection, concomitant medications, and underlying dis-
ease. For these reasons, absolute comparison of the incidence
of antibodies across the various CGRP mAbs is likely to be
misleading. The immunogenic potential of the CGRP bio-
logics is, however, incompletely described by the data that
are currently available publicly and cited in the mAb product
labels, since full assessment requires a complete phase-out
of medication for proper measurement of the persistence of
ADAs. Since the current CGRP mAbs have a long half-life,
definitive measurements of ADAs await measurements up to
6 months after last drug administration. With this caveat in
mind, however, ADA rates are generally low in all programs
and seem to be generally non-neutralizing, without safety
consequences so far.
The publication of a review paper entitled “Wiping out
CGRP – cardiovascular risks”118 no doubt gave rise to concern.
The title of the manuscript was, however, somewhat misleading,
since it implied that the authors would present real evidence of
cardiovascular risk for the CGRP modulatory mechanism in
the treatment of migraine, but did not. After careful reading, it
turns out that this paper and subsequent publications from the
same group offer a very plain position that CGRP has vascu-
lar effects, and therefore it is important to consider the effects
Headache Currents
of CGRP modulation on cardiovascular function in relevant
preclinical and clinical assays and disease settings. The CGRP
research community has certainly taken this sentiment to heart.
Preclinical studies have used human coronary arteries in
vitro119,120 and preclinical models in vivo of myocardial isch-
emia121 and chronic heart failure122 to show that CGRP an-
tagonism had no intrinsic action on cardiac vascular smooth
muscle. Additionally, CGRP antagonists had no effect on
payback myocardial reactive hyperemic responses in conscious
dogs.123 In contrast, sumatriptan increased the severity of myo-
cardial ischemia during atrial pacing in dogs with coronary ar-
tery stenosis.119 In nonhuman primates, CGRP antagonism did
not affect intrinsic coronary flow, blood pressure, nitroglycer-
in-dependent increases in carotid and coronary flow, or pacing
dependent changes in coronary flow.124
While these acute preclinical studies do not directly ­address
the speculation that chronic CGRP modulation could neg-
atively impact CGRP-mediated endogenous physiological
responses to adverse spontaneous cardiovascular events and
accidents, they provide hard data to support the cardiovascu-
lar safety of the CGRP modulatory mechanism. This view is
supported by 14-week chronic cardiovascular telemetry safety
studies in cynomolgus monkeys with the CGRP neutralizing
antibody fremanezumab given at supratherapeutic doses. No
clinically significant changes were noted in any hemodynamic
parameter at any assessment point, nor any relevant changes
noted in the ECG.125
The preclinical findings are supported by considerable clin-
ical evidence suggesting low cardiovascular risk. Early human
experiments were conducted by Petersen and colleagues, who
showed clinically that low doses of the CGRP-RA olcegep-
ant completely inhibited headache induced by CGRP,42 yet at
supratherapeutic doses there was no effect on blood pressure,
the diameter of systemic or cerebral arteries, or cerebral blood
flow.126 Clinically, studies with telcagepant (MK-0974) showed
that it had no effect on spontaneous ischemia in cardiovascular
patients,127 that it did not affect exercise time at suprathera-
peutic doses in patients with stable angina,128 that it did not
affect nitroglycerin-induced vasodilation in healthy men,129 nor
was there any hemodynamic interaction with sumatriptan.130
A partially completed study of supratherapeutic doses of telcage-
pant (600 and 900 mg) in patients with migraine and stable
coronary artery disease also supported the cardiovascular safety
of the CGRP receptor antagonist mechanism.131
Cardiovascular safety has also been shown with the CGRP
receptor mAb erenumab in patients with stable angina. The
primary endpoint was the change from baseline in treadmill
exercise time. Erenumab was similar to placebo in all parame-
ters during the 12 week follow-up.132 Sustained CGRP inhibi-
tion with the CGRP neutralizing mAb fremanezumab is also
13 | Headache | Month 2019
not associated with hemodynamic or ECG changes in a female
population at an increased age risk for cardiovascular events.133
Fremanezumab was also shown not to be associated with hemo-
dynamic changes in men and women up to 65 years of age with
chronic migraine using the vasoconstrictor triptan medications
in the context of a 3-month study. Finally, chronic studies of
the CGRP neutralizing mAb galcanezumab at supratherapeutic
doses did not reveal any vascular liabilities.134
Most importantly, in addition to these experimental clinical
studies, the widespread use of small molecule CGRP receptor
antagonists and antibodies against CGRP or its receptor in
thousands of patients during multiple clinical trials has not
­revealed any systematic cardiovascular problems. While clinical
trial data are still not real-world experience, no other class of mi-
graine medication, including those inducing vasoconstrictions
such as ergotamine and the triptans, has been so intensively and
exhaustively tested for cardiovascular safety. We conclude that
the evidence so far suggests that the cardiovascular safety of
CGRP modulation appears high, but postmarketing surveil-
lance is, of course, still necessary.
QUESTIONS TO PONDER?
While we have come a long way in our understanding of
CGRP and its inhibition in migraine therapy there are still
many unanswered questions.
Where does CGRP Come from to Trigger a Migraine
Attack?
A recent systematic review and meta-analysis of migraine
biomarkers has shown that CGRP in CSF and blood was ele-
vated in chronic migraine patients (glutamate and NGF were
also increased), and levels of the endogenous opiate β-endor-
phin decreased.135 Preclinically, it has been shown that cor-
tical spreading depolarization/depression (CSD) may trigger
the release of neuropeptides such as CGRP136 into the jugular
vein and CSF from the primary trigeminal afferent fibers,137
where it could promote sensitization of the trigeminal system.
In contrast, there are findings138 that suggest that acute ac-
tivation of CGRP receptors may not play a key role in medi-
ating CSD-evoked headache, but CGRP-mediated activation
of meningeal afferents evoked by cortical efflux of potassium
ion could promote headache. Clinically, however, in migraine
without aura there is little evidence for CSD, yet CGRP is
elevated, and CGRP modulators are effective. Interestingly,
when CGRP triggers a migraine attack in patients with mi-
graine with aura, it is an attack without aura, thereby sep-
arating the role of CGRP in migraine pain from CSD. We
can therefore hypothesize that the peripherally acting CGRP
Headache Currents
modulators (CGRP-RAs and CGRP mAbs) that we have
today should be equally effective in migraine with and with-
out aura. It would be interesting to mine the existing trial
data sets to answer this question. The evaluation of central
CGRP in migraine mechanisms awaits the development of a
brain penetrant CGRP-RA.
Where do CGRP-RAs Act to Promote Migraine Pain?
As discussed above (see Section Comparing the CGRP mAbs
Clinically – GI function), the clinical CIDV data with CGRP
peptide neutralizing vs the CGRP receptor antibody support an
extravascular peripheral site of pro-migraine activity for CGRP.
In the 1990s, Cumberbatch and colleagues139 used the intra-
vital meningeal microscopy technique with electrophysiology
recordings of second order sensory neurons in the trigeminal
nucleus caudalis, to show that exogenous intravenous admin-
istration of high concentrations of CGRP could sensitize the
trigeminal system such that the responses to non-nociceptive
sensory inputs (evoked by stimulation of the vibrissae) in sec-
ond-order sensory neurons in the brain stem that received
convergent nociceptive sensory input from the dura became ex-
aggerated. In these studies an intense train of electrical stimuli
delivered in repeated cycles to the dura mater was used in the
“seek” routine to find convergent trigeminal neurons receiving
both dural nociceptive input and sensory vibrissal input. We
hypothesize that this intense activation could have sensitized
central trigeminal pathways. If this is the case then the results
suggest that circulating CGRP, acting outside the blood-brain
barrier peripherally at CGRP receptors on perivascular trigem-
inal sensory fiber terminals or neuronal cell bodies,140,141 could
magnify central sensory and nociceptive processing in the con-
text of a trigeminal system that becomes sensitized by migraine
headache attacks.
Studies from Dan Levy in Rami Burstein’s lab, using lower
dose infusions of CGRP and single shock seek protocols that
are unlikely to have sensitized the trigeminal system, did
not reproduce the Cumberbatch findings, leading them to
challenge Cumberbatch’s interpretation and propose that
the facilitating effect of CGRP on the discharge of central
trigeminal neurons resulted from a central rather than pe-
ripheral site of action.142 There is no doubt that CGRP re-
leased or applied centrally will activate trigeminal neurons,
but clinically IV CGRP triggers migraine, and it is unlikely
to have penetrated from the blood to central CGRP recep-
tors on sensory neurons in the brain stem to exert sensitiz-
ing effects. In contrast to their original suggestion, the same
laboratory showed that pretreatment with the CGRP mAb
fremanezumab, which does not cross the blood-brain barrier,
selectively inhibited the responsiveness of neurons receiving
input from thinly myelinated Aδ fibers, but not neurons
14 | Headache | Month 2019
receiving input from neurons receiving input from unmy-
elinated C-fibers neurons, as measured by a decrease in the
percentage of neurons that showed activation by CSD.143 In
an accompanying study,144 single-unit recording was used to
assess the effects of fremanezumab on spontaneous and
evoked activity in naive and CSD-sensitized trigeminovascu-
lar neurons in the spinal trigeminal nucleus of anesthetized
male and female rats. The study showed that fremanezumab
inhibited naive high-threshold neurons, but not wide dy-
namic range trigeminovascular neurons. The inhibitory ef-
fects of fremanezumab on the neurons was limited to their
activation from the intracranial dura but not facial skin or
cornea. These studies with fremanezumab clearly indicate
that neutralization of CGRP peripherally can affect trigem-
inal sensitivity, supporting a peripheral not central site of
­action for CGRP in migraine.
There is more work to do, however, to unravel the exact site of
action of CGRP in migraine. To date there is no direct evidence
showing that CGRP does or does not activate trigeminal neu-
rons in the trigeminal ganglia or whether the observed effects of
CGRP on trigeminal sensitivity are direct or indirect. These are
areas for future study, especially as there are marked temporal
differences in the onset of effects seen in these short preclinical
experiments, compared to the time taken for exogenous CGRP
to trigger migraine in humans.
If Triptans Inhibit CGRP Release then Why aren’t Triptans
Useful Migraine Preventative Agents?
Immunohistochemical and preclinical pharmacological stud-
ies support the hypothesis that one of the key mechanisms of
­action of the triptans is to inhibit CGRP release in the ­meninges
through an action at prejunctional 5-HT1D receptors on tri-
geminal sensory nerve endings. It is likely that this is through
an action on Aδ fibers that contain CGRP and glutamate
since substance P levels, a peptide in C-fibers that is released
upon activation, were unchanged. CGRP receptors have also
been shown146 to be expressed on Aδ-fibers in the dura mater,
where they have the potential to potentiate nerve activation and
CGRP release during migraine in an axon reflex-like pharma-
cological response. Clinically, the 5-HT1D agonist sumatriptan
normalizes elevated CGRP in migraine by inhibiting its release
concomitant with providing headache relief.
In small clinical studies, naratriptan and frovatriptan had the
modest preventative efficacy147,148 against migraine, although
their full potential was not explored because of concern over
potential 5-HT1B receptor-mediated adverse cardiovascular side
effects with chronic administration at higher doses. These clin-
ical observations provide a potential link between triptan sero-
tonin agonist-induced inhibition of CGRP release and chronic
CGRP modulation in migraine prevention.
Headache Currents
Is CGRP Modulation Likely to be Effective in Other
Headache Syndromes?
CGRP has been shown, as it does in migraine, to trigger
headache in cluster patients.149 Positive Phase 3 clinical trials
have now been reported in episodic cluster headache 150but in-
terestingly not in chronic151 cluster headache. The reasons for
this difference are currently unknown. Future studies could ex-
plore the utility of CGRP modulation in chronic tension-type
headache, chronic posttraumatic headache, and other headache
disorders.
Hyperresponders – Myth or Reality?
A much-hyped finding in the migraine prevention clinical tri-
als of all the CGRP antibodies has been evidence for a significant
number of migraine patients who appear to be hyperresponders
to prolonged CGRP modulation. There is lots of speculation
about what this means.152 Does it indicate specific CGRP-
driven subtypes of migraine? Is CGRP a “gain control” for tri-
geminal sensory neurotransmission that is amplified excessively
in some migraineurs? Can we use simple fluid biomarkers153,154
to personalize treatment regimens or do we need to probe the
physiology? For example, do the CGRP hyperresponders have
exaggerated sensory (allodynia) or autonomic signs such as
flushing or vasodilation in tissues innervated by the trigeminal
system during their attacks suggestive of sensory activation? Are
these absent in non-responders?
A less exciting but highly plausible explanation for the
apparent identification of the hyperresponder phenotype is
that it simply reflects the well documented natural history
of the disorder, where in population-based studies there
is an o­bvious dynamic relapsing-remitting lability in the
number of ­attacks per time period in frequent and chronic
migraineurs. If this is the case, then might it not be expected
that an individual enrolling in any study who is either at the
peak or nadir of their attack cycle may get better or remit
during the study period independent of drug treatment? The
key question to look at is perhaps how different the 100%
super-responder rates are from placebo in any of these stud-
ies, as nonsignificant differences may indicate that the 100%
response rate is simply a reflection of the relapsing remitting
cycle of frequent or chronic migraine.
COMPETITION
The commercial market for oral acute treatment of migraine
will essentially be generic by the time a small molecule CGRP
antagonist is launched. The CGRP mechanism is clearly differ-
entiated from triptans on the basis of improved tolerability and
safety profile, as it is a non-vasoconstrictor non-serotonergic
15 | Headache | Month 2019
mechanism that will not have lingering concerns over cardio-
vascular side effect liability and serotonin syndrome. To maxi-
mize success, it will be key to consider strategies to differentiate
efficacy, in addition to tolerability and safety, of the CGRP
antagonists rimegepant and ubrogepant from the triptans.
­ tion in migraine – what we know and what we don’t know.
These may include improvement over the 24-hour triptan sus-
tained efficacy profile, and efficacy in triptan low responders
and excluded populations.
Lilly’s re-acquired (from CoLucid Pharmaceutical) cen-
trally acting serotonin 5-HT1F receptor selective agonist
lasmiditan also lacks cardiovascular side effect liability and
faces a similar challenge for differentiation from the triptans
since its efficacy, as measured by pain-free rates at 2 hours, is
similar to the triptan class (28-32% depending on the dose).
Due to its central mechanism of action, lasmiditan use is
associated with a higher rate of CNS adverse effects such as
dizziness and sedation.155,156 It is unknown whether, due to
its central site of action, lasmiditan will also carry a warning
regarding CNS serotonin syndrome.
Competition for the CGRP receptor mAbs in migraine
­prevention will likely come from the oral CGRP-RA atogepant
that showed a promising efficacy and safety profile in Phase
2 trials. The completion of successful Phase 3 clinical trials
with atogepant will provide an important non-injectable treat-
ment option for patients in the prophylaxis setting.
Finally, the next generation of potential antimigraine
drugs is beginning to be explored experimentally and clini-
cally. Neutralizing antibodies to PACAP and antibodies to its
­receptor PAC1 have been developed and are now moving into
clinical development.157,158
SUMMARY AND CONCLUSIONS
The emergence of the CGRP-class as effective antimigraine
agents is fueling detailed pharmacological studies to gain fur-
ther insight into the regulation of CGRP-family receptors and
their signaling pathways.159 It is now 25 years since the mar-
keting of the triptans, the last new class of drugs to advance
the understanding and treatment of migraine headaches. The
journal Science featured CGRP as the molecule at the future
heart of migraine therapy,160 highlighting the fact that CGRP
modulators have the potential to provide effective, differenti-
ated therapy for acute migraine treatment and prevention of
frequent episodic and chronic migraine. The availability of
­injectable CGRP biologics and small molecule oral CGRP-RAs
will provide flexible dosing options for patients, physicians, and
payers. Real-world evidence will establish their clinical profiles
and optimize their use in patients most likely to benefit from
their unique therapeutic profiles. Migraine patients are waiting.
Headache Currents
KEY CONCLUSIONS
1. CGRP modulators – the history and renaissance of a new
drug class.
2. Biology and pharmacology of CGRP and CGRP modula-
3. Properties of small molecule CGRP receptor antagonists,
receptor antibodies, and ligand neutralizing in the potential
impact on their clinical and safety profiles.
Acknowledgements: Thank you to Debbie Hay for insightful email
conversations and to Elaine Balfe for her help with preparing the
manuscript for submission. Thanks to Kirk Moldoff (http://www.
galeriekirk.com/) for permission to use the glass man graphic.
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