Expert Opinion on Investigational Drugs

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Gepants for the treatment of migraine

Andrea Negro & Paolo Martelletti

To cite this article: Andrea Negro & Paolo Martelletti (2019) Gepants for the treatment of migraine,
Expert Opinion on Investigational Drugs, 28:6, 555-567, DOI: 10.1080/13543784.2019.1618830

To link to this article: https://doi.org/10.1080/13543784.2019.1618830

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EXPERT OPINION ON INVESTIGATIONAL DRUGS
2019, VOL. 28, NO. 6, 555–567
https://doi.org/10.1080/13543784.2019.1618830

REVIEW

Gepants for the treatment of migraine

a,b a,b
Andrea Negro and Paolo Martelletti
a
Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy; bRegional Referral Headache Centre, Rome, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Migraine is the most common of all neurological disorders. A breakthrough in migraine Received 28 June 2018
treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called Accepted 10 May 2019
triptans. Triptans are used as the standard of care for acute migraine; however, they have significant KEYWORDS
limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- Atogepant; calcitonin
specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene- gene-related peptide; CGRP;
related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for gepant; migraine; migraine
the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in acute treatment;
development. rimegepant; ubrogepant
Areas covered: This article reviews the available data for first- and second-generation CGRP receptor
antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible
mechanism of action and safety of CGRP-targeted drugs.
Expert opinion: Available data suggest that second generation of gepants has clinical efficacy similar to
triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will
assess their safety, especially in specific populations such as patients with cardiovascular disease and
pregnant women.

1. Introduction both patients and physicians that a significant medical need

for migraine-specific medications with better efficacy and
Migraine is one of the most common neurological disorders and
without cardiovascular contraindications still remains unmet.
is characterized by recurrent moderate to severe headaches
A significant advance in understanding migraine mechanisms
accompanied by a plethora of other symptoms, such as nausea,
occurred almost 30 years ago when calcitonin gene-related pep-
vomiting, photophobia, and phonophobia. An important break-
tide (CGRP) was suggested to play a role in migraine pathophy-
through in the field of the acute treatment of migraine was the
siology [6]. Since then, our knowledge of this potent vasodilator
introduction in the early nineties of the 5-hydroxytryptamine1B/
peptide has increased substantially and, at present, CGRP is the
1D (5-HT1B/D) receptor agonists called triptans. They repre-
most evaluated and the best validated target for currently in-
sented the only class of migraine-specific medications that
development migraine treatments.
have been developed and approved for the acute treatment of
migraine over the past two decades and, currently, represent the
standard of care for treating acute migraine. However, triptans 2. The role of CGRP in migraine pathophysiology
have some shortcomings responsible for important clinical lim-
Migraine pathophysiology is complex, multifactorial and not
itations: 1) only about one-third of patients are pain free at 2
yet completely understood. The vascular theory of migraine
h after taking triptans [1]; 2) headache recurrence occurs in the
that has been supported for decades is now replaced by the
30–40% of treated patients [2]; 3) and the frequent use of triptans
trigeminovascular theory, that considers the dysfunction of
(10 days a month or more), even when effective, can lead to
the central nervous system (CNS) as the primum movens
worsening of migraine, progressive increase of headaches fre-
behind this condition, which is extensively reviewed elsewhere
quency and evolution into chronic migraine, often accompanied
[7,8]. In brief, the migraine attack would initiate in the CNS, in
by medication overuse headache [3].
regions of the dorsal pons, hypothalamus and thalamus [9].
Triptans are considered a safe treatment when used appro-
The activation of the trigeminal ganglion would trigger the
priately. However, they are generally associated with an
stimulation of trigeminal afferents that arise in the trigeminal
increase in odds of chest discomfort (odds ratio ranges
ganglion, project the signal to the spinal cord and convey the
between 0.63 with frovatriptan and 4.67 with eletriptan, com-
pain sensation to the CNS. These afferents synapse peripher-
pared to placebo) [4]. In addition, because of their vasocon-
ally on pain sensing intra- and extracranial structures including
strictive 5-HT1B-mediated effects, triptans are contraindicated
the dura mater and terminate behind the blood–brain barrier
in patients with established cerebrovascular or cardiovascular
(BBB) in the trigeminal nucleus caudalis and the dorsal horn of
disease and they should be used cautiously in patients with
C1 and C2 spinal levels [8]. Second-order ascending neurons
significant cardiovascular risk factors [5]. Thus, it is evident to

CONTACT Paolo Martelletti paolo.martelletti@uniroma1.it Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
© 2019 Informa UK Limited, trading as Taylor & Francis Group
556 A. NEGRO AND P. MARTELLETTI
Article Highlights
● Calcitonin gene-related peptide (CGRP) is released in parallel with
pain; successful treatment of migraine attacks aborts both the asso-
ciated pain and the CGRP release.
● Triptans are the gold standard of acute migraine treatment but have
class contraindications that limit their use in patients with cardiovas-
cular diseases.
● CGRP antagonism does not cause vasoconstriction, making it safe for
patients with migraine who cannot use triptans.
● CGRP receptor antagonists (gepants) do not have vasoconstrictive
properties; in phase 2 and phase 3 trials they have demonstrated
similar efficacy to- and fewer side effects than triptans.
● The development of the first gepants (olcegepant, telcagepant, MK-
3207 and BI 44,370 TA) was discontinued because of difficulties in
developing an oral formulation or liver toxicity concerns.
● Three new gepants (rimegepant, ubrogepant and atogepant) are still
in the development pipeline; results from phase 2 and phase 3 RCTs
show they are effective, well tolerated and safe in terms of liver
toxicity. Currently ongoing RCTs, which are expected to be completed
in 2019, will provide definite conclusions on the efficacy and safety of
these promising molecules.
This box summarizes key points contained in the article.
then transmit the pain signal to several medullary, brainstem
[10], hypothalamic [11,12], and thalamic nuclei [10,13]. The
thalamocortical projections then distribute the craniovascular
nociceptive signals to several cortical regions (e.g. the soma-
tosensory, motor, auditory, and visual cortices) [14]. In this
circuit where the signals can run in both directions, the tri-
geminal ganglion acts as an amplifier of migraine headache
pain through the activation of perivascular fibers and release
of messenger molecules implicated in pain generation and
vascular regulation, such as 5 hydroxytryptamine (5-HT), sub-
stance P, neurokinin A, pituitary adenylate cyclase activating
polypeptide (PACAP), nitric oxide and CGRP [15].
CGRP is a neuropeptide produced from alternative RNA
processing of the calcitonin gene. There are two forms in
humans: 1) α-CGRP, prevalently expressed in primary sensory
neurons of the dorsal root ganglia, throughout the trigeminal
system and in vagal ganglia; and 2) β-CGRP, prevalently found
in intrinsic enteric neurons [16]. The α-isoform is the one
primarily involved in migraine pathogenesis.
The first suggestion that CGRP is important in migraine
pathology dates back to 1985 immediately after its discovery
in the trigeminovascular system [17]. Indeed, CGRP is a potent
vasodilatory peptide and at that time the vascular theory of
migraine postulated that headaches are triggered by dilation
of intracranial blood vessels [18]. However, this theory is now
being disputed after the finding that intracranial and extra-
cranial arteries are not dilated during a migraine attack [19]
and their dilatation do not cause headache [20]. Its role in
migraine is confirmed by a growing body of evidence: 1) CGRP
levels are increased during a migraine attack [21]; 2) chronic
migraine patients show increased levels of CGRP in the per-
ipheral blood also in the pain-free interval when compared
with healthy controls [22], 3) CGPR levels return to normality
after triptans administration and consequent headache resolu-
tion [6,23,24]; 4) intravenous infusion of CGRP can induce
migraine-like attacks in migraine patients [25,26] and 5) dilata-
tion of both the middle meningeal arteries and the middle
cerebral arteries that reverses after sumatriptan administration
[27]; finally, 6) animal data suggests that CGRP is involved in
the generation of light intolerance (photophobia), typical of
a migraine attack [28].
3. The cardiovascular protective role of CGRP
Most of the physiological actions of CGRP are mediated by its
vasodilator effects and a growing body of evidence suggests
that CGRP has an important role in preventing the onset of
hypertension [29], cerebral ischemia [30], myocardial ischemia
and heart failure after cardiac infarction [31,32]. Hypertension
is the main risk factor for heart and brain infarctions. The
vascular smooth muscles are fundamental in maintaining
a normal blood pressure by regulating the vascular tone.
Unlike other vasodilator factors such as nitric oxide, prostacy-
clin and endothelium-derived hyperpolarizing factors [33] that
exert their action mainly at the endothelium, CGRP acts pri-
marily on smooth muscle cells in the vascular wall of the
microvasculature [34], which control the peripheral vascular
resistance [35]. Evidences suggest that CGRP has a protective
role in the generation of hypertension more than being
involved in the physiological regulation of blood pressure.
CGRP-knockout mice show an increase in basal blood pressure
and also a renal damage that is independent from the increase
in blood pressure [36]. In relation to these findings, the vaso-
pressor sympathetic outflow was enhanced in pithed rats after
intravenous injections of the CGRP antagonist olcegepant [37].
Animal models suggest that CGRP may also play a role in
maintaining cerebral blood flow via autoregulation in chronic
hypertension [38].
CGRP has also a neuroprotective effect increasing cerebral
blood flow after occlusion [39], acute severe hypertension, and
seizures [40]. Furthermore, CGRP may prevent delayed vasos-
pasm and subsequent ischemia after subarachnoid hemor-
rhage [41]. In animals studies CGRP levels in the basilar
artery were reduced after subarachnoid hemorrhage [42] and
the cerebrospinal fluid (CSF) administration of slow-release
CGRP tablets prevented vasospasm [43]. Similarly, in patients
with subarachnoid hemorrhage CSF CGRP levels were higher
in those without vasospasm than in those with vasospasm [30]
and intravenous administration of CGRP reduced vasospasm
as measured with transcranial Doppler [44].
Several studies in rodents indicate that CGRP has
a protective role also in the heart where it prevents myocardial
infarction by inducing vasodilatation [32,45]. Human studies
show that CGRP: 1) lowers blood pressure [46]; 2) prevents
heart failure via positive chronotropic and inotropic effects
[47]; 3) has decreased serum levels in coronary artery disease
[48]; 4) improves myocardial contractility when intravenously
infused in congestive heart failure [49]; and 5) is involved in
the response to nitroglycerine in chronic heart failure [50].
4. Potential cardiovascular risks of CGRP blockade
One concern related to the use of a drug-targeting CGRP is
that CGRP acts as a potent vasodilator throughout the vascular
system and has an important role in maintaining cardiovascu-
lar homeostasis under pathophysiological conditions. Potential

risk of a long term CGRP blockade is that a mild ischemic
event, such as cardiac angina or cerebral transient ischemic
attacks, might be transformed into full-blown infarcts [51].
The issue of cardiovascular safety is particularly relevant for
anti-CGRP and anti-CGRP receptor monoclonal antibodies
(mAbs) that have been developed for migraine prevention
and are therefore aimed to induce a long-term blockade of
CGRP signaling. Experiments conducted in normal animals
without pre-existing or induced ischemia showed that CGRP
antibodies had no effects on heart rate and arterial blood
pressure [52].
In patients with migraine, a systematic review and meta-
analysis shows that no cardiovascular AEs were reported in
five, relatively small and short-lasting, phase 2 clinical trials
with four different antibodies directed against CGRP or its
receptor [53]. Similarly, no cardiovascular AEs have been
observed in up to 6 months of phase 3 clinical trials testing
anti-CGRP and anti-CGRP receptor mAbs [54,55]. Three studies
addressed the specific issue of cardiovascular safety. Two small
studies, one in healthy women [56] and one in cynomolgus
monkeys [57], did not report cardiovascular events but had
the limitations of the small sample size and of a population
made up of cardiovascularly not compromised subjects. The
third study showed that erenumab (anti-CGRP receptor anti-
body) had no cardiological effect in a high cardiovascular risk
population of males patients aged ~65 years with stable
angina due to documented coronary artery disease, who
were monitored with electrocardiography while exercising on
a treadmill until they reported chest pain [58].
5. Putative mechanisms of action of migraine acute
treatments
Before any other considerations it is fundamental to clear if the
efficacy of an acute treatment really depends on a central
mechanism of action. If this is the case, only lipophilic drugs
with a molecular weight ≤400 Da that may cross the BBB
would be effective [51]. Triptans were originally thought to
relieve migraine through vasoconstriction and/or regulation of
trigeminal transmitter release, including CGRP [22]. Most early
animal studies apparently supported the lack of penetration of
sumatriptan, which is relatively hydrophilic, across the BBB but
more recent animal studies have shown that sumatriptan did
exert an effect inside the BBB [59]. In contrast, other more
lipophilic triptans caused an inhibition of nociception in the
trigeminal nucleus caudalis in these animal models of migraine
[59]. However, despite the central modulatory effects of lipophi-
lic triptans, the higher lipophilicity and better brain penetration
do not translate into significantly higher clinical efficacy over
sumatriptan [1]. In positron emission tomographic (PET) investi-
gation in six migraine patients, sumatriptan 6 mg normalized the
attack-related increase in brain serotonin synthesis, thus demon-
strating that it can exert an effect on the brain in migraineurs
during an attack [60]. In addition, a meta-analysis of oral triptans
showed that sumatriptan caused more CNS AEs than placebo [1],
indicating a more general effect of sumatriptan on CNS and that
the drug can cross the BBB in man [59]. However, the extent of
brain penetration is a poor indicator of central activity, especially
with potent agonists such as the triptans, since they, in contrast
EXPERT OPINION ON INVESTIGATIONAL DRUGS 557
to other CNS agents that are antagonists, require only low frac-
tional receptor occupancy to exert central effects [61].
A central mechanism of action can be advocated also for
lasmiditan, a 5-HT agonist with high selectivity for 5-HT1F and
low affinity for 5-HT1B and 5-HT1D receptors and thus lacking
vasoconstrictive effects. Lasmiditan has a peculiar and unique
chemical structure that avoids typical triptans-related side
effects (e.g., neck, jaw, and chest symptoms) and, being
a high lipophilic substance, can cross the BBB and act centrally
on trigeminal neurons [62].
On the contrary, because of greater molecular weight, anti-
CGRP antibodies and CGRP antagonists poorly penetrate
(<0.01 and 2%, respectively) the BBB, therefore the main target
must be structures outside the BBB and not only cranial blood
vessels, but also neuronal structures that are not fully pro-
tected by the BBB, such as the trigeminal ganglion and the
paraventricular structures within the brain stem [63].
The trigeminal ganglion contains sizeable population of CGRP
neurons colocalized with neurons that produce other transmit-
ters, such as pituitary adenylate cyclase- activating polypeptide,
glutamate and substance P [7]. The majority of CGRP neurons in
the human trigeminal ganglion also express 5-HT1D, 5-HT1B and
5-HT1F receptors, suggesting that the same cells are also rele-
vant targets for triptans and lasmiditan [7]. These 5-HT agonists
could share the same proposed mechanism of action that is
inhibition of the release of CGRP and other neurotransmitters
including glutamate from primary trigeminal neurons, thus
blocking activation of second order neurons [7].
6. CGRP receptor antagonists
CGRP receptor antagonists, namely ‘gepants’, have been pre-
sented in recent years as a novel and attractive approach to
treat migraine. All gepants demonstrate an extremely high
affinity for CGRP receptors of humans and non-human pri-
mates preventing in this way the interaction between CGRP
and its receptor [64]. While gepants have been developed
primarily for the acute treatment of migraine, monoclonal
antibodies targeting free CGRP (erenumab) and CGRP recep-
tors (fremanezumab and galcanezumab) are approved for the
preventive treatment of episodic and chronic migraine [65].
In four different studies (one in animals, two in isolated
human vessels and one in healthy volunteers), CGRP receptor
antagonists did not cause vasoconstriction, offering advan-
tages over the current mainstay of specific acute migraine
treatment [66–69]. At present, a total of 6 CGRP receptor
antagonists have been developed for acute migraine therapy:
olcegepant (BIBN4096BS) [70], telcagepant (MK-0974) [71–77],
MK-3207 [78], BI 44,370 TA [79], rimegepant (BMS-927,711)
[80–85], and ubrogepant (MK-1602) [86–90] (Table 1).
A seventh CGRP receptor antagonist, atogepant (MK-8031),
has been developed for the prevention of episodic migraine
[91,92].
The encouraging results of a small, double-blind, randomized
study published in 2004 showing that intravenous olcegepant
significantly alleviated symptoms during a migraine attack [70]
prompted the development of the orally active gepants. Results
from phase 2 and phase 3 clinical trials showed that gepants
were effective in both acute and preventive treatment of
558 A. NEGRO AND P. MARTELLETTI
Table 1. CGRP receptor antagonists: completed and ongoing trials.
CGRP
antagonist Alternative name Indication
Olcegepant BIBN4096BS Acute migraine treatment
Telcagepant MK-0974 Acute migraine treatment
Episodic migraine
prophylaxis
MK-3207 Acute migraine treatment
BI 44,370 TA Acute migraine treatment
Rimegepant BMS-927,711 Acute migraine treatment
BHV3000
Ubrogepant MK-1602 Acute migraine treatment
Atogepant Episodic migraine
prophylaxis
migraine [93]. Considerably, their efficacy was comparable to
that of triptans and they did not cause cardiovascular and hemo-
dynamic symptoms, which are typical triptans symptoms [93].
However, clinical development of several gepants was ter-
minated. Among them, olcegepant was discontinued because
of difficulties in developing an oral formulation; telcagepant
was discontinued because of increase of liver enzymes levels
after frequent use; MK-3207 was also discontinued because of
concerns of liver toxicity; and BI44,370TA was discontinued for
unknown reason even if it had efficacy demonstrated in
a phase 2 clinical trials [79]. Despite the clear safety concerns,
clinical trials data suggest that gepants intermittent use is
a viable and safe alternative for acute migraine treatment.
Their effectiveness in aborting migraine attacks has led to
renewed interest in developing gepants that do not cause
liver toxicity. It is worth to remember that even if gepants
have a shared mode of action, these molecules are chemically
unrelated to one another.
In the following section, we will review selected preclinical
research and clinical trials conducted so far, as well as clinical
trials currently ongoing, for each of the 3 gepants remaining in
clinical development: rimegepant, ubrogepant and atogepant.
In particular, rimegepant and ubrogepant are under evalua-
tion as acute treatment of migraine attack while atogepant is
under study for migraine prophylaxis.
7. CGRP receptor antagonists in clinical
development
7.1. Rimegepant (BMS-927,711; BHV-3000)
In 2012, the gepants family grew after the addition of a fifth
member called BMS-927,711 and today known as rimegepant
[94] (Table 2). In the same year, a phase 1, open-label, randomized
study (NCT01445067) evaluated the pharmacokinetics of two
doses of rimegepant (300 and 600 mg) in migraine patients during
an acute migraine attack and during the non-migraine period [80].
Later, a large phase 2b, double-blind, randomized, placebo-
controlled, dose-ranging trial (NCT01430442) tested rimege-
pant for the acute treatment of migraine (Table 2) [81]. A total
of 885 patients were randomized to receive placebo or one of
six doses of rimegepant (10, 25, 75, 150, 300 and 600 mg).
Sumatriptan 100 mg was used as an active comparator. The
primary efficacy endpoint was the percentage of patients who
were pain free (PF) at 2 h post-dose. The authors reported that
31.4% were PF after 2 h with 75 mg, 32.9% with 150 mg,
References of completed Development References of ongoing clinical
trials stage trials
[70] Terminated None
[71–77] Terminated None
[78] Terminated None
[79] Terminated None
[80,81] Ongoing [82–85]
[86–89] Ongoing [90]
[91,92] Ongoing None
29.7% with 300 mg dose compared to 15.3% of patients in the
placebo group. No additional benefit was observed with the
higher dose of 600 mg dose (24.4%). Rimegepant 75 mg,
150 mg, and 300 mg were significantly superior to placebo
for the percentage of patients with PF at 2 h, like sumatriptan
100 mg was (PF at 2 h 35%). Furthermore, this study also
investigated several secondary endpoints. The percentage of
subjects who experienced total migraine freedom (defined as
pain freedom, coupled with no symptoms of phonophobia,
photophobia, or nausea) at 2 h post-dose was 27.9% for
75 mg, 25.9% for 150 mg, and 23.4% for 300 mg dose.
Rimegepant 75 mg, 150 mg, and 300 mg, as well as suma-
triptan, were significantly more effective than placebo in
achieving total migraine freedom at 2 h post-dose. The per-
centage of patients with sustained pain freedom (SPF) (no
recurrence of moderate or severe migraine and no use of
rescue medication) from 2 to 24 h and from 2 to 48 h post-
dose was significantly higher for sumatriptan (26%) and for
75 mg, 150 mg, and 300 mg rimegepant doses (27.9, 28.2,
26.1%, respectively) than for placebo (7.4%). The proportion of
subjects free from photophobia or phonophobia at 2 h post-
dose was significantly higher with sumatriptan and rimege-
pant 75, 150, 300, and 600 mg compared to placebo and the
improvement continued through 24 h post-dose. Only rime-
gepant 75 and 300 mg, but not sumatriptan, were superior to
placebo in inducing nausea remission within 2 h post-dose.
However, the improvement in nausea continued up to 24 h
post-dose, with sumatriptan and rimegepant 75 mg and
300 mg showing the highest percentages of patients with
total relief from nausea. Rescue medication was used less in
the 300 mg (24.1%), 150 mg (25.6%), and 75 mg (24.4%)
groups than in the sumatriptan (31.0%) and in the placebo
(50.7%) groups. The incidence of AEs between the active
treatment groups and the placebo group was similar.
Considering the hot topic of gepants liver toxicity, no patients
had an ALT elevation that was three times above the upper
limit of normal (>3 x ULN) but a mild increase in hepatic
enzymes was reported in two patients, one in the placebo
and one in 75 mg group, the last one occurring on day 7 and
resolved after 64 days. Two unexpected findings in this trial
need an interpretation. First, rimegepant higher dose (600 mg)
was not superior to placebo for the primary endpoint. The
authors argued that this could be due to the inherent varia-
bility present in the patients randomized to this dose group
[81]. However, if future RCTs will confirm the lack of effect of
the 600 mg dose, this could be due to a ‘bell-shaped’ dose-
 EXPERT OPINION ON INVESTIGATIONAL DRUGS 559

Table 2. Rimegepant: completed and ongoing clinical trials.

ID number Official title Primary outcomes Secondary outcomes Completion date* Ref.
NCT01445067 Phase I, Open-Label, Cmax September 2012 [80]
Randomized, Single Tmax
Sequence Study With Two AUC(0–24)
Dose Groups to Compare C0.5h
the Pharmacokinetics of C2h
BMS-927,711 in Migraine CLT/F
Subjects During an Acute
Migraine Attack and During
Non-Migraine Period
NCT01430442 Phase IIb: Double-Blind, 2h PF Total migraine freedom at 2h May 2012 [81]
Randomized, Placebo Frequency and severity of AEs
Controlled, Dose-ranging 2–24h SPF
Trial of BMS-927,711 for the 2–48h SPF
Acute Treatment of
Migraine
NCT03235479 BHV3000-301: Phase 3: 2h PF (rimegepant 75 mg) 2–24h SPF January 2018 [82]
Double-Blind, Randomized, Freedom from MBS at 2h (rimegepant 75 mg) 2–48h SPF
Placebo-Controlled, Safety 2h PR
and Efficacy Trial of BHV- 2–24h SPR
3000 (Rimegepant) for the 2-48h SPF
Acute Treatment of Freedom from photophobia at 2h
Migraine Freedom from phonophobia at 2h
Freedom from nausea at 2h
Rescue medication within 24h
FDS at 2h
Pain relapse within 48 h
NCT03237845 BHV3000-302: Phase 3: 2h PF (rimegepant 75 mg) 2–24h SPF January 2018 [83]
Double-Blind, Randomized, Freedom from MBS at 2h (rimegepant 75 mg) 2-48h SPF
Placebo-Controlled, Safety 2h PR
and Efficacy Trial of BHV- 2–24h SPR
3000 (Rimegepant) for the 2-48h SPF
Acute Treatment of Freedom from photophobia at 2h
Migraine Freedom from phonophobia at 2h
Freedom from nausea at 2h
Rescue medication within 24h
FDS at 2h
Pain relapse within 48h
NCT03461757 BHV3000-303: Phase 3, 2h PF 2–24h SPF October 2018 [84]
Double-Blind, Randomized, Freedom from MBS at 2h 2-48h SPF
Placebo Controlled, Safety 2h PR
and Efficacy Trial of BHV- 2-24h SPR
3000 (Rimegepant) Orally 2-48h SPF
Disintegrating Tablet (ODT) Freedom from photophobia at 2h
for the Acute Treatment of Freedom from phonophobia at 2h
Migraine Freedom from nausea at 2h
Rescue medication within 24h
NCT03266588 A Multicenter, Open Label Safety and tolerability Elevated liver function tests July 2019 [85]
Long-Term Safety Study of (over 52 weeks) Hepatic related AEs
BHV3000 in the Acute
Treatment of Migraine
* The date on which the last participant in a clinical study was examined or received an intervention/treatment; Cmax: maximum observed plasma concentration;
Tmax: time of maximum observed plasma concentration; AUC(0–24): area under the plasma concentration-time curve from time zero to 24h; C0.5h: observed
plasma concentration at 0.5h; C2h: observed plasma concentration at 2h; CLT/F: apparent total body clearance; PF, pain freedom: total migraine freedom: pain
freedom, coupled with no symptoms of phonophobia, photophobia, or nausea); AEs: adverse events; SPF: sustained pain freedom; MBS: nausea, phonophobia or
photophobia; PR: pain relief; SPR: sustained pain relief; FDS: Functional Disability Score.

response curve for rimegepant. Second finding that needs an
interpretation, the 150 mg dose was not superior to placebo
for the secondary endpoint pain relief at 2 h. Explanations for
this discrepancy could be two; on the one hand, the study was
not specifically powered to detect differences in secondary
outcomes; on the other hand, adaptive design of this trial
that used Bayesian models may have smoothed the dose-
response curve, resulting in fewer patients being allocated to
the groups with better efficacy performance (75 and 150 mg).
Because of the promising results of the phase 2b trials,
three phase 3, double-blind, randomized, placebo controlled
studies (NCT03235479, NCT03237845, NCT03461757) were
started in 2017, one of them was completed in October 2018
but results are not available and the other two were
completed in January 2018 and on 9 January 2019 the study
sponsor submitted an extension request to delay submission
of results. (Table 2) [82–84]. A further open label long-term
(52 weeks) safety study (NCT03266588) is currently recruiting
and the completion is expected in July 2019 (Table 2) [85].
7.2. Ubrogepant (MK-1602)
Ubrogepant (MK-1602) is another orally available small mole-
cule antagonist of the CGRP receptor, chemically distinct from
telcagepant and MK-3207, which was developed for the acute
treatment of migraine (Table 3).Ubrogepant was initially inves-
tigated by the study MK-1602–005 (PN005) that was a phase 1
clinical trial in healthy postmenopausal or oophorectomized
560 A. NEGRO AND P. MARTELLETTI

Table 3. Ubrogepant: completed and ongoing clinical trials.

ID number Official title Primary outcomes Secondary outcomes Completion date* Ref.
NCT01657370 A Phase IIb, DBS concentration at 2h Freedom from photophobia at 2h December 2012 [86]
Multicenter, 2h PF Freedom from phonophobia at 2h (results first posted on clinicaltrial.gov on
Randomized, 2h PR Freedom from nausea at 2h December 2016)
Double-Blind, 2-24h SPF
Placebo-Controlled, 2-24h SPR
Pharmacokinetic Total migraine freedom at 2h
Study of MK-1602 in Total migraine freedom at 2-24h
the Treatment of
Acute Migraine
NCT01613248 A Phase IIb, 2h PF Freedom from photophobia at 2h December 2012 [87]
Multicenter, AEs within 48h Freedom from phonophobia at 2h (results first posted on clinicaltrial.gov on
Randomized, AEs within 14 days Freedom from nausea at 2h September 2016)
Double-Blind, Discontinued from study due 2-24h SPR
Placebo-Controlled, to AEs 2-48h SPR
Dose-Finding Study 2-48h SPF
of MK-1602 in the Total migraine freedom at 2h
Treatment of Acute Total migraine freedom at 2-24h
Migraine Total migraine freedom at 2-48h
NCT02867709 A Phase 3, Multicenter, 2h PF Freedom from photophobia at 2h February 2018 [88]
Randomized, Freedom from MBS at 2h Freedom from phonophobia at 2h
Double-Blind, Freedom from nausea at 2h
Placebo Controlled 2h PR
Single Attack Study 2-24h SPR
to Evaluate the 2-24h SPF
Efficacy, Safety, and
Tolerability of Oral
Ubrogepant in the
Acute Treatment of
Migraine
NCT02828020 A Phase 3, Multicenter, 2h PF Freedom from photophobia at 2h December 2017 [89]
Randomized, Freedom from MBS at 2h Freedom from phonophobia at 2h
Double-Blind, Freedom from nausea at 2h
Placebo-Controlled 2h PR
Single Attack Study 2-24h SPR
to Evaluate the 2-24h SPF
Efficacy, Safety, and
Tolerability of Oral
Ubrogepant in the
Acute Treatment of
Migraine
NCT02873221 A Multicenter, Safety and tolerability Clinically significant laboratory August 2018 [90]
Randomized, Open- (over 56 weeks) values
Label Extension Clinically significant ECGs findings
Study to Evaluate Clinically significant vital sign
the Long-Term measurements
Safety and C-SSRS
Tolerability of Oral
Ubrogepant in the
Acute Treatment of
Migraine With or
Without Aura
* The date on which the last participant in a clinical study was examined or received an intervention/treatment; DBS: dry blood spot; PF, pain freedom; PR: pain
relief; Total migraine freedom: pain freedom, coupled with no symptoms of phonophobia, photophobia, or nausea); AEs: adverse events; SPR: sustained pain relief;
SPF: sustained pain freedom; MBS: nausea, phonophobia or photophobia; ECGs: electrocardiograms; C-SSRS: Columbia-Suicide Severity Rating Scale

female subjects evaluating the effect of multiple doses of
ubrogepant 50 mg on the pharmacokinetic of an oral
contraceptive.
The characterization of the population pharmacokinetic of
ubrogepant in the treatment of acute migraine in individuals
with migraine was later investigated in the study MK-1602–007
(PN007; NCT01657370), which was a phase 2b, multicenter ran-
domized, double-blind, placebo-controlled, parallel-group trial
(Table 3) [86]. The trial also investigated the influence of demo-
graphic and other variables on ubrogepant pharmacokinetics, as
well as the relationship between ubrogepant concentrations and
efficacy of the drug. Patients were randomized to receive three
administrations of placebo or three administration of a specific
dose of ubrogepant (1, 10, 25, 50, and 100 mg): dose 1 at the
onset of a moderate or severe migraine (day 1), dose 2 in the
evening of day 3 and dose 3 on day 4.
This trial was designed as a companion to the study MK-
1602–006 (PN006; NCT01613248), which was a larger phase
2b, double-blind, randomized, placebo controlled, dose-
finding study that tested ubrogepant for the acute treatment
of migraine (Table 3) [87]. A total of 640 patients received
placebo or one of 5 doses of ubrogepant (1, 10, 25, 50, and
100 mg) (Table 5). Unlike the phase 2b study on rimegepant,
there was not an active comparator. The primary efficacy end-
points were PF and pain relief (PR) at 2 h post-dose. The trial
demonstrated a positive dose–response trend as measured by

the proportion of subjects who achieved PF at 2 h. Pairwise
comparisons for the highest dose vs placebo demonstrated
ubrogepant 100 mg significant superiority for PF at 2 h pain
(25.5% vs 8.9%) but not for the co-primary endpoint PR at 2 h
(58.8% vs 44.6%). Nominal p values (i.e. unadjusted p values)
demonstrated a nominally significantly higher PF at 2 h for
both ubrogepant 50 mg (21.0%) and 25 mg (21.4%) than for
placebo. None of the ubrogepant doses demonstrated nomin-
ally significant superiority to placebo for the endpoint PR at
2 h. The highest dose further demonstrated nominally signifi-
cant improvements vs placebo for all secondary endpoints,
with no impact on nausea at 2 h. Also ubrogepant 50 mg
showed nominally significant differences from placebo on the
majority of secondary endpoints (absence of photophobia and
absence of phonophobia at 2 h, SPF at 2-24 h, sustained pain
relief (SPR) at 2-24 h and 2-48 h, total migraine freedom at 2 h
and at 2-24 h). Even ubrogepant 25 mg showed efficacy on
some secondary endpoints (SPF at 2-24 h, SPF at 2-48 h, and
total migraine freedom at 2 h). The overall incidences of AEs
were similar for ubrogepant groups and placebo and most
commonly included dry mouth, nausea, fatigue, dizziness, and
somnolence (nausea and dizziness more common across the
ubrogepant groups, whereas somnolence was more frequent
in the placebo group). No AEs showed evident dose depen-
dence. Regarding the concerns about potential liver toxicity,
a post-treatment (5 days post-treatment) elevation >3 x ULN
of the aspartate aminotransferase (AST), but not of the alanine
aminotransferase (ALT),), was reported in the 50 mg group by
a 22-year-old white male following intense exercise. The event
was judged by the investigator to be a consequence of exer-
cise rhabdomyolysis and therefore was considered not related
to study medication. Laboratory tests taken 7 days later
showed a normalization of AST levels without medical inter-
vention. An unexpected finding in this trial needs an interpre-
tation. Ubrogepant, at all doses, failed to show benefit for PR
at 2 h, and that could depend on a somewhat low number of
patients in the 100 mg dose group or even the dose selected,
which may have been too low, considering that this trial was
a dose-ranging study. However, the most probable reason is
the high placebo response rate (44.6%) for PR, similar to the
high placebo rate for the same endpoint that was observed in
the rimegepant trial (51.2%). In both trials, the 5:1 active:
placebo treatment ratio (for rimegepant also a sixth active
arm with sumatriptan) may have created an expectancy in
participants that they would receive active treatment, giving
reason for the high placebo rate that was observed.Two phase
3, double-blind, randomized, placebo-controlled studies
(NCT02867709, NCT02828020) were completed in
December 2017 and February 2018 2018, respectively, and
only preliminary results are available (Table 5) [88,89]. Both
studies evaluated the efficacy, safety, and tolerability of 2
doses of ubrogepant compared to placebo for the acute treat-
ment of a single migraine attack; the ACHIEVE I study
(NCT02828020) investigated 50 and 100 mg doses [89] while
the ACHIEVE II study (NCT02867709) investigated 25 and
50 mg doses [88] (Table 3).
The ACHIEVE I study included 1327 adult patients rando-
mized (1:1:1) to placebo, ubrogepant 50 and 100 mg [89]. Both
doses showed a statistically significant greater percentage of
EXPERT OPINION ON INVESTIGATIONAL DRUGS 561
patients achieving PF at 2 h after the initial dose as compared
to placebo patients (11.8% for placebo; 19.2% for 50 mg;
21.2% for 100 mg) and a statistically significant greater per-
centage of ubrogepant patients achieving absence of the
most bothersome migraine-associated symptom at 2 h after
the initial dose as compared to placebo patients (27.8% for
placebo, 38.6% for 50 mg, and 37.7% for 100 mg). The most
common AEs were nausea, somnolence, and dry mouth, none
of which was reported with a frequency of ≥5%. In terms of
hepatic safety, across all treatment arms including placebo,
there were 6 cases with aminotransferase (ALT or AST) eleva-
tions >3 x ULN; there were alternative explanations in all cases
(concomitant illness or medication) and none was noted by
the liver safety adjudication board to have a probable relation-
ship to ubrogepant.
The ACHIEVE II study included 1,686 adult patients rando-
mized (1:1:1) to placebo, ubrogepant 25 and 50 mg [88]. Both
doses showed a statistically significant higher percentage of
patients achieving PF at 2 h after the initial dose as compared
to placebo patients (14.3% for placebo, 20.7% for 25 mg, and
21.8% for 50 mg) and the 50 mg dose, but not the 25 mg
dose, demonstrated a statistically significant greater percen-
tage of ubrogepant patients achieving absence of the most
bothersome migraine-associated symptom at 2 h after the
initial dose as compared to placebo patients (27.4% for pla-
cebo and 38.9% for 50 mg). The 50 mg dose of ubrogepant
also showed a statistically significant greater percentage of
patients achieving PR at 2 h, SPF from 2-24 h, and SPF from
2 to24 h as compared to placebo. In addition, ubrogepant
50 mg also showed a statistically significant greater percen-
tage of patients achieving absence of photophobia and pho-
nophobia at 2 h as compared to placebo. Ubrogepant 25 mg
compared to placebo failed to demonstrate statistical signifi-
cance in these endpoints. In ACHIEVE II, ubrogepant was well
tolerated and demonstrated a safety profile similar to placebo.
There was no signal of hepatotoxicity and the most common
adverse events were nausea and dizziness, neither of which
was reported with a frequency >2.5%. In terms of hepatic
safety within 30 days of dosing, there were 4 cases (1 in
placebo and 3 in ubrogepant arms) with aminotransferase
(ALT or AST) elevations >3 x ULN, but not higher than 5
times. None of these cases was considered to have
a probable relationship to ubrogepant. Of these cases, one
was noted within 7 days of drug administration and attributed
to exercise-induced rhabdomyolysis, on 50 mg ubrogepant.
An open label extension study (NCT02873221) to evaluate the
long-term safety and tolerability of intermittent treatment with
ubrogepant (50 mg or 100 mg) over 1 year was completed on
August 2018 but the results are not yet available (Table 3) [90].
Only patients who completed one of the two phase 3 studies
(NCT02867709 or NCT02828020) were eligible for the enrollment
in the extension study. Patients were randomized into one of three
study arms: 1) an open-label control arm with usual care as pre-
scribed by the physician as standard of care in clinical practice; 2)
ubrogepant 50 mg tablet orally plus placebo-matching ubroge-
pant tablet for the treatment of a qualifying migraine attack for up
to 8 treatments every 4 weeks; or 3) ubrogepant 100 mg (two
50 mg tablets) orally for the treatment of a qualifying migraine
attack for up to 8 treatments every 4 weeks.
562 A. NEGRO AND P. MARTELLETTI

7.3. Atogepant (MK-8031, AGN-241,689)
Atogepant, like ubrogepant, is a newly developed gepant with
a chemical structure that is different from telcagepant and the
other gepants. This compound is currently undergoing clinical
testing for migraine prophylaxis (Table 4). A phase 2/3, multi-
center, randomized, double-blind, placebo-controlled, parallel-
group study (NCT02848326) evaluated the safety and tolerability
of the following doses of atogepant: 10 mg once daily (QD),
30 mg QD, 30 mg twice daily (BID), 60 mg QD, and 60 mg BID
for the prevention of episodic migraine and will characterize the
dose/response relationship [91,92]. All active treatment groups
demonstrated a statistically significant reduction from baseline
in the primary endpoint monthly migraine/probable migraine
headache days (−2.85 days for placebo; −4.00 for 10 mg QD;
−3.76 for 30 mg QD; −3.55 for 60 mg QD; −4.23 for 30 mg BID;
−4.14 for 60 mg BID). Atogepant was well tolerated and the most
common adverse events were nausea, fatigue, constipation,
nasopharyngitis, and urinary tract infection which were reported
with a frequency >5% in at least 1 atogepant treatment arm and
greater than placebo. There was no signal of hepatotoxicity with
atogepant in this study with daily administration over 12 weeks
and the liver safety profile was similar when compared to
placebo.
8. Conclusion
Gepants have the potential to be an important addition to the
migraine treatment arsenal. RCTs evaluating the first generation
of gepants provided evidence of efficacy and safety but their
development was terminated early because of liver toxicity con-
cerns. Rimegepant, ubrogepant and atogepant represent
a second generation of gepants, chemically different from the
earlier generations; initial data showed that they are effective
and safe. If results from ongoing clinical trials confirm these
earlier findings, the new gepants could soon receive the approval
for the acute therapy of migraine and become an option for

Table 4. Atogepant: completed clinical trials.

Completion
ID number Official title Primary outcomes Secondary outcomes date* Ref.
NCT02848326 A Phase 2/3, Multicenter, Randomized, Double-Blind, Change from Change from baseline in mean monthly April 2018 [91]
Placebo Controlled, Parallel-Group Study To Evaluate baseline in mean headache days (across the 12-week
The Efficacy, Safety, And Tolerability Of Multiple monthly MPM treatment period)
Dosing Regimens Of Oral AGN-241,689 In Episodic headache days Proportion of patients with at least a 50%
Migraine Prevention reduction in mean monthly MPM
headache days (across the 12-week
treatment period)
Change from baseline in mean monthly
acute medication use days (across the 12-
week treatment period)
* The date on which the last participant in a clinical study was examined or received an intervention/treatment; MPM: Migraine/Probable Migraine.

Table 5. CGRP antagonists: primary and secondary endpoints in completed clinical trials.
Gepant Dose Pain freedom at 2 h Pain relief at 2 h 2–24 h sustained pain freedom Ref.
Olcegepant 2.5 mg 44.0 vs 2.0 (42.0)* 66.0 vs 27.0 (39.0)* 47.0 vs 15.0 (32.0)* [70]
Telcagepant 300 mg 45.2 vs 14.3 (30.9)* 68.1 vs 46.3 (21.8)§ 39.6 vs 11.0 (29.6)* [71]
400 mg 24.3 vs 14.3 (10.0) 48.2 vs 46.3 (1.9) 22.0 vs 11.0 (11.0)
600 mg 32.1 vs 14.3 (17.8)§ 67.5 vs 46.3 (21.2)§ 32.0 vs 11.0 (21.0)§
rizatriptan 10 mg 33.4 vs 14.3 (19.1)§ 69.5 vs 46.3 (23.2)§ 18.4 vs 11.0 (7.4)
300mg 26.9 vs 9.6 (17.3)* 55.0 vs 27.7 (27.3)* 20.2 vs 5.0 (15.2)* [72]
zolmitriptan 5 mg 31.3 vs 9.6 (21.7)* 56.4 vs 27.7 (28.7)* 18.2 vs 5.0 (13.2)*
MK-3207 100 mg 23.7 vs 9.8 (13.9)¢ 52.5 vs 36.1 (16.4)¢ 30.4 vs 7.5 (22.9)£ [78]
200 mg 36.2 vs 9.8 (26.4)* 69.0 vs 36.1 (32.9)* 20.3 vs 7.5 (12.8)
BI 44370 TA 400 mg 27.4 vs 8.6 (18.8)§ 56.2 vs 18.6 (37.6)¥ 20.5 vs 7.1 (13.4)€ [79]
Eletriptan 40 mg 34.8 vs 8.6 (26.2)¥ 56.5 vs 8.6 (47.9)¥ 21.7 vs 7.1 (14.6)€
Rimegepant 75 mg 31.4 vs 15.3 (16.1)$ 72.1 vs 51.2 (20.9)* 27.9 vs 7.4 (20.5)* [81]
150 mg 32.9 vs 15.3 (17.6)$ 61.2 vs 51.2 (10.0) 28.2 vs 7.4 (20.8)*
300 mg 29.7 vs 15.3 (14.4)$ 75.5 vs 51.2 (24.3)* 26.1 vs 7.4 (18.7)*
600 mg 24.4 vs15.3 (11.1)$ 78.0 vs 51.2 (26.8)* 20.7 vs 7.4 (13.3)$
sumatriptan 100 mg 35.0 vs 15.3 (19.7)* 72.0 vs 51.2 (20.8)* 26.0 vs 7.4 (18.6)*
Ubrogepant 25 mg 21.4 vs 8.9 (12.5)¢ 53.4 vs 44.6 (8.8) 14.6 vs 6.2 (8.4)¢ [87 89 88]
50 mg 21.0 vs 8.9 (12.1)¢ 57.1 vs 44.6 (12.5) 15.1 vs 6.2 (8.9)¢
100 mg 25.5 vs 8.9 (16.6)£ 58.8 vs 44.6 (14.2) 21.6 vs 6.2 (15.4)£
50 mg 19.2 vs 11.8 (7.4)§ – –
100 mg 21.2 vs 11.8 (9.4)¥ – –
25 mg 20.7 vs 14.3 (6.4)¢ – –
50 mg 21.8 vs 14.3 (7.5)¢ – –
Triptans Sumatriptan 100 mg 28.9 vs 9.4 (19.5) 59.0 vs 29.9 (29.1) 20.0 [1]
Zolmitriptan 5 mg 32.4 vs 7.2 (25.2) 62.8 vs 29.0 (33.8) 21.9
Rizatriptan 10 mg 40.1 vs 9.7 (30.4) 68.6 vs 34.0 (34.6) 25.3
Eletriptan 40 mg 27.2 vs 4.7 (22.5) 60.2 vs 25.0 (35.2) 20.9
Efficacy measures are presented as percentages: active drug vs placebo (therapeutic gain). In Ferrari et al. triptan meta-analysis [2] p values were not reported.
Level of significance (as reported in the original papers): *p ≤ 0.001; § p < 0.005; ¢ p ≤ 0.05; £ p ≤ 0.01; ¥ p < 0.0005; € p < 0.025; $ p < 0.002

triptan non-responders, for those with triptan-induced medica-
tion overuse headache and those with cardiovascular risk factors.
9. Expert opinion
Triptans were a major breakthrough in migraine therapy.
Compared to previous therapies, triptans are a significant
step forward for many migraine sufferers, who have also
learned to deal with their typical side effects, such as chest
tightness and muscle tenderness [4]. However, the most
important fact is that today the standard of care for acute
treatment of migraine is a class of drugs with important
efficacy shortcomings (with PF at two hours in the 30% [1]
and headache recurrence in the 30–40% of patients [2]).
Theoretically, to perform better than a triptan, a new acute
treatment should have a faster onset, a longer duration of action,
improved response and relapse rates, and a lower incidence of
drug-induced side effects. Considering only these features,
gepants do not appear to offer much of an improvement over
triptans (Table 5). However, only the rimegepant dose-finding
study adopted a triptan (sumatriptan) as active comparator but
the efficacy between the sumatriptan arm against the rimege-
pant treatment arms cannot be assessed because the trial was
not designed with the statistical power to allow comparison [81].
Preliminary data from a phase 3 study show that also lasmiditan
has similar efficacy to triptans (PF at 2 h: 21.3% for placebo; 28.6%
for 50 mg; 31.4% for 100 mg; 38.8% for 200 mg) [95]. Further
comparative studies are needed in order to reach a definitive
conclusion on the possible clinical advantage of new gepants (vs.
triptans and lasmiditan).
Considering the available data, what can really differentiate
these three classes of acute migraine treatments is their safety
profile that depends on their different mechanisms of action.
It is worth to remember that, as shown in a recent a meta-
analysis of 16 cohort studies including 1 152 407 subjects,
migraine was associated with a higher risk of stroke (adjusted
HR 1.41, 95% CI 1.25 to 1.61) and myocardial infarction
(adjusted HR 1.23, 95% CI 1.03 to 1.43) [96]. The American
Migraine Prevalence and Prevention (AMPP) Study estimated
that among people with EM in the US population, 900,000
women and men have contraindications to triptans [97]. The
risk of severe cardiovascular adverse events after the use of
a triptan is very low, estimated at 1:100,000 treated attacks in
subjects with low risk [98]. However, cases of myocardial
infarction, coronary vasospasm and cardiac arrhythmias in
young and adult migraine patients have been reported, in
close temporal relationship, after sumatriptan administration
[99]. The HUNT study reported a higher prevalence of unfavor-
able cardiovascular risk factors amongst migraineurs [100] and
large population studies found that patients with cardiovas-
cular risk were less likely to receive a triptan suggesting that
doctors and/or patients had concerns about cardiovascular
safety [101,102]. Therefore, high-risk patients were excluded
from triptans RCTs and, in real-life studies, they tend to use
less triptans, which could depend on an autonomous choice
or on a reduced prescription from the doctor. However, chest
symptoms such as heaviness, tightness or pain are a well-
known class effect of triptans [4] and the triptan patient
information leaflet prohibits the use in patients with history,
EXPERT OPINION ON INVESTIGATIONAL DRUGS 563
symptoms or signs of ischemic vascular disease and recom-
mends a particular attention when cardiovascular risk factors
are present.
Unlike triptans, gepants and lasmiditan do not have vaso-
constrictive properties or vascular side effects and that makes
them suitable for those patients for whom triptans are contra-
indicated. However, lasmiditan showed high incidence of CNS-
related AEs (e.g. dizziness, paresthesia, somnolence, vertigo,
and fatigue), probably because of the high CNS permeability
through the BBB [95]. The most frequent AEs were dizziness
and paresthesia, with variable incidences of 23–37% and
2–20%, respectively, with treatment emergent AEs that
increased with increasing doses of lasmiditan [103].
Unfortunately, clinical development of the first four
gepants was terminated early, two of them because of the
increase of liver enzymes levels. However, available data on
the new CGRP receptor antagonists discussed in this review
reassure on concerns of liver toxicity. The gepants still in the
pipeline showed placebo-like tolerability and a pattern of side
effects could not be identified, and this is different from what
is seen for other classes (e.g., ergot derivatives and triptans).
These data once more reinforce the tolerability of the gepants
class for acute dosing. However, the rimegepant and ubroge-
pant studies had a single-dose design, participants with actual
cardiovascular disease were not included and the use of con-
comitant drugs metabolized by cytochrome CYP3A was not
allowed to prevent changes in the pharmacokinetics of the
tested drug. All those decisions were aimed to not expose
patients to unnecessary risk in this phase of development.
Future studies with repeated use design, which resemble
how patients would use the medication in real-life, and with
less exclusion criteria, will provide definite conclusions on the
safety of these drugs, especially in terms of liver toxicity that
for the older gepants manifested only with frequent intake.
Another important concern is the cardiovascular safety of
blocking the CGRP system. This issue is particularly relevant for
the anti-CGRP and anti-CGRP receptor antibodies that are
thought to be effective for 1.5 months after administration
of the therapeutic dose [51] and require a long-term use for
migraine prevention. Available data from RCTs on anti-CGRP
antibodies do not show cardiovascular AEs but the longest
treatment did not reach the two years, and higher-risk
patients were excluded by those studies [104]. The cardiovas-
cular issue could be less relevant for gepants that are aimed to
treat migraine in acute, unless patients do not limit their use
and avoid overuse. Indeed, drugs overuse and the possible
following medication overuse headache represent a common
issue for all the marketed drugs used for acute migraine
attacks. Only studies with repeated use design and real-life
studies will clarify if this risk exists for gepants too.
Atogepant needs a separate discussion, as it is the only one
among new gepants to be under clinical testing for migraine
prophylaxis. In 2018 the 3 first-in-class mAbs acting on the
CGRP pathway (erenumab, fremanezumab and galcanezumab)
got the approval for the prevention of episodic and chronic
migraine and another (eptinezumab) is expected to enter the
market by mid-2019 [105]. Anti-CGRP(r) mAbs can be adminis-
tered monthly (erenumab, fremanezumab, galcanezumab) by
subcutaneous injection or quarterly by subcutaneous
564 A. NEGRO AND P. MARTELLETTI
(fremanezumab) or intravenous (eptinezumab) infusion. This
therapeutic schedule could be an advantage over the daily
oral intake that atogepant requires. However future compara-
tor studies are needed to evaluate how atogepant performs
compared to anti-CGRP(r) mAbs in terms of efficacy, safety,
compliance and cost-effectiveness ratio.
An issue of paramount importance is the safety of CGRP
targeted therapy during pregnancy given that migraine is
more prevalent among women of child-bearing age.
Systematic CGRP levels fluctuate during pregnancy reaching
a peak during the last trimester and then dropping after
delivery [106]. There are two lines of evidence suggesting
that CGRP contributes to the vascular adaptations during
pregnancy: 1) CGRP expression is increased in omental arteries
of pregnant women [107]; and 2) CGRP levels are lower in
women with pre-eclampsia than in those with a normotensive
pregnancy [106,108]. It is not clear if the reduced CGRP levels
are a consequence or even the cause of pre-eclampsia, but in
either the cases a CGRP blockade may negatively affect both
the mother and the fetus. Given that, for obvious ethical
reasons, pregnancy or breast-feeding were exclusion criteria
in most of the gepants studies conducted so far. Even for the
triptans, there has been the same concern for many years but
today, large pregnancy registries confirm their use is compa-
tible with pregnancy and breastfeeding [109].
With lasmiditan already submitted to FDA for approval and
the gepant that are close to complete all phase 3 trials, the
armamentarium of migraine treatments will be enriched with
valid adjunct therapies. As it happ/ens with triptans, not all
therapies will work in every patient but more options we have
the more likely we are to find the one for that individual
patient. Post-marketing studies will assess the impact these
new treatments will have on reducing the burden of migraine.
Funding
This paper was not funded.
Declaration of interest
A Negro has received speaking honoraria from and has served on the
Advisory Board of Allergan and Novartis. P Martelletti has received speak-
ing honoraria from, and has served on the Advisory Board of Allergan, Eli
Lilly, Novartis 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 dis-
cussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose
ORCID
Andrea Negro http://orcid.org/0000-0003-3590-298X
Paolo Martelletti http://orcid.org/0000-0002-6556-4128
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