Expert Opinion on Emerging Drugs

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Emerging drugs for migraine treatment: an update

Giorgio Lambru, Anna P. Andreou, Martina Guglielmetti & Paolo Martelletti

To cite this article: Giorgio Lambru, Anna P. Andreou, Martina Guglielmetti & Paolo Martelletti
(2018): Emerging drugs for migraine treatment: an update, Expert Opinion on Emerging Drugs,
DOI: 10.1080/14728214.2018.1552939

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EXPERT OPINION ON EMERGING DRUGS
https://doi.org/10.1080/14728214.2018.1552939

REVIEW

Emerging drugs for migraine treatment: an update

Giorgio Lambrua,b, Anna P. Andreoua,b, Martina Guglielmettic and Paolo Martelletti c

a
The Headache Centre, Pain Management and Neuromodulation, Guy’s and St Thomas NHS Foundation Trust, London, UK; bThe Wolfson CARD,
Institute of Psychology, Psychiatry and Neuroscience, King’s College London, London, UK; cDepartment of Clinical and Molecular Medicine,
Sapienza” University, “Sant’Andrea” Hospital, Regional Referral Headache Centre, Rome, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Migraine is a very frequent and disabling neurological disorder. The current treatment Received 27 September 2018
options are old, generally poorly tolerated and not migraine-specific, reflecting the low priority of Accepted 23 November 2018
migraine research and highlighting the vast unmet need in its management. KEYWORDS
Areas covered: Advancement in the understanding of migraine pathophysiological mechanisms and Migraine; chronic migraine;
identification of novel potentially meaningful targets have resulted in a multitude of emerging acute erenumab; fremanezumab;
and preventive treatments. Here we review the known putative migraine pathophysiological mechan- galcanezumab;
isms in order to understand the rationale of the most promising novel treatments targeting the eptinezumab; lasmitidan;
Calcitonin-Gene-Related Peptide receptor and ligand and the 5 hydroxytryptamine (5-HT)1F receptor. ubrogepant; atogepant;
Key findings on the phase II and phase III clinical trials on these treatments will be summarized. CGRP; PACAP
Furthermore, a critical analysis on failed trials of potentially meaningful targets such the nitric oxide
and the orexinergic pathways will be conducted. Future perspective will be outlined.
Expert opinion: The recent approval of Erenumab and Fremanezumab is a major milestone in the
therapy of migraine since the approval of triptans. Several more studies are needed to fully understand
the clinical potential, long-term safety and cost-effectiveness of these therapies. This paramount
achievement should stimulate the development of further research in the migraine field.

1. Background cutaneous allodynia, which is the perception of pain when

non-painful stimuli are applied to the painful skin area.
Migraine is a brain disorder affecting globally about 12% of
Finally, the postdromal phase, is described as a period where
the general population [1,2]. The lifetime prevalence of
the severe head pain has settled but other symptoms, namely,
migraine is 33% in women and 13% in men [3]. Migraine is
asthenia, fatigue, somnolence, impaired concentration, photo-
associated with a significant detrimental effect on health-
phobia, and irritability continue for hours to few days [7].
related quality of life (HRQoL) and important socioeconomic
These multiphasic process of a broad constellation of signs
impact [4]. The World Health Organization (WHO) ranks
and symptoms highlight the complexity and the diffuse invol-
migraine as the most disabling condition amongst the dis-
vement of multiple neural networks and anatomical brain
eases worldwide under the age of 50 [5]. Migraine is consid-
regions.
ered a disturbance of sensory processing with wide
According to the International Classification of Headache
implications within the central nervous system [6]. It is char-
Disorders 3 (ICHD-3), subjects with at least 15 headache days
acterized by a multiphasic process that includes a premonitory
of which at least eight fulfill the criteria for migraine with or
phase, when systemic, psychological and neurological symp-
without aura per month for at least three consecutive months
toms, the commonest of which are fatigue, impaired concen-
have chronic migraine (CM) [8]. CM affects around 2–4% of the
tration, irritability, yawning, nausea and craving for food can
general population, with an annual incidence among people
occur; an aura phase, which occurs in about 20–30% of sub-
with episodic migraine is 2 · 5–3 · 0% [9]. This type of migraine
jects with migraine and is characterized by reversible transient
is related to a higher degree of headache-related disability
visual, sensory, speech, motor, and/or brainstem disturbances
than episodic migraine and is commonly linked with medica-
occurring before, during, after the pain phase or in absence of
tion overuse headache (MOH) [10].
it. These symptoms usually last between 5 and 60 min before
Refractory migraine is still a debated definition. It refers to those
the headache begins; the migraine pain phase, often charac-
subjects predominantly with CM who fail to tolerate and/or
terized by moderate to very severe throbbing uni-bilateral
respond to adequate trials of established acute and preventive
head pain episodes lasting 4–72 hours and potentially accom-
treatments. Up to 5% of the migraine population fulfills the criteria
panied by various neurological symptoms, namely photopho-
for refractory CM. This group of patients suffers from tremendous
bia, phonophobia osmophobia, nausea, vomiting and/or
disruption of their quality of life because of the migraine [11].
diarrhoea, dizziness, and vertigo. Over 70% of patients have

CONTACT Giorgio Lambru giorgiolambru@gmail.com The Headache Centre, Pain Management and Neuromodulation, Guy’s and St Thomas NHS
Foundation Trust, London SE1 7HE, UK
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 G. LAMBRU ET AL.
2. Existing pharmacological treatments
The current management of migraine includes treatments
aiming to abort a migraine episode when it occurs and treat-
ments to prevent future migraine occurrence, along with
reducing the severity of symptoms and/or duration of the
episode. The selection between abortive, preventive, or both
strategies for a given patient, depends upon several factors
including the severity of the migraine pain and associated
symptoms and the frequency of occurrence of the migraines
and disability associated. Broadly speaking, abortive strategies
should be the main treatment for people with an episodic
migraine with infrequent attacks, whereas preventive treat-
ments should be offered in people with episodic ‘high fre-
quency’ migraine and CM. These later group of patients
should also be educated upon the potential risk of MOH,
a very common chronification factor in migraine sufferers,
which often interferes with the full potential effect of conco-
mitant prophylactic treatments [12].
Non-steroidal antinflammatory drugs (NSAIDs), triptans and
prokinetics remain the mainstay of acute migraine treatment.
Stepped-up and stepped-down approaches are adopted in
most Countries. In stepped-up care the patient is started on
the simplest treatment and increasingly efficacious medica-
tions are prescribed until a satisfactory response is obtained.
A caveat of this approach can be the delays until an effective
treatment is found. A stepped-down care involves starting
with the most effective treatment or combination of treat-
ments and subsequently reducing the dose or number of
abortive treatments taken to allow effective treatment with
the minimum amount and number of treatments. A stepped-
down approach is recommended by National Institute for
Health and Care Excellence (NICE) guidelines in the United
Kingdom (U.K.), in view of its cost-effectiveness. NICE suggests
a combination of a triptan, NSAID or paracetamol, and an anti-
emetic taken as soon as possible after the start of the head-
ache [13].
Over-the-counter medications, such as NSAIDs and acetami-
nophen, are often chosen first drug-class for mild-to-moderate
migraine attacks. NSAIDs inhibit the activity of cyclooxygenase-
1 (COX-1) and cyclooxygenase-2 (COX-2) and, thereby, the
synthesis of prostaglandins and thromboxanes, exerting an
unspecific antinflammatory effect. Potential gastrointestinal
and renal side effects along with lack of efficacy in
a significant proportion of patients, limit their use in the
migraine population. Triptans are widely considered to be first-
line drugs for patients with migraine attacks associated with
moderate or severe pain intensity [14]. This class of drug was
specifically designed to abort migraine by agonizing the sub-
types 1B/D 5-hydroxytryptamine (5-HT) receptors, although
some triptans also act at the 5-HT1F receptor site [15]. This
receptors binding leads to vasoconstriction, mediated through
activation of the postsynaptic 5-HT1B receptors at the level of
the vascular smooth muscle, and inhibition of neuronal trans-
mission along the trigeminal system by acting on pre-junctional
5-HT1B/D receptors, which can also result in inhibition of calci-
tonin gene-related peptide (CGRP) release from perivascular
sensory nerve terminals. Their pharmacological profile, as well
as more recent positron emission tomography (PET) studies
suggest that the site of action of triptans is outside the blood-
brain barrier [16]. Interestingly, despite the perception that
triptans mechanisms of action tackle paramount migraine-
specific pathways, a proportion of migraine patients find them
ineffective. Alongside with those who do not tolerate their side
effects, about 30–40% of migraine subjects are considered
triptan-non responders [14]. Furthermore, in view of their vaso-
constrictive effect, their use is contraindicated in uncontrolled
hypertension, coronary artery disease, peripheral vascular dis-
ease, or stroke. Nausea and vomiting during migraine attacks
are common symptoms that affect at least 60% of patients
suffering from migraines. These symptoms are often more dis-
abling than the headache itself, causing a great burden on the
patient’s life. Antiemetics, such as metoclopramide or domper-
idone, are often prescribed as a combined treatment to NSAIDS
and triptans aiming to increase abortive treatment’s gastric
absorption and tackle the nausea and vomiting during their
migraines [14].
Preventive pharmacological treatments are considered if
headaches occur on four or more days per month; if abortive
treatment is contraindicated and/or ineffective and if abortive
treatments need to be used ten of more days per month every
month. The preventive treatment of migraine include different
classes of drugs, namely, b-blockers, tricyclic antidepressants,
antiepileptics, calcium channel blockers or angiotensin-
converting enzyme inhibitors. The choice of preventative
treatment depends upon the individual drug’s efficacy and
side-effect profile, the presence of any comorbid conditions
and patient’s preferences. However very often migraine sub-
jects fail to adhere to these oral medications long enough to
obtain a migraine preventive effect [17].
The only two approved medications for CM are topiramate
and more recently Onabotulinum toxin type A (BoNTA). The
introduction of BoNTA has significantly advanced the manage-
ment of CM in view of its favorable tolerability profile and high
responder rate found in clinical trials [18,19] and replicated in
real-world studies [20]. Caveats in the use of BoNTA in clinical
practice include the three-monthly administration in a hospital
setting and the multiple injection sides, which can put strain
on headache services. Besides, about one-third of patients do
not respond to BoNTA [20].
For pharmacological and injectable treatments non-
responders, the label of refractory CM is used [21]. For this
severely disabled group of patients, no pharmacological
treatment has hitherto been showed to be effective.
Occipital nerve stimulation has gathered positive open-label
evidence, which were not confirmed in randomized con-
trolled trials [22–26]. However these trials were criticized for
methodological issues. The use of noninvasive neuromodula-
tion techniques, including vagus nerve stimulation, single-
pulse transcranial magnetic stimulation and transcutaneous
electrical nerve stimulation have recently emerged as alter-
natives to pharmacological treatments as well as to invasive
neuromodulation approaches. Their different mechanisms of
action [27,28] along with different patients selection may
account for the mixed efficacy outcomes observed in clinical
practise [29–31].

3. Medical need
Despite the broad arsenal of treatments, there is still a vast
unmet need for novel migraine treatments. This includes:
(1) Better tolerated abortive treatments, which could also
be used in specific subgroup of migraine patients,
namely, the pediatric population, pregnant women, sub-
jects with comorbid cardiovascular and/or cerebrovas-
cular diseases and the elderly migrainous population.
(2) More effective abortive treatments that may be bene-
ficial in the triptan non-responder population.
(3) Preventive treatments with better tolerability profiles,
long-term safety, and patient-friendly administration
routes.
(4) Specifically-designed migraine preventive treatments,
which tackle pivotal pathways involve in migraine
pathophysiology.
(5) Preventive treatments for CM refractory to established
medical treatments. At present no pharmacological treat-
ments hold compelling evidence of efficacy in this chal-
lenging-to-treat group of people. Furthermore, invasive
neurostimulation approaches, such as occipital nerve sti-
mulation, have failed to demonstrate a meaningful ther-
apeutic effect in clinical trials.
4. Scientific rationale
Current research directions aim to produce therapies that are
able to tackle known migraine underlying putative pathophy-
siological mechanisms. Based on current theories, migraine is
considered a brain disorder where subcortical and potentially
cortical modulatory structures fail to modulate normal sensory
afferent trigemino-cervical inputs from the trigeminovascular
system [6]. The consequence of activation of this system is
thought to be responsible for the perception of head pain in
migraine.
During the premonitory phase of migraine, a number of
brain imaging studies have demonstrated altered blood flow
changes in the hypothalamic region [32,33], and in some
studies also in the visual cortex [34,35]. How functional
changes in the hypothalamus can eventually drive activation
of the trigeminovascular system is not understood, but likely it
involves alterations in descending pain pathways to the trige-
minocervical complex (TCC) [36]. The trigeminovascular sys-
tem consists of trigeminal nociceptive nonmyelinated and
thinly myelinated fibers innervating the meninges and dural
vasculature. These trigeminal afferents arrive predominantly
from the ophthalmic (V1) division of the trigeminal nerve,
but also to a lesser extent, from the maxillary (V2) and man-
dibular divisions (V3). Centrally, they project to the TCC, which
extends from the trigeminal nucleus caudalis to the upper
cervical spinal cord, mainly C2-C3 [37].
Activation of the trigeminovascular system results in the
release of a number of vasoactive neuropeptides, including
CGRP and substance P [38]. The dural vascular tone is also
regulated by sympathetic and parasympathetic fibers innerva-
tion. Sympathetic fibers contain vasoconstrictive peptides,
EXPERT OPINION ON EMERGING DRUGS 3
including Neuropeptide Y and norepinephrine, while the para-
sympathetic vasodilatory innervation is characterized mainly
by Vasoactive Intestinal Peptide (VIP) and pituitary adenylate
cyclase-activating peptide (PACAP) [39]. The ascending trige-
minothalamic pathway is modulated by a complex descending
network of midbrain and brainstem nuclei, which communi-
cate to one another via a plethora of neurotransmitters,
including serotonin, glutamate, GABA, dopamine, and endo-
cannabinoids [40].
At a cortical level, cortical spreading depression (CSD) is
thought to be the physiological substrate of migraine aura
[41]. It results from depolarization, followed by a sustained
hyperpolarization of cerebral cortical neurons and glial activa-
tion, and it also induces an initial hyperemia, followed by
oligoemia, resulting in profound disturbance of the cortical
vascular tone [42]. CSD is driven by the release of glutamate
which is modulated by calcium, potassium and sodium cur-
rents [43,44]. It is not yet clear whether CSD can activate the
trigeminovascular system and, hence exacerbate pain in
migraine. Electrophysiological studies in animal models sug-
gest that both peripheral and central mechanisms are possible
[45,46]. Nevertheless, disease mechanisms involved in
migraine aura are of interest also for the migraine without
aura prevention, since some of the treatments that can block
CSD, namely sodium valproate, topiramate, and sTMS, can also
prevent migraine without aura episodes [47,48].
5. Current research goals
Targeting the peptides, or their receptors, found to be
released during a migraine attack, or blocking activation of
the trigeminovascular system along with the neurotransmit-
ters’ receptors involved in the migraine process, have been
considered of pivotal relevance for the development of novel
acute and preventive pharmacological migraine-specific treat-
ments. In view of the pitfalls in the use of triptans, research
development programmes have had the objective to develop
novel acute treatments as, or more effective and better toler-
ated than triptans, with an exquisite neural, migraine-specific
mechanism of action that when possible avoid modulation of
the vascular tone. To this purpose two main pathways have
been studied: the CGRP and the serotonin pathways, which
produced two new family of drugs: the Gepants and the
Ditans. Targeting the CGRP pathway has also led to the devel-
opment of therapies potentially effective as preventive treat-
ments, the anti-CGRP monoclonal antibodies. These classes of
drugs are in an advanced stage of development and some of
these therapies will be on the market shortly.
6. Competitive environment
6.1. Calcitonin gene-related peptide
CGRP is one of the most potent vasodilators known. It exists in
2 forms in humans: a-CGRP (37-amino acid peptide), mainly
expressed in primary sensory neurons of the dorsal root gang-
lia, trigeminal ganglia and vagal ganglia, and b-CGRP primarily
found in intrinsic enteric neurons. CGRP is an ubiquitous pep-
tide distributed within the cerebral and cerebellar cortex,
4 G. LAMBRU ET AL.
thalamus, hypothalamus inhibitory nociceptive nuclei of the
brainstem, the trigemino-cervical complex and the trigemino-
vascular system [49]. Within the trigeminal ganglia CGRP is
expressed in cells that give rise to thinly myelinated A delta-
fibers and in unmyelinated C-fibers [50]. CGRP receptors have
been identified within the above-mentioned cortical and sub-
cortical structures, while on trigeminal fibers CGRP receptors
function as autoreceptors, regulating CGRP release [51].
CGRP levels have been found to be elevated during
a migraine attack, although some studies also suggest other-
wise [52,53]. Intravenous infusion of CGRP in migraine patients
has been also shown to induce a migraine attack in about 60%
of the patients [54]. Of interest, patients with familial hemi-
plegic migraine, a rare form of migraine with aura, are not
sensitive to CGRP [55], potentially due to changes of CGRP
levels in their trigeminal system [56]. Experimental activation
of trigeminal ganglion cells is known to result in the release of
CGRP, which is dose-dependently inhibited by 5-HT1B/D ago-
nists, highlighting the trigeminal system as a key site that may
be targeted by CGRP receptor antagonists and triptans [57,58].
In addition to its vascular effects, CGRP has emerged as a key
modulator of neuronal function, which has important effects
on neurotransmitter systems such as the glutamatergic sys-
tem [59].
Based on these findings, drugs directed at modulating
CGRP activity in migraine have emerged as particularly pro-
mising future treatments. CGRP receptor antagonists, which
compete with endogenous CGRP at the receptor binding sites,
have been developed as novel anti-migraine drugs and found
to be effective in the treatment of acute migraine attacks.
Other ways to modulate CGRP activity have been introduced
recently through the development of monoclonal antibodies
(mAb) against CGRP and the CGRP receptor.
6.1.1. CGRP receptor antagonists (the Gepants)
CGRP receptor antagonist are small compounds that compete
with endogenous CGRP at the receptor binding sites. To date,
it is not clear if the CGRP receptor antagonists cross the blood-
brain barrier. The progress of the new emerging CGRP antago-
nists has followed a previous successful development of
antagonists, named olcegepant (BIBN4096BS), telcagepant
(MK-0974) and MK-3207, which had good efficacy as acute
treatments for migraine, however, their safety profile was
rather unfavorable.
In a proof of concept study in acute migraine treatment,
intravenously administered Olcegepant 2.5 mg was signifi-
cantly superior to placebo at 2 h response rate (66% versus
27% of placebo-treated patients, p = 0.001), suggesting
a potential role in acute migraine treatment [60].
Subsequently, telcagepant, developed as an oral CGRP recep-
tor antagonist, was tested in a phase II proof-of-concept study
demonstrating the efficacy of 300–600 mg dose [61]. A dose of
150 mg, 300 mg were then tested in a randomized placebo-
controlled, parallel-treatment trial compared with zolmitriptan
5 mg in acute migraine. Telcagepant 300 mg was found to be
superior to placebo and similarly effective to zolmitriptan 5 m
in pain-freedom, pain relief, and other secondary outcomes.
Side effects did not differ much from placebo [62]. However,
when Telcagepant was tried on a daily basis as a preventive
migraine treatment, it caused liver enzymes derangement and
the trials were discontinued [63].
MK-3207 was the third oral CGRP receptor antagonist
developed and tested in migraine. A phase II multicenter,
double-blind, randomized, placebo-controlled, parallel-group
study showed superiority to placebo above the dose of 10 mg
in 2-h pain freedom, whether secondary outcomes of 2 h
freedom from photophobia/phonophobia/nausea and 2 to
24 h sustained pain freedom were significant at a much higher
dose (200 mg) only [64]. Similarly to other gepants however,
MK-3207 development was discontinued because of liver toxi-
city issues.
BI 44370 TA was another CGRP receptor antagonist used in
a phase II study which assessed its safety, tolerability, and
efficacy in the treatment of an acute migraine attack in episo-
dic migraine sufferers. The doses of 50 mg, 200 mg, and
400 mg were tested against placebo and eletriptan 40 mg.
The dose of 50 mg and 200 mg did not meet the primary
endpoint pain-free at two hours. The 400 mg dose of BI 44370
TA and eletriptan 40 mg were more effective than placebo. BI
44370 TA 400 mg and eletriptan 40 mg were also superior to
placebo on the absence of photophobia, phonophobia and
nausea as well as a reduction in functional disability at 2
h [65]. Although outcomes from this study did not support
a concern for unfavorable side effects, studies on this agent
are now discontinued.
6.1.1.1. Ubrogepant (MK-1602). Ubrogepant (MK-1602) is
a novel oral CGRP receptor antagonist chemically distinct
from telcagepant and MK-3207 (Figure 1). The safety and
efficacy of Ubrogepant at different doses (1 mg, 10 mg,
25 mg, 50 mg, 100 mg) was explored in a Phase IIb, multi-
center, randomized, double-blind, placebo-controlled trial [66].
Study primary efficacy endpoints were pain freedom at two
hours post-dose (reduction in headache severity from grade 2
or 3 at baseline to grade 0) and headache response at two
hours post-dose (reduction in headache severity from grade 2
or 3 at baseline to grade 1 or 0). Several other secondary
endpoints including safety endpoints were also analyzed.
A total of 834 participants were randomized to 1 mg, 10 mg,
25 mg, 50 mg, 100 mg of ubrogepant and placebo. The study
showed a positive response trend across ubrogepant doses
regarding the 2-h pain freedom endpoint. Ubrogepant 100 mg
was statistically superior to placebo for 2-h pain freedom
(25.5% vs 8.9%, P = 0.003), followed by ubrogepant 50 mg
(21.0% vs 8.9%, p = 0.020) and ubrogepant 25 mg (21.4% vs
8.9%, p = 0.013) However the two-hour headache response
did not significantly differ between different ubrogepant
doses and placebo. Ubrogepant 100 mg showed significant
improvements vs placebo on all secondary endpoints except
the absence of nausea at 2 h. With regards to adverse events
(AEs), their overall incidence were similar for ubrogepant
groups and placebo. The most common ubrogepant side
effects were dry mouth, nausea, fatigue, dizziness, and som-
nolence. The incidence of triptan-associated AEs in the ubro-
gepant groups was comparable to that of placebo. There were
no serious AEs within 14 days post-dose. Importantly, there
were no observed post-treatment elevations of ALT >3 ULN

a b
Figure 1. Chemical structures of (a) ubrogepant. (b) rimegepant. (c) atogepant.
and no other abnormal laboratory values of clinical relevance,
as found with the earlier CGRP antagonists. This promising
results supported further progression into phase 3 clinical
trials. Initial positive efficacy and safety results of two phase
III multicenter randomised, double-blind, placebo-controlled
clinical trials comparing ubrogepant 50 mg and 100 mg versus
placebo (Achieve 1) and ubrogepant 25 mg and 50 mg versus
placebo (Achieve 2) were recently presented at the American
Headache Society (AHS) conference in San Francisco, California
(28 June to 1 July 2018).
Overall the available data support the role of this new
treatment in the acute management of migraine, although
data on consistency of effect as well as safety data on subjects
in whom triptans are contraindicated are needed to confirm
its role as an alternative treatment to triptans.
6.1.1.2. Rimegepant (BMS-927711). Rimegepant is also
a novel CGRP-receptor antagonist chemically distinct from
telcagepant (Figure 1). Rimegepant’s efficacy and safety in
the acute treatment of migraine were tested in a phase II,
double-blind, randomized, placebo-controlled, dose-ranging
trial in 885 participants [67]. Patients were randomized to
receive one of six doses of BMS-927711 (10 mg, 25 mg,
75 mg, 150 mg, 300 mg, or 600 mg), sumatriptan (100 mg),
or placebo for the treatment of a moderate or severe migraine
attack. The primary endpoint was pain freedom at two hours
post-dose. Secondary endpoints included a composite end-
point consisting of freedom from headache pain coupled
with no symptoms of photophobia, phonophobia, and nausea,
at 2 h post-dose. Other secondary efficacy and safety end-
points were studied. The percentage of participants who met
the primary endpoint of pain-freedom at two hours was
higher in the group taking Rimegepant 150 mg (32.9%) com-
pared to the other Rimegepant doses (p < 0.001): 31.4% in the
75 mg, 29.7% in the 300 mg dose, 15.3% in the placebo group.
Sumatriptan 100 mg was superior to all dose of Rimegepant
(35%). The dose of Rimegepant 75 mg was the most effective
in meeting the secondary efficacy endpoint of total migraine
freedom (28.2%) and it was statistically superior than placebo.
Sumatriptan 100 mg was superior to each dose of Rimegepant
at this secondary endpoint. The percentage of patients with
headache freedom up to 24 h post-dose was superior to
placebo for several doses of Rimegepant and for sumatriptan.
Most of the AEs were mild to moderate in intensity. No
EXPERT OPINION ON EMERGING DRUGS 5
c
patients discontinued because of AEs. Two patients had
increased hepatic enzymes reported as an adverse event, on
in the Rimegepant group and one in the placebo group.
The findings of this study suggest that Rimegepant has
similar efficacy to sumatriptan 100 mg in the treatment of
a migraine attack, with potentially less triptan-related side
effects, namely paresthesia, and chest discomfort. A phase III
study comparing the efficacy of Rimegepant 75 mg versus
placebo has been recently completed. Furthermore
a prospective multicentre open-label long-term safety study
is underway and recruitment is anticipated to be completed
by late 2019. The finding of these two studies will shed more
lights on the consistency and safety of this molecule in
migraine therapy.
6.1.1.3. Atogepant (AGN-241689). Atogepant, a small
molecule with distinct, but similar structure to that of ubroge-
pant (Figure 1) is currently the only CGRP receptor antagonist
used in a study for the prevention of migraine. It has a higher
potency and longer half-life than ubrogepant, making it sui-
table for preventive treatment. A phase II/III, multicentre ran-
domized, double-blind, placebo controlled, parallel-group
study evaluated the efficacy, safety, and tolerability of multiple
dosing regimens of oral atogepant in episodic migraine pre-
vention (NCT02848326). Adult patients were randomized to
placebo, 10-mg QD, 30-mg QD, 30-mg BID, 60-mg QD, and 60-
mg BID, respectively, and treated under double-blind condi-
tions 12 weeks for the prevention of episodic migraine. The
primary efficacy endpoint was the change from baseline in
mean monthly migraine/probable migraine headache days
across the 12-week treatment period. All active treatment
groups demonstrated a statistically significant reduction from
baseline in the primary efficacy parameter (10 mg QD vs
placebo, Δ −1.15, p = 0.0236; 30 mg QD vs placebo, Δ −0.91,
p = 0.0390; 60 mg QD vs placebo, Δ −0.70, p = 0.0390; 30 mg
BID vs placebo; Δ −1.39, p = 0.0034, 60 mg BID vs placebo, Δ
−1.29, p = 0.0031). Atogepant appeared to be well tolerated
with the most common adverse events being nausea, fatigue,
constipation, nasopharyngitis, and urinary tract infection. The
liver safety profile for atogepant was similar when compared
to placebo, with no indications of hepatotoxicity with the daily
administration over 12 weeks. The development program of
this treatment is going to be moving to the next stage.
6 G. LAMBRU ET AL.

6.1.2. Anti-CGRP and anti-CGRP receptor monoclonal
antibodies
The CGRP pathway has been targeted also via antibodies
against CGRP and the CGRP receptor. This is the first time
engineered antibodies are used in the field of migraine and
initially their development was faced with some skepticism.
Three monoclonal antibodies (mAbs) target the ligand pre-
venting the binding of CGRP to its receptor. These are: galca-
nezumab (LY2951742), a fully humanized mAb anti CGRP,
fremanezumab (TEV-48125), a fully humanized mAb anti-
CGRP and eptinezumab, a genetically engineered humanized
anti-CGRP antibody. Erenumab (AMG 334), is a fully huma-
nized mAb targeting the CGRP receptor.
The favorable pharmacological profile of these compounds
includes their long half-life, the lack of a vasoconstrictive effect or
other relevant hemodynamic changes [68]. Given their high
molecular weight, these compounds do not cross the blood-
brain barrier, indicating a reduced likelihood of central nervous
system-related side effects, which are commonly observed with
pharmacological prophylaxis treatments currently used in
migraine. Furthermore, their administration route, which is either
subcutaneously (sc) or intravenously (IV) at different rates ran-
ging between once every three months to twice a month
depending on the compound, may improve long-term patients’
treatment compliance compared to oral treatments.
Methodologically similar randomized, double-blind, pla-
cebo-controlled Phase II and III clinical trials explored the
efficacy and safety of these novel treatments in the prevention
of episodic and CM.
6.1.2.1. Erenumab (AMG334). In a phase II trials in partici-
pants with episodic migraine, erenumab 70 mg given monthly
for three months was found to significantly reduce the num-
ber of migraine days per month by 3.4 days compared to
placebo (−2.3 days) at 12 weeks [69].
Subsequently, the STRIVE study, a multicenter, randomized,
double-blind, placebo-controlled, parallel-group, phase III trial,
assessed the efficacy and safety or subcutaneous (sc) injection
of either erenumab, at a dose of 70 mg or 140 mg, or placebo
in episodic migraine prevention monthly for 6 months. The
primary end point was the change from baseline to months 4
through 6 in the mean number of migraine days per month.
Secondary endpoints included the proportion of participants
with ≥50% reduction in mean migraine days per month.
Amongst other secondary endpoints the study evaluated
changes in scores on the physical-impairment and every day-
activities domains of the Migraine Physical Function Impact
Diary (scale transformed to 0 to 100, with higher scores repre-
senting greater migraine burden on functioning) [70]. The
overall mean number of migraine days/month was 8.3 at
baseline. Table 1 showed the main efficacy outcomes of the
study, highlighting the superiority of both doses of erenumab
compared to placebo in reduction of migraine days and
responder rate. The study showed also a significant improve-
ment of the disability questionnaires for both doses of
Erenumab compared to placebo (p < 0.001).
The ARISE trial consisted in a randomized, double-blind,
placebo-controlled, phase III study assessing the efficacy and
safety of erenumab 70 mg only vs placebo in episodic
migraine participants [71]. The primary endpoint was changed
in monthly migraine days. Secondary endpoints included
≥50% reduction in monthly migraine days and changes in
migraine disability scores. The efficacy outcomes of the study
were superior to placebo and interestingly similar to the
STRIVE study ones as summarised in Table 1. However this
study, unlike the STRIVE study, did not show significant
improvement in the migraine disability scores. Both the
STRIVE and ARISE trials indicate a favorable safety and toler-
ability profile of erenumab. Most frequent adverse events
were upper respiratory tract infection, injection site pain, and
nasopharyngitis.
The interim analysis of the planned 5-year long open-label
extension of the phase II clinical trial [69] with Erenumab
70 mg included 383 episodic migraine participants who had

Table 1. Efficacy outcomes in phase II and phase III clinical trials using mAbs anti-CGRP for the prevention of episodic migraine.
Change in migraine days
Δ
active placebo (p-value) 50% response rate
Erenumab STRIVE −3.2 −1.8 −1.4 Active: 43.3%-50%*
(70,140 mg) –3.7 –1.9 Placebo: 26.6%
(<0.001)
ARISE −2.9 −1.8 −1.0 Active: 39.7%*
(70 mg) (<0.001) Placebo: 29.5%
Galcanezumab EVOLVE-1 −4.7 −2.8 −1.9 Active: 62.3%-60.9%*
(120, 240 mg) –4.6 –1.8 Placebo: 38.6%
(<0.001)
EVOLVE-2 −4.3 −2.3 −2.0 Active: 59.0%-57.0%*
(120, 240 mg) –4.2 –1.9 Placebo: 36.0%
(<0.001)
Fremanezumab Phase IIb −6.2 −3.4 −2.8 Active: 53.0%-59.0%*
(225, 675 mg) –6.0 –2.6 Placebo: 28.0%
(<0.0001)
Phase III −4.0 −2.6 −1.5 Active: 47.7%-44.4%*
(225, 675 mg**) –3.9 –1.3 Placebo: 27.9%
(<0.001)
Eptinezumab IV −5.6 −4.6 −1.0 Active: 75.0%*
(1000 mg) (p = 0.030) Placebo: 54.0%
*Statistically significant difference compared to placebo
**One single injection quarterly

failed up to two previous preventive treatments [72]. This
study looked at 1-year changes in migraine days, percentage
of participants achieving ≥50%, ≥75% and 100% reduction in
monthly migraine days, change in disability score using HIT-
6, MIDAS and MSQ and safety profile. From an average base-
line of 8.8 migraine days/month of those who took part in
the open-label trial, at week 64, 28% of participants discon-
tinued the treatments for various reasons. Of the remaining
participants, a mean reduction of 5 migraine days was found.
Looking at participants who were treated with erenumab
70 mg since month 1 of the randomized controlled phase,
from month 3 to month 64 the mean number of migraine
days diminished from −3.4 to – 5 days/month, with an
estimate gain of −1.6 migraine days less after 52 months.
At week 64, 65%, 42%, and 26% achieved, respectively, 50%,
75%, and 100% reduction in migraine days. Disability and
quality of life scores displayed a meaningful improved at
week 64. No safety concerns emerged during the open-
label extension.
The safety and efficacy of Erenumab in the prevention
of CM were evaluated in a randomized, double-blind, placebo-
controlled phase II clinical trial [73]. Patients were randomly
assigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, or
erenumab 140 mg, given every 4 weeks for 12 weeks. The
primary endpoint was the change in monthly migraine days
from baseline to the last 4 weeks of double-blind treatment
(weeks 9−12). Secondary endpoints included the percentage
of participants achieving 50% reduction in monthly migraine
days, change in the use of monthly acute migraine treatments
and change in cumulative headache hours from baseline.
Safety endpoints were also analyzed. At baseline the mean
monthly migraine days ranges between 17.8 and 18.2 days.
Table 2 outlines the reduction in migraine days compared to
placebo with erenumab 70 mg and 140 mg and the 50%
response rate. There was a significant reduction in monthly
acute medicines intake in both erenumab groups, but no
significant reduction in cumulative monthly headache hours.
No safety issues emerged during the trial.
Erenumab (Aimovig) obtained FDA approval in May 2018
for the prevention of migraine in adults.
Table 2. Efficacy outcomes in phase II and phase III clinical trials using mAbs anti-CGRP for the prevention of chronic migraine.
Change in migraine days
active
Erenumab (Phase II) −6.6
(70, 140 mg)
Galcanezumab (Phase III) −4.8
(120, 240 mg) –4.6
Fremanezumab Phase IIb −6.04
(675/225, 900 mg) –6.16
Phase III −4.6
(225, 675 mg**) –4.3
Eptinezumab (Phase III) −7.7
(100, 300 mg) –8.2
*Statistically significant difference compared to placebo
**One single injection quarterly
EXPERT OPINION ON EMERGING DRUGS 7
6.1.2.2. Galcanezumab (LY2951742). Galcanezumab is
a humanized monoclonal antibody that blocks CGRP activity
by blocking the ligand and not the receptor. Phase II proof-of-
concept trials conducted in episodic migraine participants.
LY2951742 (150 mg) or placebo were given as a sc once
every 2 weeks for 12 weeks. The primary endpoint was the
mean change in number of migraine headache days [74].
Safety outcomes were also assessed. The primary endpoint
was met with a mean reduction of 4.2 monthly migraine
days compared to a reduction of 3.0 days in the placebo
arm (p = 0.003). Erythema, upper respiratory tract infections,
and abdominal pain were the most frequently adverse events
reported in the trial. No serious adverse events were reported
in the active arm.
A recently published phase IIb clinical trial of
Galcanezumab and placebo in episodic migraine sufferers
aimed to assess the superiority of galcanezumab administered
sc monthly at different doses (5, 50, 120, 300 mg) for three
months compared to placebo. The primary efficacy outcome
was mean change from baseline in migraine days from week 9
to 12 post-randomization. Galcanezumab 120 mg significantly
reduced migraine headache days compared with placebo
(−4.8 days vs −3.7 days) [75].
These initial findings led to the development of two phase
III randomized, multicenter, double-blind, placebo-controlled
trials in episodic migraine patients (EVOLVE-1 and EVOLVE-2)
[76,77]. In the both trials, the efficacy and safety of monthly sc
injections of galcanezumab 120 and 240 mg versus placebo
for 6 months were assessed. Participants were subsequently
followed-up for 5 months after the last injection. Primary end-
point was overall mean change from baseline in monthly
migraine headache days. Secondary outcomes included
≥50%, ≥75%, and 100% reduction in monthly migraine head-
ache days. Disability, quality of life, and safety measures were
also analyzed. Both studies met the primary and secondary
efficacy endpoints for both doses at 6 months as shown in
Table 1. There was no significant difference in migraine
improvement between 120 mg and 240 mg. Migraine disabil-
ity outcomes were significantly improved compared to pla-
cebo. Injection site pain was the most common AE.
Δ
placebo (p-value) % of participants achieving 50% migraine days reduction
−4.2 −2.4 Active 70 mg: 40%*
(<0.0001) Active 140 mg: 41%*
Placebo: 23%
−2.7 −2.1 Not reported but superior to placebo
–1.9
(<0.001)
−4.2 −1.8 Active: 53.0%; 55.0%*
–1.9 Placebo: 31.0%
(0.0023)
−2.5 −2.1 Active: 41.0%; 38.0%*
–1.8 Placebo: 18.0%
(<0.001)
−5.6 −2.1 Active: 57.6%; 61.4%*
–2.6 Placebo: 39.3%
(<0.0001)
8 G. LAMBRU ET AL.
The REGAIN study (NCT02614261) is a double-blind, rando-
mized, placebo-controlled, 3-month study with a 9-month
open-label extension for the prevention of a migraine in par-
ticipants in CM. The study preliminary results were presented
as a poster at the AHS 2018. Participants were randomized
2:1:1 to sc placebo, galcanezumab 120 mg or 240 mg given
monthly for three months. The primary endpoint was the
overall mean change from baseline in the number of monthly
migraine days during the 3-month double-blind treatment
phase. Secondary efficacy outcomes included the percentage
of patients with 50%, 75%, and 100% reduction in monthly
migraine days, along with migraine-related disability and qual-
ity of life scores. The study met the primary endpoint at
3 months as it is shown in Table 2. Compared to placebo
there was a higher incidence of injection site reaction,
erythema, and sinusitis in the galcanezumab arms.
6.1.2.3. Fremanezumab (TEV48125). Fremanezumab is
a fully humanized monoclonal antibody targeting CGRP.
Similarly to the other monoclonal CGRP antibodies, favorable
Phase I studies encouraged the development of phase II stu-
dies in the prevention of migraine. The efficacy and safety of
sc TEV-48125 (225 mg and 675 mg) versus placebo was stu-
died in a multicentre, randomized, double-blind, placebo-
controlled, phase 2b study in episodic migraine. Participants
were randomized to receive either TEV-48125 225 mg or
675 mg or placebo every 28 days for 3 months. The primary
efficacy endpoint was the mean decrease from baseline in the
number of days migraine days during the third treatment
cycle (weeks 9–12). Primary safety parameters were also ana-
lyzed. In post-hoc analyses, the proportion of participants
obtaining at least 50% and 75% decrease in the number of
migraine-days compared to baseline was evaluated. The study
met the primary efficacy outcome with both doses of TEV-
48125 (Table 1). No safety or tolerability issues were identified.
The most common treatment-related adverse events were
mild injection-site pain or erythema [78].
Subsequently, the preventive effect of TEV-48125 (frema-
nezumab) in episodic migraine was studied in a randomized,
double-blind, placebo-controlled, parallel-group phase III trial
[79]. The design of the trial implied the injection of monthly sc
fremanezumab 225 mg, or 675 mg following a quarterly dose
regimen, or placebo. The primary study endpoint was mean
change in number of monthly migraine days/month at the 12-
week period. Secondary efficacy end points included the pro-
portion of patients obtaining at least a 50% reduction in the
mean number of monthly migraine days from baseline to
week 12 as well as changes in migraine-related disability
scores. The mean number of monthly migraine days at base-
line ranged between 8.9 and 9.3 days in the three study arms.
The study met the primary efficacy endpoint for both monthly
and quarterly regimens, showing superiority to placebo in
reduction of mean migraine days. No significant difference
was noticed between the two different fremanezumab regi-
mens. The most common AEs were injection site reactions.
Similar low proportion of participants in the different arms
discontinue because of AEs (2%).
The main strength of this study includes for the first time
the outcomes of a single dose therapy given quarterly. Given
the similar results compared to monthly injections, this strat-
egy may open interesting avenues on potentially effective
multiple injection regimens in migraine prevention.
The safety, tolerability, and efficacy of TEV-48125 (fremane-
zumab) were also tested in CM in a multicentre, randomized,
double-blind, placebo-controlled, phase IIb study [80]. The
dose of the active treatment differ from the episodic migraine
trials. TEV-48125 was administered at the dose of 675 mg in
the first treatment cycle and 225 mg in the second and third
treatment cycles, or at the dose of 900 mg monthly for three
months versus placebo. The efficacy endpoints also differed
from the episodic migraine studies. For this trial, change from
baseline in the number of headache-hours during the third
treatment cycle (weeks 9–12) was set as primary outcome. The
change in the number of moderate or severe headache-days
was considered a secondary endpoint. At baseline, partici-
pants had a mean of 162 headache-hours/month, 21.1 head-
ache-days of any duration and 16.8 migraine days/month. The
majority of participants had not tried any preventive treat-
ment at baseline. During weeks 9–12, a significant reduction
in a number of headache-hours was demonstrated for both
doses compared to placebo (675/225: – 59.84; 900 mg: –
67.51 h; placebo: – 37.10 h, p = 0 · 0386 and p = 0.0057).
Similarly, a significantly greater reduction in mean number of
headache days was found for both doses compared to pla-
cebo (Table 2). The higher fremanezumab doses were fairly
well tolerated and no serious concerns emerged in terms of
AEs from this trial.
On the basis of the promising results of the phase II study,
a randomized, double-blind, placebo-controlled, parallel-
group trial was subsequently conducted to confirm the effi-
cacy of fremanezumab for the prevention of CM [81].
Participants with CM were randomized in a 1:1:1 ratio to
receive fremanezumab quarterly (a single dose of 675 mg at
baseline and placebo at weeks 4 and 8), fremanezumab
monthly (675 mg at baseline and 225 mg at weeks 4 and 8)
or placebo. The primary end point was the mean change from
baseline in the average number of headache days, defined
according to the International Headache Society (IHS) criteria.
Interestingly the mean number of monthly migraine days at
baseline was higher than the number of headache days but
lower than the number of days of any severity and duration.
Furthermore, the majority of participants did not use topira-
mate or BoNTA at baseline. The study met the primary end-
point for both doses and showed a significantly greater
percentage of participants obtaining at least 50% reduction
in headache days with fremanezumab compared to placebo
(Table 2). Discontinuation of the trial due to adverse events
was infrequent. Similarly to other trials, fremanezumab was
associated with a higher incidence of injection-site reactions
than placebo, though the severity of such reactions did not
differ significantly among the trial arms.
Fremanezumab (Ajovy) was granted FDA approval on the 14th
of September 2018, making it the second anti-CGRP monoclonal
antibodies approved for the preventive treatment of migraine in
adults and the first one with quarterly and monthly dosing options.

6.1.2.4. Eptinezumab (ALD403). ALD403 (Eptinezumab) is
a genetically engineered, humanized antibody targeting both
forms of human CGRP. Its efficacy, safety, and tolerability have
been evaluated in a phase II proof-of-concept study in parti-
cipants with an episodic migraine [82]. The primary aim of the
study was to assess the safety of a single dose of 1000 mg of
ALD403 administered intravenously compared with placebo.
Secondary outcomes included efficacy and migraine-related
disability measures at 12 weeks post infusion. In particular
change from baseline to weeks 5–8 in migraine days was
evaluated. The frequency of migraine days at baseline was
8.8 in the placebo and 8.4 in the active group. Adverse events
were experienced by 52% participants in the placebo group
and 57% in the ALD403 group. The most frequent AEs were
upper respiratory tract infection, urinary tract infection, fati-
gue, back pain, nausea and vomiting, and arthralgia. Most of
them were mild or moderate in severity. None of the infre-
quent serious adverse events were considered related to the
active drug. In terms of the efficacy endpoints, there was
a significant reduction in the mean number of migraine days
between baseline and weeks 5–8 for ALD403 compared to
placebo (Table 1). Interestingly a very high proportion of
participants obtained 50% reduction of migraine days at
weeks 5–8. It was also noted that the placebo response rates
in this trial were remarkably high compared to the previous
trials using anti-CGRP monoclonal antibodies, possibly
because of the intravenous administration of the drug.
These preliminary findings led to the development of a phase
III randomized, double-blind, placebo-controlled study to evalu-
ate the efficacy and safety of different doses of eptinezumab in
episodic migraine (PROMISE 1) (NCT02559895). The primary end-
point was the mean change in migraine days over weeks 1–12
compared to a 28-day baseline. Baseline migraine days averaged
8.5 days/month across groups. Participants were randomized to
receive eptinezumab 300 mg, 100 mg, 30 mg, or placebo by
intravenous infusion every 12 weeks. The study met the primary
efficacy endpoint. A significantly greater reduction of migraine
days was achieved at all eptinezumab doses compared to pla-
cebo (−4.3, −3.9, −4.0 vs −3.2). Furthermore, a significantly
greater proportion of participants given eptinezumab had
a 50% reduction in migraine days (49.8%-56.3% vs placebo:
37.4%). No AEs issues emerged in this trial. In most of the anti-
CGRP monoclonal antibodies trials have emerged the remark-
able fast response compared to placebo normally within the first
month for active drug administration. Eptinezumab was shown
to be able to reduce migraine from day 1 and to maintained
similar improvement at four and 12 weeks post-infusion. The
preliminary findings of this study were presented at the
American Academy of Neurology 2018 (AAN) Conference, Los
Angeles, California.
The efficacy, safety, and tolerability of eptinezumab in CM
were assessed in a phase II and a phase III trial. A randomized,
double-blind, placebo-controlled phase II study tested various
doses of ALD403 versus placebo. Participants were rando-
mized to receive a single intravenous dose of ALD403
300 mg, 100 mg, 30 mg, 10 mg, or placebo. Unlike other anti-
CGRP monoclonal antibodies trials, the primary endpoint here
was the percentage of patients achieving a 75% reduction in
EXPERT OPINION ON EMERGING DRUGS 9
migraine days per month from baseline to week 12. The
percentage of participants achieving 75% reduction in
migraine days with ALD403 300 mg and 100 mg was signifi-
cantly greater than the one receiving placebo (33% and 31%
vs 21%). These results were presented at the AAN 2018 con-
ference Los Angeles, California.
The PROMISE 2 (PRevention Of Migraine via Intravenous
ALD403 Safety and Efficacy 2) is a Phase III, randomized,
double-blind, placebo-controlled trial evaluating the safety,
and efficacy of eptinezumab for the prevention of CM.
Patients were randomized to receive eptinezumab (300 mg
or 100 mg), or placebo administered by infusion once every
12 weeks (NCT02974153). The primary endpoint was the mean
change from baseline in monthly migraine days over the
12 week, double-blind treatment period. Secondary efficacy,
migraine-related disability, and safety outcomes were also
analyzed, including the percentage of participants showing
reduction in migraine prevalence at day 1 post-infusion. The
baseline mean frequency of migraine days was 16.1 across the
groups. Both eptinezumab doses met the primary endpoint
with mean migraine reduction of 7.7 days (dose 100 mg), –
8.2 days (dose 300 mg) versus placebo (−5.6 days) (p < 0.0001)
(Table 2). Interestingly, 51% who received 100 mg and 52%
who received 300 mg of the active drug compared to 27% of
those who received placebo, showed a reduction in migraine
risk beginning at day one post-infusion, which was then sus-
tained through day 28. The safety profile of eptinezumab in
this study was comparable to the one of previous studies.
These preliminary results were presented at the AAN 2018
Conference, Los Angeles, California.
6.2. 5-HT1F receptor and 5-HT1F receptor agonists (the
DITANS)
The 5-hydroxytryptamine (serotonin) receptor 1F, also known
as 5-HT1F receptor, is a member of the 5-HT1 subfamily of the
5-HT serotonin receptors that bind to the endogenous neuro-
transmitter serotonin. Like other 5-HT1 receptors, 5-HT1F is
a protein coupled to Gi/Go and mediates inhibitory neuro-
transmission. Interestingly, this receptor is found at the pre-
junctional site of the trigeminal fibers but is lacking from the
vascular smooth muscles. Centrally is found in the TCC, cere-
bellum, and cortex [83].
Triptans, mediate part of their effect through modulation of
5-HT1F receptors on trigeminal sensory neurons; hence, 5-HT1F
agonist compounds were postulated to have an abortive anti-
migraine effect without the vasoconstrictive effect [84]. This
led to the development of the first 5HT1F agonist LY334370
which was investigated in a small randomized, double-blind,
placebo-controlled, parallel-design clinical trial, and proved to
be effective for the acute treatment of migraine attacks at
60 mg and 200 mg. Unfortunately, frequent adverse events
such as asthenia, dizziness, and somnolence, as well as, com-
pound-specific safety concerns stopped further clinical devel-
opments [85].
Following this, lasmitidan (COL-144, LY573144), a more spe-
cific 5-HT1F receptor agonist with a novel pyridinoyl-piperidine
structure, was developed. Lasmitidan showed promising
10 G. LAMBRU ET AL.
results in a proof-of-concept study where doses above 20 mg
infused intravenously, produced pain relief at 2 h in a signifi-
cantly higher percentage of cases than placebo during an
acute migraine attack. The efficacy became evident at 20–-
40 min after administration, in the absence of serious adverse
events [86]. Subsequently, a phase II study with oral lasmitidan
tested at the doses of 50, 100, 200 and 400 mg for the acute
migraine attack, showed superiority with respect to placebo at
2 h. Also, migraine-associated symptoms improved with all
doses. Fifty percent of treated subjects reported a return of
headache within 24 h after treatment. The most severe
adverse events included dizziness [87].
Two Phase III randomized, double-blind, placebo-controlled
studies have been tested lasmitidan in an episodic migraine
acute treatment. In the SAMURAI trial (NCT02439320), partici-
pants were randomized to lasmitidan 200 mg, 100 mg or pla-
cebo. In the SPARTAN study (NCT02605174) participants were
randomized to lasmitidan 200, 100, 50 mg or placebo. Key stu-
dies endpoints were the proportion of participants who become
headache-free at 2 h post-dose and the proportion of partici-
pants who free from the most bothersome symptom at 2 h post-
dose. Secondary outcomes including headache recurrence,
changes in pain-killers utilization and freedom from migraine-
associated symptoms. A statistically significant proportion of
participants using Lasmitidan 50 mg, 100 mg, and 200 mg
were headache-free and most bothersome symptom-free com-
pared to placebo at 2 h post-dose. In particular 32.2% in the
SAMURAI study and 38.8% of the participant in the SPARTAN
study receiving lasmiditan 200 mg compared to 15.3% and
21.3%, respectively, in the placebo group, became headache-
free and 40.7% in the SAMURAI and 48.7% in the SPARTAN study
were free from the most bothersome symptom compared to
29.5% and 33.5%, respectively, in the placebo group.
Lasmiditan 50, 100 and 200 mg was also superior to placebo in
proportion of participants with headache relief, percentage of
participants needing to use rescue medication, percentage of
participants reporting photophobia and phonophobia-freedom
at two hours, but not in nausea-freedom. The most common side
effects with lasmiditan were dizziness, paresthesia, somnolence,
fatigue, nausea, and lethargy. These data were presented at the
AAN 2018 Conference, Los Angeles, California.
An open-label Phase III study, called GLADIATOR aiming to
evaluate the long-term safety of lasmiditan for the acute
treatment of migraine is underway. Furthermore, a global,
multicenter, double-blind, modified parallel, placebo-
controlled study has been planned to assess the safety, effi-
cacy, and consistency of lasmiditan in the acute treatment of
multiple migraine attacks with or without aura. The results of
these studies will confirm the long-term efficacy and consis-
tency of response of this novel medication for the acute
treatment of migraine.
6.3. Pituitary adenylate cyclase-activating polypeptide
(PACAP) and pituitary adenylate cyclase-activating
polypeptide type 1 receptor (PAC1)
Pituitary adenylate cyclase-activating polypeptide (PACAP) is
another neuropeptide that has been implicated in migraine
pathophysiology [88]. PACAP is closely related to VIP and is
found in two isoforms, PACAP-38 and PACAP-27 with PACAP-
38 to be more abundant. In neuronal tissues, the isoform
PACAP-38 predominates [89]. It is known to play hypophysio-
tropic, neuromodulatory, and neurotransmitter roles, and has
been associated with differentiation- and proliferation-
inducing effects in the developing nervous system, as well as
with cytoprotective, anti-apoptotic, and anti-inflammatory fea-
tures within various target organs [90]. Within the trigeminal
ganglia, PACAP is localized in small neurons which in addition
store CGRP [91]. Other structures relevant to the pathogenesis
of migraine, such as in trigeminal afferents in the dura mater,
the cerebral vessels, the TCC, brainstem nuclei, as well as the
sphenopalatine and otic ganglia also express PACAP [92–94].
In a recent preclinical study, it was found that both VIP and
PACAP similarly cause transient vasodilation of meningeal
arteries, yet only PACAP was able to trigger a delayed sensiti-
zation of second order trigeminocervical neurons [95,96]. In
migraine patients, elevated levels of plasma PACAP-38 were
revealed in the ictal migraine period but not during interictal
phase in migraineurs [97,98]. Stimulation of the trigeminal
ganglion was shown to increase PACAP expression in the
trigeminal nucleus caudalis, a phenomenon blocked by
kynurenic acid analogues and NMDA receptor antagonists
[99]. be Additionally, intravenous infusion of PACAP-38, but
not VIP, was shown to trigger migraine-like headaches in
migraine patients [100,101].
The pituitary adenylate cyclase-activating polypeptide type
1 receptor (PAc1) has been identified as a receptor which
binds the PACAP molecule with high affinity [90]. A novel
molecule, AMG 301, is a PAc1 receptor selective monoclonal
antibody which has been developed for the prevention of
migraine, potentially by inhibition of trigeminal autonomic
signaling. A phase IIa randomized double-blind placebo-
controlled study that aims to evaluate the efficacy and safety
of AMG 301 in migraine prevention is currently underway
(NCT03238781).
6.4. Unresolved questions from previous clinical trials
6.4.1. Nitric oxide synthase
Nitric oxide synthases (NOS) are a family of enzymes catalyzing
the production of nitric oxide (NO) from L-arginine. Nitric
oxide is a gaseous molecule which involved in a variety of
functions including endothelial-dependent vasodilation,
neural signaling, and development. Nitric oxide is produced
in mammals by the endothelial (eNOS) and neuronal (nNOS),
while the inducible isoform, iNOS produces NO as an immune
response. NO donors are known to induce a delayed migraine
attack in a portion of migraine patients and are used for the
experimental induction of migraines [102]. NO donors are
widely used in animal models of migraine and have been
shown to induce fos activation in many migraine-related
areas, including the TCC, brainstem, and hypothalamus [103].
Hence, the development of selective NOS inhibitors has been
suggested as an emerging therapy for migraine [104].
Research has focused on other specific NOS inhibitors, with
the initial study of a specific iNOS inhibitor GW274150 failing
to reach its clinical end point in both an acute and preventive

study [105]. A mixed triptan and nNOS inhibitor NXN-188 was
also found to be ineffective in both migraine without aura and
specifically in the aura phase [106]. The question about
a possible effect of a specific nNOS inhibitor remains
unresolved.
On the other hands the role of peripherally produced NO as
a therapeutic agent is currently investigated in a clinical trial
using B244- ammonia-oxidizing bacteria (AOB). AOB is
a naturally occurring type of nitrifying bacteria that metabolize
the ammonia found in sweat, creating nitrite and nitric oxide
[107]. In an ongoing a randomized, vehicle-controlled, double-
blind, phase II study the safety, tolerability, and efficacy of
B244 delivered as an intranasal spray is tested for preventive
treatment in subjects with an episodic migraine
(NCT03488563). The hypothesis that is being tested is that
by increasing local and systemic NO levels, this bacteria exert
an anti-inflammatory effect that may have a potential thera-
peutic effect in migraine.
6.4.2. Orexin receptors
Orexin A and B are neuropeptides that are synthesized in the
hypothalamus and thought to play a role in nociception. They
exhibit their action by activating their receptors orexin 1 (OX1)
and orexin 2 (OX2). In an animal models of trigeminovascular
activation, activation of the OX1 and OX2 receptor in the
posterior hypothalamus has been shown to differentially mod-
ulate nociceptive dural input to the TNC [108]. Activation of
the OX1 receptor was found to elicit an anti-nociceptive effect
whereas OX2 receptor activation elicits a pro-nociceptive
effect. Filorexant, is a dual OX1 and OX2 receptor antagonist
which was originally developed to treat insomnia [109] and
was found to have some effect in animal models of migraine
[110]. In a phase IIa trial for the prophylaxis of migraine,
Filorexant was found to be ineffective [111]. It remains to be
evaluated though if a more specific OX2 receptor antagonist or
a specific OX1 agonist will have different outcomes in migraine
prevention.
6.4.3. Glutamate receptor antagonists
Glutamate is the main excitatory neurotransmitter of the ner-
vous system and the neurotransmitter that manifest transmis-
sion from primary trigeminal neurons to second-order neurons
in the TCC, along the ascending trigeminothalamic pathway
and from third order thalamic neurons to the cortex. Glutamate
is implicated in many aspects of migraine pathophysiology,
including trigeminovascular activation, central sensitization,
and CSD [112]. Glutamate exhibits it actions on ionotropic
glutamate receptors, namely: N-methyl-D-aspartate (NMDA), α-
amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA),
and kainite, and metabotrobic glutamate receptors (mGLuR),
namely: mGluR1-8. Antagonizing glutamate transmission along
the ascending trigeminovascular-trigeminothalamic pathways
would have been an ideal treatment for migraine. However,
blockade of central glutamatergic transmission can have tre-
mendous results for the brain.
Small clinical trials using specific glutamate receptor
antagonists, that do not antagonise the main ionotropic
receptors NMDA and AMPA, aimed to investigate their efficacy
in an acute migraine. Such treatments could offer a non-
EXPERT OPINION ON EMERGING DRUGS 11
narcotic, non-vascular approach to the management of head-
ache pain and represent a potentially promising alternative to
current migraine treatments. Tezampanel (LY293558) was
a small molecule initially developed against the GluK5 subunit
of the kainite receptor, although further studies demonstrated
an additional competitive action for the AMPA receptor [113].
Preclinical studies have demonstrated a role for kainate recep-
tor in migraine pathophysiology and selective antagonists in
the trigeminovascular model were shown to suppress trigemi-
novascular stimulation [114]. In a placebo and active-
controlled phase II trial in patients with acute migraine, the
compound, administered intravenously, achieved statistical
significance in all primary and secondary endpoints which
included pain relief at two hours and relief of nausea, photo-
phobia, and phonophobia. Tezampanel demonstrated an
attractive safety and pharmacokinetic profile [113].
Unfortunately, no further developments were carried on with
this molecule or other kainite receptor-specific antagonists,
although this is an avenue worth exploring further.
ADX10059 was an mGluR5 negative allosteric modulator
used in a small clinical trial for the acute treatment of
a migraine. The primary efficacy endpoint for the clinical
trial, 2 h pain-free, demonstrated a significant effect of
ADX10059 375 mg, 17%, versus placebo, 5%, with transient
dizziness being the most common treatment-emergent event
in about half the patients [115]. ADX10059 was also used in
a phase II randomized, double-blind, placebo-controlled study
for the prevention of a migraine. However, the study was
terminated early following the emergence of a higher than
expected rate of liver enzyme abnormalities [116]. Targeting
mGluRs was thought to be a more safe approach to blocking
glutamate in the CNS. Although mGluR5 did not meet this
expectation, positive allosteric modulators against other
mGluRs may have a therapeutic value for migraine that
remains to be investigated [117].
6.5. Future targets for emerging treatments
6.5.1. The tryptophan-kynurenic pathway
An increasing number of preclinical studies highlight the
importance of the kynurenine pathway in the pathophysiol-
ogy of migraine [118]. The tryptophan-kynurenic pathway is
the second most prevalent metabolic pathway of tryptophan
and accounts for approximately 90% of tryptophan catabo-
lism, with the synthesis of the synthesis of 5HT to account for
the metabolism of ~3% or less of non-protein tryptophan
[119]. Major components of the pathway – quinolinic acid
and kynurenic acid – were shown to act on NMDA receptors,
with quinolinic acid having an excitatory action and kynurenic
acid being an antagonist of ionotropic glutamate recep-
tors [120].
A number of preclinical studies implicated the kynurenic
pathway in the nociceptive activation of the trigeminal sys-
tem. Administration of nitroglycerine, which induces migraine
to patients, sensitizes the trigeminal system of animal and was
shown to downregulate a number of enzymes of the kynure-
nic pathway, with a potential influence on the glutamatergic
system [121]. Pre-treatment with kynurenic acid was shown to
prevent the nitroglycerine-induced neuronal activation and
12 G. LAMBRU ET AL.
sensitization in the TCC in rodents [122]. In the same model,
the kynurenic acid analog 1 was shown to suppress nitrogly-
cerine-induce hyperalgesia and to suppress the increased
levels of CGRP, nNOS, and cytokines in the trigeminal system
[123,124]. Kynurenic acid and its derivatives have been also
shown to suppress nociceptive activation of the trigeminal
pathway [125–128], and to reduce the release of glutamate,
the excitatory neurotransmitter that drives activation of the
ascending trigeminothalamic pathway [125].
Recent studies in CM patients found altered serum levels of
all kynurenine metabolites [129]. Of interest, altered serum
levels of kynurenine metabolites were also found in cluster
headache patients [130]. Further studies for the potential
utilization of the kynurenine pathway in the treatment of
migraine may open new therapeutic perspectives.
6.5.2. Cannabinoids
Cannabinoids may have therapeutic use in pain and may also
have a role in the treatment of migraine. There are two cloned
cannabinoid receptors the cannabinoid receptor 1 (CB1) is
present on neurons in the peripheral and central nervous
system, while the CB2 receptor is found predominantly in
immune cells [131,132]. CB1-immunoreactive neurons are
found in the trigeminal ganglia and TCC [133]. In animal
models of migraine endogenous cannabinoids and cannabi-
noid agonists have an inhibitory effect on trigeminovascular
activation through the cannabinoid receptor 1 (CB1) [134].
Very few studies exist on the potential role for the canna-
binoid system in migraine. CB1 binding was shown to be
increased interictally in female migraine patients [135], while
variations in the CB1 CNR1 gene were suggested to predis-
pose to migraine [136]. Despite the lack of solid evidence for
the potential role of CB1 in migraine pathophysiology, many
individuals are currently using cannabis for the treatment of
migraine with positive results [137]. Currently, there is not
enough evidence from well-designed clinical trials to support
the use of cannabis for headache, but there are sufficient
anecdotal and preliminary results, as well as plausible neuro-
biological mechanisms, to warrant properly designed clinical
trials. Such trials are needed to determine short- and long-
term efficacy for specific headache types, compatibility with
existing treatments, optimal administration practices, as well
as potential risks.
6.5.3. Advanced botulinum toxin molecules
BoNTA is an approved treatment with established efficacy in
migraine prevention [138–140]. Its limitations include its toxi-
city and the unwanted muscle paralysis that limit a potentially
higher dose-effect. Finding a potentially better injections-
paradigm has been suggested as a new way forward in advan-
cing its clinical outcomes and currently a clinical trial is under-
way to investigate the effect of 90U of BoNTA injected along
the skull sutures (NCT03543254), where trigeminal fibers may
be exiting the skull [141].
However, the field of BoNT engineering has progressed
significantly in recent years. A number of approaches have
been used in the engineering of novel BoNT molecules. Such
approaches include among others, recombining of the BoNTA
protein domains, creating of BoNTA/E chimeras, chimera pro-
teins that incorporate the endopeptidase and translocation
domains of BoNTA combined with targeting binding ligand
[142,143].
Senrebotase (AGN-214868) was a retargeted endopepti-
dase with a synthetic nociceptin receptor-binding BoNT mole-
cule which was used in clinical trials for painful overactive
bladder and post-herpetic neuropathy. The trials ended earlier
due to the lack of statistically significant differences in the
long-term observations. Although no attempts have been
made in studying advanced BoNT molecules in clinical trials
of migraine, an increasing number of data now suggests an
emerging role for such molecules in migraine treatment.
BiTox is the first synthetic recombinant BoNTA chimera that
appears to lack paralytic effects, while it suppresses trigeminal
activation in animal models of migraine [144,145]. BiTox has
been also shown to attenuate inflammatory mediators in ani-
mal models of inflammatory pain [146]. In the pain field other
advanced BoNT molecules have been tested with significant
outputs. Using the BoNTA binding domain as a delivery vehi-
cle to selected cell populations has very recently shown to be
an exciting new avenue in the field of pain. A dermorphin-
botulinum and a SP-botulinum constructs have been shown to
target pain-processing neurons in the dorsal horn upon
intrathecal application and to suppress chronic pain in animal
models [147]. Dolly et all, produced a recombinant BoNTA/E
chimera by attaching the BoNTE protease moiety to an enzy-
matically inactive mutant of BoNTA. The resultant molecule is
a long-acting superior inhibitor of motor neuron and C-fibre-
mediated transmission. In vivo, local injection of this recombi-
nant BoNTA/E molecule resulted in extended amelioration of
inflammatory pain [142].
7. Conclusion
There is a vast unmet need in the current migraine treat-
ment options that can be summarised into efficacy, toler-
ability issues and lack of migraine-specific treatments
besides the triptans. This review summarises the current
understanding of the pathophysiological mechanisms
known to be relevant targets for the development of
novel migraine treatments. A multitude of abortive and
preventive migraine-specific treatments are currently in
advanced stages of their development. The positive phase
III trials results for CGRP receptor antagonist Ubrogepant
and 5-HT1F receptor agonist lasmiditan, suggest that these
treatments may be available in the near future in triptans
nonresponders or in those category of patients in whom
triptans are contraindicated. Some of the anti-CGRP mono-
clonal antibodies have already been approved by the FDA
and the EMA and currently used in some Countries as
migraine preventive treatments (Tables 3 and 4). These
treatments could dramatically improve the way migraine
has been managed so far, besides promoting new research
in the development of further antibodies against other
relevant targets such as PACAP.
 EXPERT OPINION ON EMERGING DRUGS 13

Table 3. Competitive environment: abortive migraine treatments.

Compound Company Structure Indication Stage of development Mechanism of action
Olcegepant Boehringer Ingelheim Abortive migraine Phase II (discontinued) CGRP receptor
Pharmaceuticals treatment antagonist

Telcagepant Merck & Co. Abortive migraine Phase II (discontinued) CGRP receptor
treatment antagonist

MK-3207 Merck & Co. Abortive migraine Phase II (discontinued) CGRP receptor
treatment antagonist

BI 44370 TA Boehringer Ingelheim Abortive migraine Phase II (discontinued) CGRP receptor

Pharmaceuticals treatment antagonist

Ubrogepant Allergan Abortive migraine Phase III CGRP receptor

treatment antagonist

Rimegepant Biohaven Pharma Abortive migraine Phase III CGRP receptor

treatment antagonist

Lasmitidan Eli Lilly Abortive migraine Phase III 5-HT1F receptor agonist
treatment

8. Expert opinion vascular comorbidities are necessary to determine the benefit

The migraine field has recently been experiencing an explo-
sion of novel, specifically-designed acute and preventive treat-
ments, reflecting advances in the understanding of this
disorder and better acknowledgement of its global detrimen-
tal impact on sufferers’ quality of lives.
The chemically modified CGRP receptor antagonist
Ubrogepant seems to overcome the disappointing safety issues
that stopped this class of medication from further develop-
ment. Along with selective 5-HT1F agonist Lasmitidan, both
these novel compound could play a role in the future of acute
migraine treatments as an alternative to triptans in triptans
non-responders or in those in whom triptans are contraindi-
cated or not tolerated. Future studies in patients with cardio-
of the lack of arterial tone modulation, mechanism, that distin-
guishes these novel medications from the triptans.
The most promising data come from the anti-CGRP monoclonal
antibodies. All phase II and III trials performed have shown con-
sistent superiority to placebo. Beside remarkable efficacy out-
comes, this class of medication seems to offer a fast onset of
migraine frequency reduction, along with potentially cumulative
benefit overtime, at least according to some initial evidence.
Further meaningful findings that emerged from published trials
highlight the high adherence to treatment, along with the efficacy
of different injections regimens. No particular issues in terms of
safety and tolerability have emerged as confirmed by the very low
dropout rates shown across the clinical trials. Their excellent
14 G. LAMBRU ET AL.

Table 4. Competitive environment: preventive migraine treatments.

Compound Company Structure Indication Stage of development Mechanism of action
Erenumab Amgen/ Preventive migraine FDA and EMA approved Anti-CGRP receptor antibody
Novartis treatment

Galcanezumab Eli Lilly Not available Preventive migraine Phase III Anti-CGRP receptor antibody
treatment
Fremanezumab TEVA Preventive migraine FDA approved Anti-CGRP receptor antibody
treatment

Eptinezumab Alder Not available Preventive migraine Phase III Anti-CGRP receptor antibody
treatment
Atogepant Allergan Preventive migraine Phase IIB/III Anti-CGRP receptor antibody
treatment

EMA: European Medical Agency; FDA: Food and drug administration

tolerability profiles seem to be one of the major advantages com-
pared to the established oral preventive treatments currently used
in migraine. One of the problems with the use of mAbs may be the
long-term risk effect in women of childbearing age, given their
longer half-life. The use of an oral CGRP receptor antagonist like
atogepant may overcome this issue.
Future studies should concentrate on long-term preventive
efficacy and safety of these treatments. Indeed the risk of long-
term blockade of CGRP signaling is unknown [148]. Furthermore
studies in challenging-to-treat migraine patients are needed to
establish whether the promising results showed in clinical trial
environment, will be replicated in real-life patients.
Although, the anti-CGRP treatments are not the cure for
migraine, they have undoubtedly stimulated further research
into different migraine targets that could be inhibited by specifi-
cally designed antibodies. This will hopefully facilitate the devel-
opment of treatments for those patients who currently do not
respond to treatments targeting the CGRP pathway.
ElectroCore, Springer, Amgen and Daiichi Sankyo. G Lambru has received
research and educational funds, travel grants or fees for advisory board
participation from: Allergan, Novartis and Autonomic Technologies.
A P Andreou has received honoraria from Allergan for consultancies
advisory board participation and delivering education presentations. She
has also received a research grant from eNeuro. 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 apart from those
disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Paolo Martelletti http://orcid.org/0000-0002-6556-4128

Funding References

This paper was not funded.
Declaration of interest
P Martelletti has received research and educational funds, travel grants or
fees for advisory board participation from: Teva, Allergan, Novartis,
Papers of special note have been highlighted as either of interest (•) or of
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