EXPERT OPINION ON DRUG SAFETY
2020, VOL. 19, NO. 10, 1237–1250
https://doi.org/10.1080/14740338.2020.1811229
REVIEW
CGRP inhibitors for migraine prophylaxis: a safety review
Eduardo Rivera-Mancillaa, Carlos M. Villalónb and Antoinette MaassenVanDenBrink
a
a
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The
Netherlands; bDepartment of Pharmacobiology, Cinvestav-Coapa, Mexico City, Mexico
ABSTRACT
ARTICLE HISTORY
Introduction: Since calcitonin gene-related peptide (CGRP) plays an important role in the pathophysiology of migraine via the activation of the trigeminovascular system, the newest prophylactic treatments directly block CGRP or its receptor. However, the safety of these novel antimigraine drugs is not
yet sufficiently established.
Areas covered: Based on the blockade of CGRP or its receptor, this review considers: (i) the effects of
the novel prophylactic antimigraine drugs (i.e. gepants and monoclonal antibodies) in clinical trials; and
(ii) the potentially negative effects of blocking CGRP or its receptor in terms of safety.
Expert opinion: In the last decade, clinical trials have demonstrated the efficacy of new drugs for the
preventive treatment of migraine which aim to (i) block CGRP or its receptor; (ii) increase tolerability as
compared to the currently available prophylactics; and/or (iii) be more effective and safer than other
treatments. However, these trials are limited to study the safety on the short term, and a cardiovascular
risk with prolonged use cannot be excluded. Clearly, basic science experimental studies and long-term
clinical trials (i.e. Phase IV) are required to delineate the safety of the newest prophylactic antimigraine
drugs without causing unwanted side effects due to chronic CGRP (receptor) blockade.
Received 9 June 2020
Accepted 13 August 2020
1. Introduction
Migraine is a common neurovascular disorder characterized by
recurrent moderate to severe headaches accompanied by
nausea, vomiting, phonophobia, and/or photophobia, lasting
from 4 to 72 hours [1,2]. Due to its high prevalence and high
socioeconomic and personal impact worldwide, it has been
considered as the third most prevalent disorder, the secondhighest specific cause of disability, and the first in those
people under 50 years of age [2,3].
The exact pathophysiological mechanisms underlying the
onset of a migraine attack remain unclear. However, extensive
research in the last three decades has demonstrated that
calcitonin gene-related peptide (CGRP) plays an important
role in the genesis of migraine via the activation of the trigeminovascular system [4–7]. In this respect, as previously
reported: (i) activation of the trigeminovascular system
(which includes the meninges and intracranial blood vessels)
results in cranial vasodilation mainly mediated by CGRP
release [6]; (ii) serum levels of CGRP are elevated during
migraine attacks [4]; and (iii) intravenous administration of
CGRP produces vasodilation of the middle meningeal artery
[12] and triggers migraine-like headaches [13,14]. These findings, which further support the key role of CGRP in the pathophysiology of migraine, indicate that CGRP and its receptor
may be therapeutic targets for developing new antimigraine
drugs [15].
While the triptans (which act as agonists at 5-HT1B/1D/1F
receptors) are considered the gold standard for acute
KEYWORDS
Antimigraine drugs; CGRP;
CGRP blockade; CGRP
receptor; CGRP receptor
blockade; migraine;
prophylactic treatment
antimigraine treatment [16,17], some patients with a high
frequency of migraine attacks or chronic migraine require
prophylactic antimigraine treatment [18,19] in order to reduce
the frequency, severity, and duration of attacks, as well as the
associated disability [18,20,21]. This prophylactic treatment,
which encompasses a wide variety of drugs with mechanisms
of action unrelated to blocking the CGRPergic system, includes
β-blockers, antiepileptics, Ca2+ channel blockers, 5-HT receptor
antagonists, angiotensin-converting enzyme inhibitors and
angiotensin II receptor antagonists [17,20]. It is noteworthy
that these drugs were not originally developed for the prophylactic treatment of migraine, but over time they proved
useful in migraine management. Moreover, their specific
mechanisms of action are not well understood and, in most
cases, remain speculative [17].
Since migraine is related to several comorbidities (e.g. cardiovascular, pain disorders, psychiatric, or neurological comorbidities) [20], the use of these prophylactic drugs should be
considered based on the comorbidity presented by the
migraine patient. In addition, the possibility of recurrent
migraine attacks may result when the use of the prophylactic
medications is withdrawn.
Interestingly, novel prophylactic antimigraine treatments,
which directly target CGRP or its receptor, have been explored
in the last decade (Figure 1) [15,22]. These novel antimigraine
treatments include: (i) small-molecule CGRP receptor antagonists (i.e. gepants); and (ii) monoclonal antibodies targeting
either CGRP or its receptor (see Table 1), which have now been
approved by the Food and Drug Administration (FDA) and/or
CONTACT Antoinette MaassenVanDenBrink
a.vanharen-maassenvandenbrink@erasmusmc.nl
Division of Vascular Medicine and Pharmacology,
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, CA 3000, The Netherlands
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
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E. RIVERA-MANCILLA ET AL.
2. CGRP and migraine
Article highlights
●
●
●
●
Migraine is a highly disabling, complex, and multifactorial neurological disorder that involves activation of the trigeminovascular system,
resulting in the release of CGRP from the sensory nerves.
Although there is a wide variety of prophylactic antimigraine drugs
that act via different mechanisms of action (e.g. β-blockers, antiepileptics, Ca2+ channel blockers, 5-HT receptor antagonists, etc.), CGRP
(receptor) blockade is critical for the novel prophylactic treatments of
migraine.
For prophylactic antimigraine treatment based on CGRP (receptor)
blockade, the gepants (rimegepant and atogepant) and the monoclonal antibodies (erenumab, eptinezumab, fremanezumab, and galcanezumab) are effective and safe in the short term.
Regarding the novel antimigraine treatments that involve CGRP
(receptor) blockade, basic science experimental studies and longterm clinical trials and/or registries (Phase IV) are required to confirm
their safety and effectiveness and to delineate their potential cardiovascular side effects.
by the European Medicines Agency (EMA) for the preventive
treatment of migraine in adults. Additionally, the Spiegelmers
(CGRP-neutralizing mirror-image L-aptamers) have been proposed as a new candidate for the prophylactic antimigraine
treatment [23]. However, to our knowledge, no further studies
have demonstrated their antimigraine effectiveness.
Despite the highly promising potential of the gepants and
monoclonal antibodies for the prophylactic antimigraine treatment, the safety of these drugs and their mechanisms of
action have not yet been explored in long-term trials [15,25–
27]. Accordingly, this review attempts to provide an overview
of the contributions of blocking CGRP or its receptor in terms
of: (i) tolerability and safety, covering the efficacy of the new
prophylactic antimigraine treatments (see Table 1); and (ii) the
possible negative side effects and/or risks produced by the
long-term blockade of the CGRPergic system.
In addition to serotonin, histamine, and nitric oxide [28], CGRP
plays an important role in the pathophysiology of migraine [4–
7]. CGRP is a 37-amino acid neuropeptide localized in the
peripheral and central sensory nervous system, acting as
a potent vasodilator as well as a neurotransmitter [29,30].
CGRP mainly mediates its biological effects through its interactions with the CGRP receptor. This canonical receptor is
a complex of two subunits, namely: (i) a G-coupled protein
receptor called calcitonin receptor-like receptor (CLR); and (ii)
a receptor activity-modifying protein 1 (RAMP1) [31] (see
Figure 2). In humans, CGRP is present in two isoforms, αCGRP and β-CGRP. Since α-CGRP is the principal isoform localized in the peripheral and central sensory nervous system
[32], its biological activity seems more important in the pathophysiology of migraine. However, in terms of side effects, we
cannot exclude the β-CGRP isoform (which plays a role in the
enteric transmission) [33] since some CGRP-blocking drugs (i.e.
monoclonal antibodies such as eptinezumab, fremanezumab,
and galcanezumab) are not selective and can block both the
α-CGRP and β-CGRP isoforms.
In the last decades, different studies have shown the role
of CGRP during a migraine attack. In this respect, CGRP is
released from the trigeminal ganglion via the activation of
the trigeminovascular system [34]. As previously reviewed by
Iyengar et al. [35], the trigeminal ganglion sends central
afferent projections to the trigeminal nucleus caudalis in
the brain stem and also to the C2 segments of the cervical
spinal cord (trigeminocervical complex); and peripheral projections through sensory nerves, which innervate the cranial
vasculature and the dura mater. Then, the released neuropeptide can bind to its receptor localized in the human
cranial arteries producing vasodilation [36]. Furthermore, it
Figure 1. An overview of some antimigraine drugs that directly block CGRP or its receptor. Since CGRP plays an important role in the pathophysiology of migraine,
in the last decades new antimigraine drugs have been developed for migraine treatment. These drugs include: (i) gepants, which act by directly blocking the CGRP
receptor (i.e. rimegepant and atogepant); and (ii) monoclonal antibodies, which directly block CGRP (i.e. eptinezumab, fremanezumab and galcanezumab) or its
receptor (i.e. erenumab). CLR, calcitonin receptor-like receptor; RAMP1, receptor activity-modifying protein 1.
EXPERT OPINION ON DRUG SAFETY
1239
Table 1. The new antimigraine drugs targeting CGRP or its receptor.
Compound
Gepants
Rimegepant
(BMS-927,711)
Atogepant
(MK-8031,
AGN-241,689)
Monoclonal
antibodies
Erenumab
(AMG-334)
Eptinezumab
(ALD-403)
Mechanisms
of action
Dosage
Notes
Ref.
CGRP
receptor
antagonist
75 mg
Oral
(i) Acute migraine treatment
(ii) Ongoing for prophylactic
treatment
[47,48,53–
(i) FDA approved for the acute treatment of migraine
(ii) Ongoing phase II/III clinical trial (NCT0372368) to evaluate its 56]
the effectiveness as preventive treatment for migraine in
adults
CGRP
receptor
antagonist
10, 30,60 mg
Oral
Prophylactic treatment for
episodic and chronic migraine
(i) Phase IIb/III clinical trials
(ii) Ongoing Phase III clinical trial (NCT03855137)
[49–52]
CGRP
receptor
blocker
70, 140 mg
Prophylactic treatment for
Subcutaneous episodic and chronic migraine
(i) The side effects were similar to placebo
(ii) FDA approved in May 2018
(iii) EMA approved in July 2018
[24,60–
66]
Prophylactic treatment for
episodic and chronic migraine
(i) FDA approved in February 2020
[72–75]
Prophylactic treatment for
episodic and chronic migraine
(i) FDA approved in September 2018
(ii) EMA approved in March 2019
[76–85]
CGRP blocker 225, 675 mg Prophylactic treatment for
Subcutaneous episodic and chronic migraine
(i) FDA approved in September 2018
(ii) EMA approved in November 2018
[86–93]
CGRP blocker 30, 100,
300 mg
Intravenous
Fremanezumab CGRP blocker 225, 675 mg
(TEV-48,125)
Subcutaneous
Galcanezumab
(LY-2,951,742)
Indication (type of treatment)
FDA, Food and Drug Administration; EMA, European Medicines Agency.
Figure 2. Composition of the human calcitonin-family receptors and the relative affinity/potency of binding of CGRP, AM and AMY to canonical and non-canonical
receptors. CGRP can exert its pathophysiological effects via the activation of its receptor (CGRP receptor) or via the activation of distinct CGRP-responsive receptors
with moderate affinity/potency for AM receptors, and practically the same potency for the AMY receptors, as compared to their endogenous ligands. CGRP,
calcitonin gene-related peptide; AM, adrenomedullin; AMY, amylin; CLR, calcitonin receptor-like receptor; CTR, calcitonin receptor; RAMP, receptor activity-modifying
protein. Human and *rodents values of apKi, bpEC50, and cpKd [98,100].
has been reported that CGRP concentrations in serum [4,8–
11] and saliva [37] are elevated in migraine patients, and
that these levels are normalized or reduced after treatment
with triptans [8,13,14]. Moreover, intravenous injections of
CGRP can trigger moderate to severe migraine-like
headaches in migraine-prone patients (but not in nonmigraine patients), suggesting that migraine patients are
unusually sensitive to CGRP [13,14]. This approach has led
to the development of experimental animal models for the
study of migraine, which include, among others: (i) electrical
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E. RIVERA-MANCILLA ET AL.
stimulation of the trigeminal ganglion; (ii) electrical/chemical
stimulation of the meninges; (iii) administration of CGRP; (iv)
genetic manipulation of CGRP [38,39]; and (v) in vivo (using
infusions of headache-inducing substances) and in vitro
(using isolated cranial and coronary arteries) human models
[40]. These models have been used in an attempt to clarify
and understand the pathophysiological mechanisms of
migraine, as well as to carry out preclinical studies that
lead to the development of new antimigraine drugs.
Finally, the fact that there are selective drugs targeting
CGRP (or its receptor) with antimigraine efficacy (as discussed below), supports the link between CGRP and
migraine [41].
3. Blockade of CGRP or its receptor as a treatment
for migraine
Based on the background showing the role of CGRP in
migraine, new antimigraine drugs targeting CGRP or its receptor have been developed in the last decades. These new
antimigraine drugs are focused on reducing vasodilation and
neurogenic inflammation, relieving pain, reducing the associated symptoms of migraine and avoiding the occurrence or
intensity of migraine attacks. Moreover, they have been shown
to be effective, well tolerated and safer than other drugs
initially used in the preventive treatment of migraine.
As previously reviewed by de Vries et al. [15], antimigraine
drugs targeting CGRP or its receptor can currently be divided
into: (i) drugs for the acute treatment of migraine (i.e. gepants,
which block the CGRP receptor); and (ii) prophylactic antimigraine drugs (i.e. gepants and monoclonal antibodies against
CGRP or its receptor) (see Table 1).
In this respect, seven CGRP receptor blockers have been
developed for migraine therapy. Four have been discontinued
due to several disadvantages including: (i) poor oral bioavailability (i.e. olcegepant, previously known as BIBN4096BS) [42]);
and (ii) hepatotoxicity [i.e. telcagepant (MK-0974), MK-3207,
and BI 44,370 TA] [43–45]. In contrast, both ubrogepant (MK1602) [46] and rimegepant (BMS-927,711) [47] have been
approved by the FDA in 2019 and 2020, respectively, for
acute antimigraine treatment. Interestingly, rimegepant is currently undergoing a clinical trial for approval as a prophylactic
treatment (phase II/III trial, NCT0372368) [48]. The seventh
CGRP receptor antagonist, atogepant (MK-8031, AGN241,689) is the first gepant specifically developed for the
prophylaxis of episodic and chronic migraine [49–52].
On the other hand, next to the gepants, the monoclonal
antibodies against CGRP or its receptor represent a new hope
for the treatment of migraine. Currently, there are four monoclonal antibodies that have been approved by the FDA and/or
the EMA for the prophylactic treatment of migraine, namely: (i)
erenumab; (ii) eptinezumab; (iii) fremanezumab; and (iv) galcanezumab (see Table 1). These monoclonal antibodies
against either the CGRP receptor (the former) or the CGRP
receptor (the latter three) seem to be promising for the prophylaxis of migraine and have been shown to be safe in the
short term [15,25,26].
3.1. Prophylactic antimigraine treatment
As previously described, the goal of prophylactic antimigraine
drugs is to reduce the frequency, duration and severity of
migraine attacks and, as a result, to decrease the suffering
and disability associated with migraine. Some of these drugs
have been approved for use in migraine treatment since 2018
and, due to their mechanisms of action on the trigeminal
system, have offered specificity and tolerability over the existing classical treatments (i.e. β-adrenoceptor antagonists, antiepileptics, Ca2+ channel blockers or 5-HT receptor
antagonists). Therefore, CGRP receptor antagonists (i.e. rimegepant and atogepant) and monoclonal antibodies against
CGRP (eptinezumab, fremanezumab and galcanezumab) or
its receptor (erenumab) have been shown to be effective for
migraine treatment and seem to have fewer or no side effects
compared to ergots, triptans, or even the existing classical
prophylactic treatments [15,26].
3.1.1. CGRP receptor antagonists: second-generation
gepants
Gepants are small-molecule CGRP receptor antagonists developed in the last decades for the treatment migraine. These
small molecules, which avoid the interaction between CGRP
and its receptor (located in the trigeminal ganglion and the
vascular smooth muscle cells; Figure 1), can be divided into: (i)
first-generation gepants (developed for the acute treatment of
migraine); and (ii) second-generation gepants, used for the
acute (i.e. ubrogepant and rimegepant) and prophylactic
[rimegepant (ongoing clinical trials) and atogepant] treatment
of migraine.
3.1.1.1. Rimegepant. Rimegepant (BMS-927,711) is a smallmolecule CGRP receptor antagonist developed by Biohaven
Pharmaceutical Holding Company Ltd., and has recently been
approved by the FDA (February 2020) for the acute treatment
of migraine [47].
In a Phase II clinical trial, 75, 150, and 300 mg rimegepant
showed an excellent tolerability profile [53] (similar to that placebo), with no serious side effects (see Table 2). The results after
2 hours rimegepant 75, 150 and 300 mg showed that the percentage of pain-free patients (31.4%; 32.9%; and 29.7%, respectively)
was significantly higher than that of the placebo group (15.3%).
Additionally, a secondary endpoint showed that 27.9%; 25.9%;
and 23.4% of patients treated with rimegepant 75, 150 and
300 mg, respectively, had complete migraine freedom (i.e. pain
freedom, and no symptoms of phonophobia, photophobia, or
nausea) at 2 hours post-dose [53]. Based on the results obtained
in this clinical trial, the dose of 75 mg was chosen for Phase III trials
[54] to test its efficacy, safety, and tolerability. In this study, the
authors reported that rimegepant 75 mg was more effective in
21% of patients (who were pain free) compared with the placebo
group (11%). The most common side effect in the rimegepanttreated patients were nausea (2–8%), vomiting (2–3%), dizziness
(2–4%), and urinary tract infection (2–3%) [53,54]. Moreover, since
rimegepant produced no cardiovascular side effects or hepatotoxicity in the population [53–56], it was suggested that this
gepant is safe for the treatment of migraine. Furthermore, the
efficacy and safety of rimegepant as a prophylactic antimigraine
EXPERT OPINION ON DRUG SAFETY
Table 2. Overview of side effects reported for the prophylactuc anti-migraine drugs.
Compound
Most common side effects (%)
Gepants
Rimegepant
Placebo (11%); Rimegepant 75 mg (13%)
(BMS-927,711)
Placebo
Rimegepant 75 mg
Nausea
<1
2-8
Vomiting
2
2-3
Dizziness
<1
2-4
Urinary tract infection
<1
2-3
Atogepant
Placebo (19.35%); Atogepant 10 mga (18.28%), 30 mga (25.68%), 60 mga (27.96%); Atogepant 30 mgb (24.42%), 60 mgb
(MK-8031, AGN-241689)
(28.57%)
Placebo
10 mga
30 mga
60 mga
30 mgb
60 mgb
Nausea
4.84
5.38
7.10
11.29
8.14
9.89
Fatigue
3.20
1.08
1.64
2.69
2.33
9.89
Constipation
2.15
2.15
5.46
4.84
3.49
6.59
Nasopharyngitis
2.15
3.23
5.46
7.53
1.16
1.10
Monoclonal antibodies
Erenumab
Placebo (39-63%); Erenumab 70 mg (40-58%); 140 mg (45-55%)
(AMG-334)
Placebo
70 mg
140 mg
Injection-site pain
0.3-4
3-6
0.3-4
Fatigue
2-3
2-4
2-4
Nasopharyngitis
2-8
3-10
<3
Upper respiratory tract infection
1-6
3-7
3-5
Nausea
1-5
2-3
<3
Eptinezumab
Placebo (45-60%); Eptinezumab 30 mg (58%); 100 mg (40-63%); 300 mg (52-58%); 1000 mg (57%)
(ALD-403)
Placebo
30 mg
100 mg
300 mg
1000 mg
Upper respiratory tract infection
5-7
<11
4-10
5-10
9
Urinary tract infection
1-6
<3
<4
1
Fatigue
1-4
<3
2-3
1-4
4
Nausea and vomiting
1-4
4
<2
<4
4
Fremanezumab
Placebo (40-65%); Fremanezumab 225 mg (46-66%); 675 mg (69-70%); 225 mg+675 mg (53-70%); 900 mg (47%)
(TEV-48125)
Placebo
225 mg
675 mg
225+675 mg
900 mg
Injection-site pain
3-28
9-30
4-30
7-26
9
Nausea
1-4
<2
<3
<2
Upper respiratory tract infection
4-5
4-6
2-5
<4
Nasopharyngitis
2-5
2-4
2-5
1-4
1
Fatigue
<1
<2
2-3
Urinary tract infection
1-3
<2
<4
<5
2
Galcanezumab
Placebo (50-63%); Galcanezumab 120 mg (51-65%); 240 mg (67-71%)
(LY-2951742)
Placebo
120 mg
240 mg
Injection-site pain
2-17
6-17
7-20
Nausea
2-4
2-8
3-6
Upper respiratory tract infection
2-9
3-11
3-15
Nasopharyngitis
2-9
6-18
2-13
Fatigue
<3
<3
<3
Urinary tract infection
1-4
<4
1-6
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Ref
[24-25]
[30-31]
[35-38]
[41-43]
[46-49]
[55-59]
The doses were used for the treatment of both episodic or chronic migraine during short-term trials. aDaily doses; btwice-daily doses.
treatment is being evaluated through a randomized, doubleblind, placebo-controlled, phase II/III clinical trial (NCT0372368).
This trial will evaluate the efficacy and safety of 75 mg rimegepant
as compared with placebo in migraine patients, with a study
completion date of 30 January 2021 [48].
3.1.1.2. Atogepant. Atogepant (MK-8031 or AGN-241,689) is
a CGRP receptor antagonist with a higher potency and longer
half-life than ubrogepant (which is used for the acute treatment of migraine). For this reason, its use has been proposed
for the prevention of episodic and chronic migraine (see Table
1) [49–52].
A Phase IIb/III randomized, double-blind, placebo controlled in parallel-group study clinical trial evaluated the
efficacy, safety, and tolerability of atogepant at different
daily (10, 30, or 60 mg) or twice daily (30 or 60 mg) oral
doses or placebo during 12 weeks. All active treatment
groups showed a significant reduction in their mean
monthly migraine/probable migraine headache days
(−4.00 for 10 mg; −3.76 for 30 mg; −3.55 for 60 mg; and
−4.23 or 4.14 for the twice daily 30 or 60 mg, respectively)
compared to placebo (−2.85 days). Moreover, atogepant
was well tolerated with not significant and/or serious side
effects (placebo = 19.35%; atogepant 10, 30 and 60 mg
daily = 18.28%, 25.68%, and 27.96%, respectively; or atogepant 30 and 60 mg twice daily = 24.42% and 28.57%,
respectively) and ≥5% patients presented the most common side effects, namely: nausea (5–11%), fatigue (1–10%),
constipation (2–6%), nasopharyngitis (1–7%) and urinary
tract infection, with not sings of hepatoxicity [49,50].
Currently, a Phase III clinical trial (NCT03855137) is in progress,
with
a
study
completion
date
of
31 August 2021 [52].
In addition, data obtained from in vitro studies using
human intracranial and coronary arteries showed that atogepant is more effective and potent in antagonizing CGRPinduced vasodilation in human meningeal arteries as compared with human coronary arteries, suggesting that atogepant would have a safety benefit when considering
cardiovascular side effects [57]. Obviously, long-term clinical trials are necessary to fully verify the safety of
atogepant.
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E. RIVERA-MANCILLA ET AL.
3.1.2. Monoclonal antibodies
The development of monoclonal antibodies targeting CGRP or
its receptor represents a strategy complementary to gepants
for migraine treatment. Since their plasma half-life is much
longer than that of the gepants, their use has been proposed
and recommended by current European Headache Federation
guidelines as prophylactic drugs to prevent episodic and
chronic migraine attacks [58]. Nevertheless, their specific site
and/or mechanisms of action in the trigeminal system are still
unknown. Interestingly, as previously reviewed by Edvinsson
et al. [59], the therapeutic effect of monoclonal antibodies can
be completely peripheral due to its low permeability into the
blood-brain barrier), and it is likely to affect targets within the
trigeminovascular system [59]. Currently, there are four different monoclonal antibodies (see above and Table 1): (i) one
fully human monoclonal antibody (i.e. erenumab) that directly
blocks the CGRP receptor, preventing the binding of CGRP to
its canonical receptor; and (ii) three human monoclonal antibodies that directly block CGRP (i.e. eptinezumab, fremanezumab, and galcanezumab) (see Figure 1). Therefore, the
monoclonal antibodies targeting the CGRP pathway symbolize
a novel and specific therapeutic approach in the prevention of
migraine.
3.1.2.1. Erenumab. Erenumab (AMG-334) is the only fully
human monoclonal antibody that directly blocks the canonical
CGRP receptor (see Figure 1) [60], and the first to be approved
by the FDA (May 2018) and by the EMA (July 2018) for the
prophylactic treatment of migraine (see Table 1) [61,62].
Data from two Phase II clinical trials have been presented.
First, in a 12-week multicenter, randomized, double-blind,
placebo-controlled monthly dose of 7, 21 and 70 mg erenumab were tested. Only the 70 mg dose reduced the number of
monthly headache days to −3.4 days when compared with the
placebo group (−1.1 days) with a difference of −1.1 days
(P = 0.021) [63]. In the second clinical trial, doses of 70 and
140 mg produced a significant reduction in the number of
monthly headache days, both doses −6.6 days versus placebo
−4.2 (P < 0.0001) post-dose [64]. Furthermore, there are data
from two Phase III clinical trials, namely, the ARISE and STRIVE
studies. In the ARISE study (NCT02483585), 557 patients were
randomized to monthly subcutaneous injections of 70 mg
erenumab or placebo. The results showed a reduction in the
number of monthly headache days at the third moth postdose. In this trial, erenumab-treated patients (70 mg) showed
a change of −2.9 days in monthly migraine days compared
with −1.8 days for placebo-treated patients (difference of
−1.1 days, P = 0.001); achieving a ≥ 50% reduction in monthly
migraine days by 39.7% for erenumab 70 mg and 29.5% for
the placebo group (P = 0.01) [65]. Similar results were
obtained from the STRIVE study (NCT02456740), in which
a total of 955 patients (monitored during 6 months) were
randomized and divided into (i) 317 patients for testing erenumab 70 mg; (ii) 319 for testing erenumab 140 mg; and (iii)
319 for the placebo group. Erenumab produced a reduction in
monthly migraine days by 3.2 days in the 70 mg erenumab
group and 3.7 days in the 140 mg erenumab group, as compared with 1.8 days in the placebo group (P < 0.001). In
addition, a ≥ 50% reduction in the monthly migraine days
was achieved by 43.3% and 50% after erenumab 70 and
140 mg, respectively, as compared with 26.6% in the placebo
group (P < 0.001) [66].
On the other hand, erenumab has also been evaluated in
the long term in episodic [67] and chronic [68] migraine
patients. In this respect, during the open-label treatment
phase clinical trial for episodic migraine (NCT01952574),
patients received monthly erenumab 70 mg. After 2 years,
the initial dose was increased to 140 mg in order to evaluate
the long-term safety and tolerability of the higher dose. The
side effects patient incidence rate was 132.0 per 100 patientyears (142.0 after erenumab 70 mg and 128.1 after erenumab
140 mg). Moreover, the most frequent side effects in at least
≥4.0 per 100 patient-years were (expressed in incidence rate):
viral upper respiratory tract infection (12.9), upper respiratory
tract infection (7.2), sinusitis (4.6), influenza (4.2) and back pain
(4.2); these effects did not increase relative to placebo based
on the results obtained from the placebo-controlled clinical
trials [67]. Regarding the chronic migraine patients, an openlabel extension study (NCT02174861) evaluated the effect of
monthly erenumab 70 mg following erenumab 140 mg (which
was increased between weeks 4 or 28) to evaluate the longterm efficacy and safety during 52 weeks [68]. The results
showed an efficacy with a reduction in the monthly migraine
days of 9.4 and 8.8 days at weeks 40 and 52, respectively. In
addition, a ≥ 50%, ≥75% and ≥100% reductions in the
monthly migraine days was achieved at week 52 by 59.0%,
33.2% and 8.39% of patients, respectively. In terms of safety,
the total incidence rate in erenumab-treated patients was
126.3 per 100 patient-years, and 132.0 and 148.5 per 100
patient-years pots-dose erenumab 70 mg and 140 mg, respectively. The most common side effects (expressed as incidence
rate per 100 patient-year) were: viral upper respiratory tract
infection (16.4), upper respiratory tract infection (7.2), sinusitis
(7.1) and arthralgia (4.2), which did not increase when compared with the double-bind treatment phase [68].
Moreover, an in vitro study by Rubio-Beltrán et al. [69]
showed that erenumab is capable of inhibiting CGRPinduced vasodilatory responses in human-isolated middle
meningeal, internal mammary and coronary arteries. This
monoclonal antibody showed no direct contractile or relaxant
effects, as well as specificity at inhibiting the vasodilator
responses to CGRP without interactions with other vasoactive
compounds [69]. These findings seem favorable in terms of
vascular safety. However, as discussed below, some other
issues must be considered to adequately explore the cardiovascular safety of erenumab, including the interaction of CGRP
with non-canonical receptors [31,70].
In all clinical trials, erenumab showed to be well tolerated,
effective and safe. The most common side effects (without
showing differences with the placebo group) (see Table 2)
were injection-site pain (0.3–6%), fatigue (2–4%), nasopharyngitis (2–11%), upper respiratory tract infection (3–7%) and
nausea (2–3%) [63–66]. Indeed, erenumab has proven to be
a safe monoclonal antibody for the prevention of migraine (in
short term) since its administration does not produce cardiovascular side effects or hepatotoxicity (due to its route of
administration). In addition, this monoclonal antibody for the
EXPERT OPINION ON DRUG SAFETY
CGRP receptor resulted 5000-fold more selective for the canonical receptor, as compared with other human calcitonin
family receptors [i.e. adrenomedullin (AM), calcitonin (CT) or
amylin (AMY) receptors] [60]. However, we cannot categorically rule out whether CGRP receptor blockade will be selective in the long term or whether there will be involvement of
non-canonical receptors. If this were the case, blocking the
CGRP receptor with erenumab would leave the possibility
open for CGRP to bind to the amylin AMY1 receptors, keeping
in mind that CGRP can mediate its effects through CGRP
receptors or distinct CGRP-responsive receptors [31]. In fact,
it has been shown that the AMY1 receptor: (i) could potentially
function as an additional CGRP receptor in coronary arteries
[70]; and (ii) is located in the trigeminal system [71], which
could suggest an important role in migraine. Nevertheless,
further studies are necessary to elucidate the safety of erenumab and its exact mechanism(s) of action (in the long term), as
well as the role of AMY1 receptors in migraine.
3.1.2.2. Eptinezumab. Eptinezumab (ALD-403) is the first
intravenously administered humanized monoclonal antibody
that directly blocks CGRP. It was developed by Alder
BioPharmaceuticals Inc. and H. Lundbeck A/S, and has recently
been approved by FDA (February 2020) for the preventive
treatment for migraine (see Table 1) [72].
In a first Phase II, randomized, double-bind, placebocontrolled clinical trial, intravenous eptinezumab (1000 mg)
was tested for 24 weeks and showed a significant reduction in
monthly migraine days in patients with episodic migraine as
compared with placebo. In this respect, the mean change in
migraine days between baseline and weeks 1–4; 5–8; and 9–12
in eptinezumab (1000 mg) and the placebo group was −5.6
and −3.9 days (difference of −1.7 days); −5.6 and −4.6 days
(difference of −1.0 days); and −5.6 and −4.6 days (difference of
−1.0 days), respectively. Furthermore, 33% of eptinezumabtreated patients experienced a ≥ 75% reduction in monthly
migraine days over 12 weeks compared with 9% in the placebo group, as well as 51% of eptinezumab-treated patients
showed ≥50% reduction in monthly migraine days compared
to 33% in the placebo group [73]. Additionally, in a Phase III
clinical trial, eptinezumab 30, 100 and 300 mg (PROMISE-I) or
eptinezumab 100 and 300 mg (PROMISE-II) showed to be
effective in reducing monthly migraine days in episodic
migraine (PROMISE-I) by reducing the frequency of migraine
days during weeks 1–2 from baseline to −4.0 days (30 mg);
−3.9 days (100 mg); and −4.36 days (300 mg) when compared
to the placebo group (−3.2 days), with a difference of −0.82;
−0.69; and −1.11 days, respectively (P < 0.0.01) [74]; and by
reducing the monthly migraine days in chronic migraine
patients treated with eptinezumab (100 and 300 mg) by −7.7
and −8.2 days, respectively, versus the placebo group
(−5.6 days) with a difference of −2.0 and −2.6 days
(P < 0.0001) (PROMISE-II) [75].
The most frequent side effects reported in the eptinezumab-treated group were (see Table 2): upper respiratory tract
infection (4–11%), urinary tract infection (1–3%), fatigue (2–4%), nausea and vomiting (1–4%); which were similar in the
placebo group (5–7%; 1–5%; 1–4%; 1–4%; respectively, [72–
1243
75], with no signs of hepatotoxicity or cardiovascular side
effects. Therefore, the results from clinical trials showed the
efficacy, tolerability, and short-term safety of eptinezumab for
the preventive treatment of migraine.
3.1.2.3. Fremanezumab. Fremanezumab
(TEV-48,125) is
another humanized monoclonal antibody that directly blocks
the α-CGRP and β-CGRP isoforms [76], avoiding the binding of
CGRP to its receptor (Figure 1). This monoclonal antibody is
the second one to be approved by the FDA (September 2018),
and the third one to be approved by the EMA (March 2019) for
use in the prevention of episodic and chronic migraine (see
Table 1) [77,78].
For episodic migraine, results from a Phase IIb clinical trial
showed that subcutaneous doses of 225 and 675 mg (given
once every 28 days for 12 weeks) reduced the number of
monthly headache days by 2.81 days in the 225 mg fremanezumab group and 2.64 days in the 675 mg fremanezumab
group compared to the placebo group (P < 0.001). In this
respect, the percentage of patients treated with fremanezumab 225 or 675 mg with at least 50% of reductions in
migraine days was 53% and 59%, respectively, compared
with the placebo group, 28% (P < 0.001) [79]. Similar results
were obtained from a Phase III clinical trial [80]. A total of 875
patients were randomized to monthly 225 mg injections or
quarterly 675 mg injections of fremanezumab. The high dose
(675 mg) produced a decrease in the number of monthly
migraine days by 1.3 days compared to placebo, while the
low dose (225 mg) reduced the number of monthly headache
days by 1.5 days. Moreover, at least 50% of reduction in
migraine days was observed at week 12 in 47% of patients
treated with fremanezumab 225 mg; and in 44.4% of the
patients treated with fremanezumab 675 mg (38%); compared
with 27.9% in the placebo group (P < 0.001 when comparing
both fremanezumab-treated groups with the placebo-treated
group) [80].
Regarding chronic migraine, a Phase IIb clinical trial
showed that subcutaneous administration of fremanezumab
675 mg (in the first treatment cycle) plus 225 mg (in
the second and third treatment cycles) produced a reduction
in the number of monthly headache hours with 22.74 hours
compared to placebo. Additionally, fremanezumab 900 mg (in
all three treatment cycles) produced a decrease of 30.41 hours
in the number of monthly headache hours compared to placebo [81]. Moreover, in a Phase III clinical trial, patients with
chronic migraine received a quarterly subcutaneous injection
of fremanezumab 675 mg at baseline (and placebo at weeks 4
and 8) or a single dose of fremanezumab 675 mg followed by
two doses of 225 mg at weeks 4 and 8. Both groups showed
a reduction in the number of monthly headache days with
1.8 days (quarterly 675 mg fremanezumab) and 2.1 days
(monthly 675 mg plus 225 mg fremanezumab) compared to
placebo. Additionally, a reduction of at least 50% in the average number of headache days per month was observed in
38% in the fremanezumab-quarterly group; in 41% in the
fremanezumab-monthly group; and 18% in the placebo
group (P < 0.001 when comparing both fremanezumabtreated groups with placebo group) [82].
1244
E. RIVERA-MANCILLA ET AL.
In all cases, fremanezumab 225 and 675 mg showed to be
safe, well tolerated and effective for the prevention of episodic
and chronic migraine in the short term. The most common
side effects (see Table 2) were pain at the injection site, upper
respiratory infection, nasopharyngitis, urinary tract infection,
fatigue, and nausea, without cardiovascular side effects or
hepatotoxicity [76,79–85]. On this basis, it has been suggested
that fremanezumab seems a promising option (in terms of
safety) as a preventive treatment for migraine, even in the
long term [85].
3.1.2.4. Galcanezumab. Galcanezumab
(LY-2,951,742) is
a humanized monoclonal antibody that directly blocks both
the α-CGRP and β-CGRP isoforms, preventing their binding to
the CGRP receptor (Figure 1) [86]. This monoclonal antibody
received FDA approval in September 2018 [86] and EMA
approval in November 2018 [87] for the prophylaxis of
migraine in adults (see Table 1). More recently, Eli Lilly and
Company applied for an extension of indication of galcanezumab to add the prevention of attacks throughout a cluster
period in adults with episodic cluster headache. However, EMA
recommended the refusal of a change to the marketing
authorization for this drug [88].
Results from a Phase IIb clinical trial for episodic migraine
showed that i.v. administration of galcanezumab (120 mg
given monthly during 3 months) produced a significant reduction in the monthly headache days as compared with placebo
by −4.8 versus −3.7 days, respectively (compared to the baseline values of 6.6 and 6.7 days, respectively). Moreover, in
a secondary endpoint, the galcanezumab-treated patients
(120 mg) reported 50% and 100% reduction in the number
of monthly headache days during the third study period [89].
Additionally, in two Phase III clinical trials (EVOLVE-1 and
EVOLVE-2), monthly injections of galcanezumab 120 and
240 mg (during 6 months) produced a reduction in the
monthly migraine headache days as compared with placebo,
without showing differences between both doses [90,91]. In
this respect, during the EVOLVE-1 trial, the treatment with
galcanezumab 120 and 240 mg produced a significant reduction in the monthly migraine headache days by −4.7 and
−4.6 days, respectively, compared with placebo (−2.8 days),
with a difference of −1.9 days for galcanezumab 120 mg and
−1.8 days for galcanezumab 240 mg (P < 0.001 versus placebo
[90]. Similar results were obtained during the EVOLVE-2 trial,
where the patients showed a reduction in the monthly
migraine headache days by −4.3 and −4.2 days post-dose of
galcanezumab 120 and 240 mg, respectively, compared with
the placebo group (−2.3 days) [91]. Regarding chronic
migraine, results from Phase II clinical trials showed that
both doses of galcanezumab (120 and 240 mg, given subcutaneously) during 9 months [92] or 12 months [93] are effective in reducing the number of monthly migraine headache
days by −4.8 and −4.6 days (when compared with placebo
−2.7 days, P < 0.001) [92]; and by −5.6 and −6.5 days post-dose
of galcanezumab 120 and 240 mg, respectively [93]. Likewise,
this monoclonal antibody has been shown to be well tolerated
since the incidence rate of side effects was low (see Table 2)
both in patients with episodic (51–65% for galcanezumab
120 mg; 67–71% for galcanezumab 240 mg; when compared
with the 50–63% in the placebo group) [89–91] and chronic
migraine (58% for galcanezumab 120 mg; 57% for galcanezumab 240 mg; compared with the placebo group, 50%) [92].
4. New antimigraine treatments?
In an attempt to find new alternatives for migraine treatment,
more recent studies have analyzed the direct effects of small
RNA sequences on CGRP. A first approach to block the effect
of CGRP is the use of specific CGRP-neutralizing L-aptamers or
Spiegelmers. Indeed, next to gepants or monoclonal antibodies, Spiegelmers seem to be candidates for the treatment/
prevention of migraine [23]. Spiegelmers are single-stranded
mirror-image RNA oligonucleotides, which are capable of specifically binding to CGRP and of inhibiting its function [94].
In this respect, two Spiegelmers have been shown to bind
selectively to CGRP, namely, NOX-C89 and NOX-L41. Indeed,
NOX-C89 was shown to reduce CGRP release from the cranial
dura mater caused by antidromic activation of meningeal
afferents, and produced a dose-dependent inhibition of the
electrically evoked increases in meningeal blood flow [94].
Moreover, NOX-L41 can inhibit both CGRP-induced cAMP formation and neurogenic plasma protein extravasation in the rat
dura mater [23]. Based on these findings, the use of these
Spiegelmers was proposed as an alternative for the treatment
of migraine. However, since NOX-C89 preferentially binds to
mouse/rat CGRP than human CGRP and it is cross-reactive to
AMY, it was considered insufficient for further clinical development [94]. In contrast, no compelling study has yet reported
the effectiveness of NOX-L41 in migraine, but its potential use
has been suggested for migraine prevention [23].
On the other hand, a second approach would be the
possibility of genetically manipulating the gene expression of
CGRP or its receptor. Since the use of RNA interference (RNAi)
and small interfering RNA (siRNA) have been proposed for the
treatment of some neurological disorders, we can speculate
that post-transcriptional silencing of CGRP could be used as
a therapeutic tool for migraine attacks. However, in view that
CGRP exerts protective functions, the complete silencing of
gene may or may not be effective in the prevention of
migraine, keeping in mind that it could alter the vascular
function or increase the possible harmful cardiovascular consequences. Therefore, we hypothesize that if the silencing of
gene expression is an alternative for the treatment of
migraine, it should be considered at what time and/or how
long should the genetic silencing be applied, as well as if it is
necessary to apply a complete or partial genetic silencing and/
or intermittent or continuous. This leads us to pose the question: will genetic engineering be safe to treat migraine? This
still remains a crucial issue that needs to be further analyzed
before RNAi or siRNA are ready for clinical use.
5. Side effects associated with CGRP (receptor)
blockade
An important concern related to the long-term use of CGRP
blockers for the prophylactic treatment of migraine (specifically using monoclonal antibodies) is that CGRP acts as an
potent vasodilator, maintaining an important role in the
EXPERT OPINION ON DRUG SAFETY
homeostasis of the gastrointestinal [95–97] and cardiovascular
[98] systems under pathological conditions. Therefore, longterm blockade of CGRP or its receptor could cause a loss of the
protective effect of CGRP.
In this respect, since the monoclonal antibodies eptinezumab, fremanezumab and galcanezumab are nonselective for
directly blocking CGRP and can bind to the α-CGRP and βCGRP isoforms [73,76,86], a long-term CGRP blockade could
cause gastrointestinal system-related side effects (e.g. mucosal
damage, ulcers, constipation, and/or diarrhea). Evidently, its
long-term effects should be investigated to rule out these
possible side effects and to verify the safety of these monoclonal antibodies.
Regarding the cardiovascular side effects, this issue seems
to be relevant since migraine patients may have an increased
cardiovascular risk [98]. While data obtained from several clinical trials have shown that the four monoclonal antibodies do
not produce cardiovascular adverse effects in the short term
[63–66,73–76,79–84,91–93], some fatal cardio – and cerebrovascular events such as atherosclerosis, right thalamic infarction or transient attack of ischemia occurred during the
evaluation of erenumab or eptinezumab [15], even during
the long-term clinical trials [67]. It is noteworthy that most of
these clinical trials were limited to the evaluation time of the
treatment (no more than 2 years). In addition, although most
short-term clinical trials to assess cardiovascular safety of
monoclonal antibodies include patients without cardiovascular complications, data showing that erenumab 140 mg shows
vascular safety in patients with cardiovascular disorders (i.e.
angina and coronary artery disease) after exercise treadmill
suggesting that inhibition of the canonical CGRP receptor
with erenumab does not worsen myocardial ischemia [99].
Certainly, this study was designed with the purpose of demonstrating the safety of erenumab including patients with cardiovascular disorders. However, this study has important
limitations that cast doubt on its validity, including that: (i)
78% of the study population were male considering that
migraine is a predominantly female disorder; therefore, it
could be assumed that blocking the effects of CGRP receptor
with erenumab may have different effects in female patients
than in male patients; (ii) although the study included patients
with cardiovascular diseases (i.e. stable angina, a mainly
macrovascular disease), patients with microvascular diseases
better represent the population at cardiovascular risk; and (iii)
there is no evidence that intravenous infusion with erenumab
140 mg already induces CGRP receptor blockade after 30 min
[100]. On this basis, we consider that additional studies are still
needed to assess the cardiovascular safety of monoclonal
antibodies.
On the other hand, as previously reviewed by
MaassenVanDenBrink et al. [98], women might be at
a higher cardiovascular risk during CGRP (receptor) blockade
than men, specifically after menopause or during pregnancy. Therefore, in an attempt to clarify the cardiovascular
safety from long-term use of monoclonal antibodies and
considering the pharmacokinetic differences over gepants
(e.g. longer half-lives), further studies should be conducted
in patients with cardiovascular diseases and in pregnant (or
preeclamptic) women.
1245
Since this experimental strategy would obviously raise ethical concerns, an approach using relevant animal models
seems most appropriate. In this respect, several studies have
demonstrated the effects resulting from CGRP or its receptor
by using gepants and/or monoclonal antibodies in animal
models. One such example is a mouse study, where
a harmful effect of CGRP receptor blockade by olcegepant
(1 mg/kg) or rimegepant (10 mg/kg) on cerebral ischemic
outcome was described. Both gepants worsened ischemic
stroke in mice with familial hemiplegic migraine type 1 via
collateral dysfunction [101]. In addition, it has been reported
that CGRP-induced diarrhea in C57BL/6 J mice (transgenic
nestin/hRAMP1 mice) is blocked by anti-CGRP antibodies
[102]. Finally, α-CGRP knockout mice model showed to have
increased hypertension and aortic hypertrophy, suggesting
that upregulation of CGRP plays a protective role in the vascular system [103]. Notwithstanding the use of gepants and/or
monoclonal antibodies to block the CGRPergic system has
shown no vascular or gastrointestinal side effects in shortterm clinical trials, the long-term effects in specific patient
group still need to be explored.
6. Conclusion
Based on the advances in basic and clinical research, CGRP has
emerged as one of the main targets for the treatment of
migraine. In this respect, during the last decades, the development of drugs for the acute or prophylactic treatment of
migraine has been based on the direct blockade of the CGRP
pathway, including either CGRP or the CGRP receptor.
Regarding the new prophylactic antimigraine drugs, results
from clinical trials have shown the gepants or monoclonal
antibodies to be safe in the short term, and even in the long
term in the case of erenumab. These findings could suggest
that direct blockade of CGRP or its receptor represents a novel
option for the prevention of this disorder, particularly in
patients who: (i) fail to respond to other treatments: or (ii)
have contraindications to existing treatments (i.e. triptans). In
addition, some basic research studies have shown the ‘vascular safety’ of some of these prophylactic antimigraine drugs.
However, we think that chronic or long-term blockade of the
CGRPergic pathway (which has not been explored yet) for the
prevention of migraine attacks could cause unwanted (mainly
cardiovascular) side effects. Therefore, basic science experimental studies and Phase IV clinical trials are necessary to
further confirm the long-term safety of the new prophylactic
antimigraine drugs.
7. Expert opinion
Migraine is a complex neurovascular disorder that requires
specific drugs for its acute or prophylactic treatment.
However, many patients use nonspecific drugs to alleviate
migraine-related pain or symptoms (i.e. nonsteroidal antiinflammatory drugs, analgesics, or a combination of both). In
an attempt to improve the quality of life of migraine patients,
new drugs have been developed in order to reduce the side
effects produced by the classical antimigraine drugs (e.g.
ergots and triptans). In this respect, the association of CGRP
1246
E. RIVERA-MANCILLA ET AL.
with the pathophysiology of migraine has led to the development of specific drugs that directly block CGRP or its receptor
(see Figure 1). These drugs have been shown to be safe in the
short-term prophylactic antimigraine treatment. However,
their mechanism(s) of action and their long-term effects with
reference to safety have not yet been explored. Consequently,
there are still some pending issues (described right below) to
ensure the safety of these novel prophylactic antimigraine
drugs.
Firstly, CGRPergic blockers are not highly ‘selective’. This
means that some prophylactic antimigraine drugs can block
both the α-CGRP and β-CGRP isoforms (i.e. eptinezumab, fremanezumab, and galcanezumab). Since β-CGRP is mainly present in the gastrointestinal system and its function is to
regulate the enteric tone (i.e. by maintaining the mucosal
integrity and gastrointestinal motility [95–97]), it is reasonable
to question whether it would be safe to block CGRP at long
term in the gastrointestinal system. In fact, long-term CGRP
blockade could cause damage on the gastrointestinal mucosa,
contribute to inflammatory bowel disease, or alter gastrointestinal motility (which could exacerbate episodes of diarrhea
or constipation). Therefore, it would be prudent to consider
the appropriate treatment of migraine in patients with gastrointestinal disorders (including ulcers).
Secondly, CGRP plays an important role in maintaining
cardiovascular homeostasis, by acting as a potent vasodilator.
Moreover, migraine is associated with increased risk of cardio –
and cerebrovascular events [98]. Within this framework, CGRP
seems to be relevant in some vascular diseases by preventing
hypertension [103], preeclampsia [104], cerebral ischemia
[105], as well as myocardial infarction and heart failure after
cardiac ischemia [106]. From this perspective, the prophylactic
treatment with drugs that block CGRP or its receptor in
patients with migraine turns out to be beneficial to prevent
it. Notwithstanding, would the blockade of the CGRPergic
system be beneficial in the long term?; or would this blockade
trigger unwanted (cerebro)vascular events? Certainly, clinical
trials have evaluated the safety of approved drugs for the
prevention of migraine, reporting that patients have no cardiovascular side effects. Nonetheless, these trials were conducted in the short term (lasting less than 2 years) and
excluded higher-risk patients. Hence, future clinical trials
should include patients with preexisting cardiovascular
disorders.
Thirdly, as shown in Figure 2 and described above, CGRP can
also bind to CGRP-responsive receptors, namely, the AM and
AMY receptors [31]. Since these receptors can be found in the
trigeminovascular system [59], they may well play a role in the
pathophysiology of migraine. However, to the best of our
knowledge, there is no compelling evidence of their significance. In this respect, it is noteworthy that CGRP displays: (i)
a high-affinity/potency for the human AMY1, AMY2, and AMY3
receptors (human pEC50 values of 8.7–10.7; 6.2–9.7; and 7.6–9.7,
respectively); and (ii) a moderate affinity for the human AM1 and
AM2 receptors (human pKd or pKi values of 6.0 and 6.5–6.8,
respectively) [107]. Accordingly, CGRP receptor blockade by
the use of gepants or monoclonal antibodies (i.e. erenumab),
particularly in the long term, would also allow CGRP to bind to
the AMY or AM receptors (see Figure 2). Hence, since the AMY1
receptor is considered as a second physiological CGRP receptor
[71], the possibility that this receptor may play a role during
migraine attacks cannot be categorically excluded. In addition,
the direct blockade of CGRP by using monoclonal antibodies (i.e.
eptinezumab, fremanezumab, or galcanezumab) would allow
the AM or AMY ligands to bind to the CGRP receptor. If this
were indeed possible: what effects could trigger the binding of
these vasodilators (less potent than CGRP) to the CGRP receptor? In fact, even the less potent effects produced by AM or AMY
could explain a lower risk of (cardio)vascular disorders such as
brain injury, hypertension, and ischemic heart disease [85].
However, despite the fact that CGRP shows a moderate affinity
for both the AM1 and AM2 receptors (pKd and pKi values of 6.0
and 6.5–6.8, respectively) (see Figure 2), the role of AM in
migraine seems less likely since intravenous administration of
this neuropeptide fails to cause migraine (unlike intravenous
administration of CGRP) [108]. On the other hand, AMY has
moderate potency to bind at the CGRP receptor (pEC50 value
of 6.63) [109] (see Figure 2) and exerts biological actions similar
to those of CGRP. Therefore, we can question whether AMY
plays an important role in migraine triggering or in migraine
pathophysiology. Hence, further studies are needed in order to
determine: (i) the potential role and the possible mechanism(s)
of action of the non-canonical CGRP receptors and their ligands
in migraine; and (ii) whether blocking CGRP is more effective
than blocking its receptor, or vice versa.
Fourthly, migraine is associated with comorbid illnesses
besides cardiovascular diseases, especially painful disorders
which include visceral pain, myofascial pain syndromes, or
fibromyalgia [20,110,111]. Indeed, in most short-term clinical
trials, the patient selection criteria were strict, excluding
patients with medical comorbidities, which can be
a limitation to evaluate the tolerability of monoclonal antibodies against the CGRPergic system. Definitively, consideration should be given to whether the CGRPergic system
blockade can be beneficial in treating pain-related comorbidities such as visceral pain or fibromyalgia, keeping in mind
that in most cases the treatment of migraine and comorbidities may require two different medications [20]. Therefore,
more long-term studies are needed to determine whether the
monoclonal antibodies can help alleviate various pain-related
syndromes, and even to determine their effects in migraine
patients with a variety of comorbidities. On the other hand,
despite the results obtained from clinical trials are promising;
certainly there are still several limitations including the assessment of anti-migraine drugs in the real-life condition.
Recently, data from a real-life study showed a higher efficacy
and safety of erenumab than those of the clinical trial in
chronic migraine patients with previous preventive failures
and with medication overuse [112,113]. Moreover, the realworld population could be more susceptible to the side
effects produced by drugs to treat migraine due to their
comorbidities [113]. Therefore, future studies should focus
on evaluating the effect of anti-migraine drugs on real-life
populations in order to compare the data obtained from
short-term clinical trials, and considering the most frequent
comorbidities and the treatment duration.
EXPERT OPINION ON DRUG SAFETY
Finally, the human clinical trials analyzing the monoclonal
antibodies for migraine prevention have been carried out in the
short term (except for erenumab, which has been evaluated in
the long term [67,68]. Nevertheless, it is still unknown whether
or not long-term blockade of CGRP or its receptor may generate
few (especially cardiovascular) side effects; this is indeed
a reasonable concern in view that the blockade of CGRPinduced vasodilator effects could represent potential cardiovascular risks. Furthermore, another interesting issue that cannot be
excluded is the immunological safety of monoclonal antibodies;
in this regard, undoubtedly, there may be a potential for the
production of autoantibodies, despite the fact that these monoclonal antibodies are humanized antibodies. Therefore, basic
science experimental studies and long-term studies (i.e. Phase
IV) in patients with cardiovascular comorbidities (e.g. obesity,
diabetes mellitus, etc.) are required to delineate the safety of the
new prophylactic antimigraine drugs.
Funding
This article was supported by the following research grants: (i) Consejo
Nacional de Ciencia y Tecnología (Postdoctoral Grant No. 740678, Mexico)
for E. Rivera-Mancilla; and (ii) the Dutch Research Council (NWO, Vici Grant
09150181910040) for A. MaassenVanDenBrink.
Declaration of interest
A Maassen van den Brink has received grants and/or fees from Amgen/
Novartis, Lilly, and Teva. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants, or patents
received or pending, or royalties.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they have received
personal fees or honoraria for lectures and/or advisory boards from
Pharm Allergan, BIAL, Desitin, Eli Lilly, Hormosan, Novartis and TEVA. All
other peer reviewers on this manuscript have no relevant financial or
other relationships to disclose.
ORCID
Antoinette MaassenVanDenBrink
http://orcid.org/0000-0001-7176-126X
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
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•• Excellent review on the pharmacological CGRPergic treatment
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EXPERT OPINION ON DRUG SAFETY
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•• This clinical trial show the long-term safety and efficacy of
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