Current Pain and Headache Reports (2023) 27:479–488

https://doi.org/10.1007/s11916-023-01142-1

EPISODIC MIGRAINE (S PARIKH, SECTION EDITOR)

A Brief Review of Gepants

Diana Li1 · Jessica Abreu1 · Stewart J. Tepper1

Accepted: 20 June 2023 / Published online: 2 August 2023

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023

Abstract
Purpose of Review Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their
favorable side effect profile and versatility in treating headaches acutely and preventively, gepants are preferred over triptans. We
will cover the indications for the four FDA-approved gepants in adults: rimegepant, atogepant, ubrogepant, and zavegepant. This
review will illustrate how gepants will continue to revolutionize the acute and preventive treatment of headaches.
Recent Findings Gepants are now available in oral tablet, dissolving tablet, and intra-nasal spray formulations. Recent
studies have shown promising utility in treating the pre-headache or prodromal phase. They have favorable tolerability, no
evidence for association with medication overuse, and remain a safer alternative in those who have cerebrovascular risk
factors. Additional research is needed to explore occurrence of Raynaud’s phenomenon in participants treated with gepants,
as it has been associated with CGRP monoclonal antibodies, but are not extensively studied in gepants.
Summary Gepants are expected to play a significant role in the next generation of migraine treatments.

Keywords Gepant · CGRP · Ubrogepant · Rimegepant · Atogepant · Zavegepant

Introduction medication adverse effects, such as weight gain from amitrip-

Migraine is one of the most prevalent debilitating neurologic
conditions in the world, affecting up to 14% of the global
population according to epidemiological studies published
in 2022 [1]. Annually, about 2.5% of those with episodic
migraine (EM) will progress to chronic migraine (CM) [2].
The landmark American Migraine Prevalence and Preven-
tion Study (AMPP) estimated the 1-year prevalence for
migraine was 11.7% of the US population [3].
EM is defined as having 14 or fewer migraine days per
month, whereas CM is defined as having 15 or more migraine
days per month. High Frequency EM (HFEM) is defined as
having 8–14 migraine days per month and is associated with
a higher risk of developing CM. Progression to CM is influ-
enced by modifiable risk factors, such as obesity, depression,
and medication overuse, as well as non-modifiable factors,
such as age, female gender, and head injuries [4, 5]. Many
of these modifiable risk factors are often associated with
* Diana Li
diana.z.li.md@gmail.com
1
Dartmouth Headache Center, Neurology Department,
Dartmouth-Hitchcock Medical Center, 1 Medical Center
Drive, Lebanon, NH 03756, USA
tyline or triptan-related medication overuse. The development
of gepants and other calcitonin gene-related peptide (CGRP)
targeted therapies revolutionized migraine management by
avoiding these adverse side effects.
Triptans and the Discovery of CGRP
Triptans are serotonin (5-HT) 5-HT1D and 5-HT1B receptor
agonists and are considered first line headache treatments.
Activation of the 5-HT1D receptor pre-synaptically inhibits
CGRP release. Activation of the 5-HT1B receptor post-syn-
aptically on blood vessels causes vasoconstriction.
Sumatriptan was the first triptan and was approved by
the FDA in 1992. Triptan use is contraindicated in vascular
disease due to vasoconstrictive effects. Triptan use is also
limited due to unfavorable side effects in some patients such
as nausea, dizziness, fatigue, or tightness in the jaw, throat or
chest. Triptan treatment in migraine is often complicated by
migraine recurrence after initial relief, generally occurring
around 12 h later. The AMPP study showed that, depending
on the baseline frequency of monthly headache days, triptan
overuse was associated with increased progression from EM
to CM [6, 7].

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CGRP was discovered in the 1980s by two independent
research groups, led by Dr. Susan Brain in the UK and Dr.
Lars Terenius in Sweden. Both investigated the effects of
neuropeptides on the blood vessels when they discovered
that CGRP was released from nerve fibers in response to
electrical stimulants and chemical irritants [8, 9]. The con-
nection between CGRP and migraine was first made by Drs.
Lars Edvinsson and Peter Goadsby and published in 1988.
Their work eventually led to their sharing the Brain Prize
in 2021 [10].
CGRP infusion can induce headaches [11–13]. CGRP
levels rise during migraine attacks and are lower interictally
[14, 15]. CGRP is especially prevalent in in the trigeminal
nerve, where it is found in nearly 50% of the neurons [16,
17]. Release of CGRP causes meningeal vasodilation and
neurogenic inflammation. Peripheral release of CGRP in
the meninges also results in mast cell degranulation, further
contributing to neurogenic inflammation.
Gepants are small molecules that target the canonical
alpha calcitonin gene related peptide (CGRP) receptor.
Gepants generally have a more favorable side effect profile
than triptans. Unlike CGRP monoclonal antibodies, which
have a half-life of 1 month, gepants have a half-life of hours.
The CGRP receptor is composed of 3 subunits: the calci-
tonin receptor-like receptor (CRLR), the receptor activity-
modifying protein 1 (RAMP1), and the intracellular/recep-
tor component protein (RCP) [18]. The RAMPs are single
transmembrane-spanning proteins that help determine ligand
specificity and modify G-protein coupled receptor functions.
The CGRP ligand binds to the CGRP ligand cleft interface
between CRLR and RAMP1. The CGRP pathway is then
coupled to the Gαs signaling pathway leading to increased
intracellular cAMP and activated protein kinase A [19]. This
sequence can also increase phosphorylation of the gluta-
mate N-methyl-D-aspartate (NMDA) subreceptor 1 (NR-1),
resulting in postsynaptic initiation of cortical spreading or
depression (CSD) in aura [20–22].
Early Gepants
Olcegepant
In 2004, BIBN4096BS, or olcegepant, was the first selective
small molecule CGRP antagonist/gepant studied in humans.
A placebo-controlled clinical trial analyzed 126 participants
who were given this drug intravenously [23]. A 2.5 mg dose
resulted in a 2-h pain relief rate of 66% (versus 27% for pla-
cebo, p = 0.001). The active drug also showed superiority
over placebo on the pain-free rate at 2 h (44% versus 2%),
the rate of sustained response over 24 h, headache recur-
rence rate, and on the improvement of most bothersome
symptoms such as nausea, photophobia, phonophobia, and
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Current Pain and Headache Reports (2023) 27:479–488
functional capacity. The overall rate of adverse events (AEs)
was 25% versus 12% for placebo. Paresthesias were the most
commonly reported AE, and no serious AEs (SAEs) were
reported. This molecule was not found to significantly affect
cerebral or baseline hemodynamics [24]. The lack of signifi-
cant cerebrovascular side effects is a significant advantage
over triptans and suggested that gepants might be a promis-
ing alternative to patients with cerebrovascular disease or
risk factors. This drug’s development was discontinued due
to difficulty in coming up with an oral formulation [25].
Telcagepant
Multiple randomized controlled trials for acute treatment of
migraine on an oral gepant MK-0974 (telcagepant) were con-
ducted in the early 2000s and demonstrated a 2-h pain free
response rate of 24.3% for the 400 mg dose and 32.1% for the
600 mg dose (versus 33.4% for rizatriptan 10 mg) [26].
Telcagepant was also studied for preventive migraine
treatment. However, a trial studying 140 mg versus 280 mg
versus placebo twice daily was stopped prematurely due to
hepatotoxicity [27]. In the telcagepant group, 13 participants
had liver enzyme elevation greater than three times the upper
limit of normal ranges. No hepatotoxic effects were observed
when used intermittently as rescue therapy over an 18-month
period. Another study using telcagepant in prevention of
menstrual migraine also indicated a potential liver problem,
and the drug development was stopped [28].
Two other gepants, BI 44370 TA and MK-3207, tested in
phase 2 trials were effective in acute treatment of migraine
but showed liver abnormalities, and development was
stopped [29].
Gepants Approved for Acute Treatment
Ubrogepant for Acute Treatment
Ubrogepant was the first oral gepant approved by the FDA
in December 2019 for use in acute migraine treatment. The
recommended dose is 50 mg or 100 mg taken orally, with a
second dose that can be taken at least 2 h after the first dose
if needed [30]. The maximum daily dose is 200 mg. Patients
with severe renal or hepatic failure can start with initial dose
of 50 mg, followed by second dose of 50 mg if needed. This
medication should not be taken in those with end stage renal
disease. The half-life is 5–7 h.
The FDA approved ubrogepant after the publication of
the phase 3 ACHIEVE-1 and ACHIEVE-2 studies. Both
studies included participants with diagnosis of migraine
with and without aura with history of two to eight mod-
erate-to-severe migraines per month [31, 32]. Addition-
ally, both studies excluded participants with concurrent
Current Pain and Headache Reports (2023) 27:479–488
diagnosis of chronic migraine and history of 15 or more
headache days per month. Individuals with a previous his-
tory of chronic migraine were eligible for inclusion if they
experienced fewer than 15 headache days per month while
undergoing preventive treatment that did not involve a
CGRP monoclonal antibody.
The first trial, ACHIEVE-1, studied 1672 participants
who received 50 mg or 100 mg ubrogepant or placebo [31].
It showed that pain freedom at 2 h was achieved by 19.2%
on 50 mg (p = 0.002) and 21.2% on 100 mg (p < 0.001) com-
pared to placebo at 11.8%. Freedom from most bothersome
symptoms (MBS) at 2 h was achieved by 38.6% in the 50 mg
group (p = 0.002), 37.7% in the 100 mg group (p = 0.002),
compared to 27.8% in the placebo group. The most com-
mon AEs were nausea, somnolence, and dry mouth. These
were more frequent in the 100 mg group. No SAEs occurred
within 48 h of ingestion that were clearly related to ubroge-
pant. One participant with a seizure was in the 100 mg group
and may have had alprazolam withdrawal; his seizure was
considered by the investigator to be related to trial treatment,
but this remains unresolved.
The ACHIEVE-2 trial compared placebo, 25 mg and
50 mg in 1,686 participants [32]. Pain freedom at 2 h was
14.3% in the placebo group, 20.7% in the 25 mg group
(p = 0.03), and 21.8% in the 50 mg group (p = 0.01). The
absence of MBS achieved significance only with the 50 mg
dose. The most common AEs at any dose were nausea (2.0%
at 50 mg, 2.5% at 25 mg, 2.0% at placebo) and dizziness
(1.4%, 2.1%, 1.6%, respectively).
A 52-week open-label extension trial was then conducted
and involved enrolling participants who completed one of
the phase 3 ACHIEVE trials and were re-randomized to
usual care, 50 mg or 100 mg for 1 year [33]. The most com-
mon treatment emergent AEs (TEAEs) in any dose group
were nausea (1.5% and 1.7% for 50 mg and 100 mg, respec-
tively), dizziness (0.5% and 1.5%), and somnolence (1.5%
and 1.2%). Only one SAE, sinus tachycardia, was considered
related to treatment in a participant with history of supraven-
tricular tachycardia with ablation. Despite this AE, the par-
ticipant continued to take ubrogepant without further issues.
Twenty cases of transaminase elevation greater than three
times the upper limit of normal values were reported. Two
of the 20 cases were judged possibly related to ubrogepant
50 mg in settings of increased alcohol and acetaminophen
use. Only one case at 100 mg was judged probably related
to treatment, but confounders included use of prednisone
for psoriasis exacerbation. All cases with greater than three
times the upper limit of normal transaminase levels resolved
in those who continued to take ubrogepant. Due to overall
low TEAEs, SAEs, and discontinuations due to AEs, the
authors concluded long-term intermittent use of ubrogepant
50 mg and 100 mg in one or two doses per headache attack
was safe and well-tolerated.
481
A post hoc analysis of ACHIEVE 1 and 2 showed the
safety and efficacy of ubrogepant 50 mg groups after 48 h
and 30 days in those cardiovascular risk factors [34]. Eleven
percent of the participants were categorized as moderate to
high cardiovascular risk using an algorithm based on the
National Cholesterol Education Program and Framingham
risk factors. This study showed that there was no increased
risk of TEAE (cardiac arrhythmia, central nervous vascular
disorders, embolic and thrombotic events, hypertension, and
ischemic heart disease) between ubrogepant and placebo. No
stroke or myocardial infarction were reported in the ubroge-
pant group.
Rimegepant for Acute Treatment
Rimegepant was another oral gepant approved by the
FDA, this time in February 2020 for the acute treatment of
migraine. It is available as a 75 mg oral-dissolving tablet
dose with maximum dosing once a day.
Two phase 3 trials described the efficacy and safety of
rimegepant 75 mg to treat a single migraine attack [35, 36].
In both studies, participants had at least 1-year history of
migraine with or without aura. The participants experienced
between two to eight migraine attacks of at least moderate
intensity per month and reported having headaches on fewer
than 15 days per month in the past 3 months. Individuals
receiving preventive migraine medications were eligible if
they were receiving a stable dose for at least 3 months. Those
receiving CGRP monoclonal antibodies were excluded from
this study. The primary end points were freedom from pain
and freedom from most bothersome symptom (MBS).
In participants treated with rimegepant, the pain freedom
at 2 h was achieved in 19.6–21.0% (p < 0.001) compared to
12–11% in placebo. The MBS freedom at 2 h was achieved
in 35.0–37.6% (p < 0.001) and 25.2–27.0% in placebo. The
most common AEs were nausea and urinary tract infection.
Mild transaminase increases were reported in both treatment
arms, and there were no SAEs. The prescribing information
states that rimegepant should be avoided in patients with
severe hepatic impairment. Rimegepant has not been studied in
patients with end stage renal disease. These initial pivotal stud-
ies did not investigate the effects of repeated rimegepant use.
A subsequent post hoc analysis of the open-label phase
2/3 safety study of rimegepant was published in 2022
[37]. This analysis specifically examined the utilization of
rimegepant for acute treatment among 1044 participants over
52 weeks. It was found that rimegepant use in those with at
least 6 monthly migraine days was associated with reduction
of at least two monthly migraine days. This reduction was
observed without an increase in monthly tablet utilization
and was accompanied by improvements in health-related
quality of life. Furthermore, there was no evidence that
rimegepant use led to medication over-use headache.
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Ubrogepant for Prodrome or Pre‑headache Treatment
While oral gepants are generally tolerated better, they tend
to have a slower onset of action compared to most triptans.
Oral triptans can take 30–60 min to work, while subcutane-
ous injections and nasal sprays can work even more quickly
at 5–15 min. A phase 3 randomized, double-blind, placebo-
controlled cross-over study, called the PRODROME trial,
examined what would happen if ubrogepant were taken in
the first phase of migraine, which is the prodromal phase and
occurs prior to onset of headache pain [38•]. These results
were presented at the April 2023 American Academy of
Neurology Annual Meeting. The participants included those
with two to eight migraines per month. Eligible participants
were allowed to treat two qualifying prodrome events, either
with placebo or 100 mg ubrogepant in randomized crosso-
ver order. These events were defined as a migraine with
prodromal symptoms in which a headache would follow
in 1–6 h. The primary end point was absence of moderate/
severe intensity headache within 24 h and was achieved in
45.5% of the treatment group versus 28.6% in placebo group.
The absence of moderate/severe headache within 48 h was
40.7% versus 24.6% (p < 0.0001). There were no SAEs when
administered during the prodrome.
In the PRODROME screening period, the most com-
mon prodromal symptom identified was photosensitivity,
followed by fatigue, neck pain, phonophobia, and dizziness
[39]. The drug versus placebo groups reported prodromal
photosensitivity at 60.9% versus 60.8%, fatigue at 50.7%
versus 50.3%, neck pain at 40.2% versus 40.1%, phonopho-
bia at 35.9% versus 36.1%, and dizziness at 29.0% versus
31.0% [40]. The proportion of events with absence of pho-
tophobia after ubrogepant 100 mg intake was significantly
greater than after placebo, beginning 2 h post-dose. Similar
results were observed for other common symptoms. In those
treated with ubrogepant, time to absence of each prodromal
system was shorter. Ubrogepant 100 mg during prodrome
was significantly associated with greater ability to function
normally, reduction in activity limitation, and drug satisfac-
tion [41]. There was evidence for continued benefit from the
ubrogepant for up to 48 h [40].
Zavegepant for Acute Treatment
In March 2023, the FDA approved zavegepant for acute
treatment of migraine, and it became the first approved
intranasal gepant spray for acute migraine therapy. At the
time of this writing, it is anticipated that it will be avail-
able for prescription and use in the USA in July 2023. This
formulation may be favorable for those with severe nausea
or emesis or for those who need faster onset of action.
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In two phase 1 placebo-controlled, randomized, double-blind
sequential studies with healthy volunteers, single and multiple
daily doses of 5 mg to 40 mg for up to 14 days were analyzed,
with ­Tmax of 30 min for most doses and half-life of about 7 h.
Doses of 10 mg or more were more predictive of efficacy [42].
The first phase 2/3, randomized placebo-controlled trial
investigated the safety and efficacy of 5 mg, 10 mg, and
20 mg versus placebo in those with moderate or severe head-
aches [43]. Study participants had at least 1-year history of
migraine with or without aura and had two to eight head-
ache attacks per month and fewer than 15 days of headache
(including migraine and non-migraine). The use of CGRP
biologics must have been discontinued at least 6 months prior
to the screening visit and were prohibited in this study.
The primary end points were pain freedom and free-
dom from MBS at 2 h. A total of 1581 participants were
analyzed for efficacy. Zavegepant 10 mg and 20 mg were
shown to be more effective than placebo on the primary
end points of pain freedom at 2 h (placebo at 15.5%; 10 mg
at 22.5%, p = 0.0113; 20 mg at 23.1%, p = 0.0055), as well
as freedom from MBS at 2 h (placebo at 33.7%; 10 mg
at 41.9%, p = 0.0155; 20 mg at 42.5%, p = 0.0094). No
hepatotoxicity was detected, and no SAE was considered
treatment-related. The most bothersome side effects were
dysgeusia, followed by nausea, and then nasal discomfort.
A phase 3 trial analyzing 1,269 participants (623 zavegepant
10 mg group, 646 placebo) similarly showed that the 10 mg
dose had more pain freedom after 2 h (24% versus 15% pla-
cebo, p < 0.0001) and freedom from MBS (40% versus 31%,
p = 0.0012) than placebo [44••].Participants had two to eight
migraine attacks per month and fewer than 15 headache days
per month (including migraine or non-migraine). Most common
AEs were similar to those from the phase 2/3 study. One partici-
pant in the zavegepant group and two in the placebo group had
transaminase concentrations greater than three times the upper
limit of normal values; none was symptomatic. There were no
SAEs and no AEs led to drug discontinuation. In this study, pain
relief from 10 mg nasal spray started 15 min after initial dose
and lasted for 48 h.
A long-term safety study recently concluded in December
2021. This study involved 974 participants self-administering
zavegepant nasal spray, taken up to 8 times per month for
1 year [45]. SAEs reported were 1.16% in the treatment group,
but the formal analysis has not been published yet.
Gepants Approved for Migraine Prevention
Rimegepant for EM Prevention
When rimegepant was first studied for acute treatment,
it was studied for use in a single headache attack. When
Current Pain and Headache Reports (2023) 27:479–488
repeated rimegepant doses were associated with reduced
mean monthly migraine days (MMDs), it prompted further
study in possible use for preventive treatment.
Rimegepant was eventually approved by the FDA in May
2021 for the prevention of EM. As noted, it had already been
approved in February 2020 for acute treatment of migraine,
and thus, rimegepant is the only medication FDA approved
for both acute and preventive migraine treatment. Rimege-
pant is currently available only as an oral-dissolving tablet,
dosed at 75 mg every other day for prevention of EM. This is
also the dose for acute treatment as needed, maximum once
per day. It has a half-life of about 11 h [46].
The study that led to approval for EM prevention was a
phase 2/3 randomized, double-blind, placebo-controlled
trial in which 695 participants (348 on treatment, 347 on
placebo) were analyzed over 12 weeks [47]. Participants
had at least 1-year history of migraine with or without aura
or chronic migraine. They were required to have a mini-
mum of four and a maximum of 18 migraine attacks, and
they were permitted to use a single preventive medication
if they had been on a stable dosage for at least 3 months.
Individuals were excluded if they took CGRP monoclonal
antibodies or antagonists or had not responded to more
than two drug categories for migraine preventive.
This study demonstrated that rimegepant was supe-
rior to placebo in the primary endpoint, which was the
change in MMDs at weeks 9–12; the change in MMDs
was − 4.3 days with rimegepant and − 3.5 days with
placebo (p = 0.0099). Thirty-six percent of those who
received rimegepant reported an AE; there were no SAEs
in the treatment-related group. Four participants (1%) who
were treated with rimegepant had liver enzymes greater
than three times the upper limits. Seven (2%) participants
discontinued the medication due to an adverse event. The
most common TEAE was nausea (3%, 1% in placebo).
An ongoing study is evaluating the safety and tolerabil-
ity of daily rimegepant in EM prevention.
No studies have evaluated the safety of utilizing rimege-
pant preventively with other gepants for rescue.
Among all the gepants, only rimegepant has been for-
mally studied in relation to lactation. Data related to the
presence of rimegepant in breast milk come from a study
involving 12 lactating participants between 2 weeks and
6 months postpartum [48]. Participants were administered
a single dose of rimegepant 75 mg, and breast milk was
collected at specified intervals for 36 h after the dose. It is
important to note that no infants consumed breast milk in
this study. The authors of the study calculated the relative
infant dose (RID) to be 0.51%. According to established
guidelines, breastfeeding is generally considered accept-
able when the RID is less than 10% [49]. These findings
seem to suggest that this drug could be potentially safe to
take in lactation, but more studies are needed.
483
Atogepant for EM Prevention
Atogepant is an oral gepant that was approved by the FDA
for prevention of EM in September 2021. It is available in
10 mg, 30 mg, or 60 mg doses for EM prevention. Follow-
ing oral administration, time to peak concentration is 2–3 h,
while half-life is around 11 h [50]. No dose adjustments
were needed in patients with mild or moderate liver impair-
ment. Atogepant can be taken at 10 mg for EM in those with
severe renal impairment or end stage renal disease. Patients
with severe renal impairment of potent CYP43A4 inhibitors
should be limited to a maximum of 10 mg daily.
Initial dose-related findings from phase 2/3 trials showed
that atogepant was well tolerated [51]. The most common
treatment related side effects included nausea, constipa-
tion, and fatigue. No liver toxicity was observed in doses
up to 60 mg twice daily. No dose response relationship was
observed leading to discontinuation.
From December 2018 to June 2020, the phase 3
ADVANCE trial evaluated safety and tolerability of partici-
pants randomized to placebo or atogepant at 10 mg, 30 mg,
or 60 mg for EM prevention [52]. Participants had to have
at least 1-year history of migraine with or without aura, with
four to 14 migraine days per month. They were excluded if
they had current diagnosis of chronic migraine, medication
overuse headache, or if they averaged 15 or more headache
days per month. Participants were excluded if they had an
inadequate response to more than four oral preventive medi-
cations with at least two different mechanisms of action.
The primary end point in the phase 3 ADVANCE trial
was the change from baseline in MMDs across the 12-week
treatment period. In the first treatment period, the mean
change from baseline in MMD was − 3.7 for 10 mg, − 3.9 for
30 mg, − 4.2 for 60 mg, and − 2.5 for placebo (p < 0.001 for
all groups). In terms of secondary outcomes, the 50% reduc-
tion in 3-month average of MMDs was 29.0% for placebo,
55.6% for 10 mg, 58.7% for 30 mg, and 60.8% for 60 mg
(p < 0.001 for all groups).
Investigators also found that the benefits of atogepant over
placebo in prevention were evident as early as the first day
after treatment, with 25.2% participants reporting migraine
compared with 10.8–14.1% of participants treated with vari-
ous doses of atogepant (p ≤ 0.0071 for all groups) [53••].
In the atogepant groups, the most commonly reported side
effects were constipation (6.9–7.7%), nausea (4.4–6.1%), and
upper respiratory infection (3.9–5.7%). Two participants in the
10 mg group, two in the 30 mg group, one in the 60 mg group,
and four in the placebo group had elevated liver enzyme levels
that were at least 3 times the upper limit of normal. No serious
cases of liver disease were reported [52].
An unexpected side effect was a dose-dependent decrease in
body weight in post hoc analysis from the phase 3 ADVANCE
studies. These results were presented at the 2022 American
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484
Headache Society conference, with 3.2% of those on placebo
demonstrating at least 7% weight loss compared with 4.1%,
2.7%, and 5.7% for the atogepant 10 mg, 30 mg, and 60 mg
groups, respectively [54]. The mechanism of weight loss is
unclear. The weight loss has not been formally compared to
topiramate, but is generally felt to be mild.
There have been additional safety studies on atogepant.
Post hoc analysis of the ADVANCE study showed that
cardiovascular TEAEs occurred at similar rates in pooled
atogepant (13, 1.9%) and placebo groups (7, 3.2%) [55].
Hypertension was observed in four (0.6%) atogepant treated
participants and zero placebo treated participants. Overall,
the studies showed that atogepant for EM had a relatively
safe cardiovascular profile. Supratherapeutic doses (300 mg)
have been studied to investigate cardiac repolarization in
healthy adults. The trial did not report any impact on car-
diac repolarization [56]. Another study analyzing atogepant
170 mg daily for 28 days showed that the elevated dose did
not produce ALT elevation above 1.5 times the upper limit
of normal values; in fact, the change from baseline ALT was
not significantly different from those receiving placebo [57].
Atogepant for CM Prevention
In April 2023, the FDA approved atogepant 60 mg daily
for chronic migraine prevention following the results of the
PROGRESS study, which was an international randomized
double blind, placebo-controlled phase 3 clinical study in
which participants were randomized to atogepant 30 mg
BID, 60 mg daily, or placebo [58]. The participants had at
least 1-year history of chronic migraine, with at least 15
monthly headache days. This study met its primary end-
point of statistically significant reduction from baseline in
MMDs compared to placebo across the 12-week treatment
period. The results were presented at the 2022 American
Headache Society meeting and the 2023 American Acad-
emy of Neurology annual meeting: the mean change from
baseline across 12 weeks was − 7.5 days for 30 mg BID
(p < 0.0001), − 6.9 for 60 mg daily (p = 0.0009), and − 5.1
for placebo [59]. A key secondary endpoint was the propor-
tion of participants with greater than 50% reduction in the
3-month average of MMDs, which was achieved by 42.7% in
30 mg BID (p < 0.0003), 41.0% in 60 mg daily (p = 0.0009),
and 26.0% in placebo. Compared to the ADVANCE trial
for EM prevention, the percentage of participants meet-
ing 50% reduction in MMDs were slightly lower. Similar
to ADVANCE, the most common TEAEs across all groups
were constipation (10.9% in 30 mg BID, 10.0% in 60 mg,
3.1% in placebo), and nausea (7.8%, 9.6%, and 3.5%, respec-
tively). Serious TEAEs were reported, but none was consid-
ered treatment-related.
In a post hoc analysis of PROGRESS, low rates of cardiovas-
cular TEAEs occurred in the participants with cardiovascular
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Current Pain and Headache Reports (2023) 27:479–488
risk factors [60]. In this study, 78.6% in the atogepant group
had at least one cardiovascular risk factor, with 50.4% having
two or more cardiovascular risk factors, with the most common
being dyslipidemia, BMI ≥ 25, and hypertension. Cardiovas-
cular TEAEs included palpitations and elevated blood pres-
sure, all in the 30 mg twice daily group. Palpitations led to one
discontinuation, but this was not considered treatment-related.
Future Directions
The studies so far suggest that gepants have favorable toler-
ability and a safer cardiovascular profile relative to triptans.
This review suggests a few areas of potential exploration and
research that could further broaden or clarify gepant use.
Combination Treatment Safety
With gepants approved for acute treatment and prevention,
it was inevitable that there would be questions surrounding
the safety of using gepants for both acute and preventive
treatment, or with other CGRP inhibitors. A current study is
evaluating the safety of using ubrogepant for acute treatment
and atogepant for prevention. This combination treatment
will need to be carefully evaluated for efficacy, safety, and
tolerability [61, 62].
Cerebral Hemodynamic Changes
Since gepants have a limited ability to cross the blood brain
barrier, it is postulated that they would be unlikely to cause
significant cerebral hemodynamic changes, but further stud-
ies would be helpful to clarify. It would be helpful to study
these hemodynamic changes in an elderly population, who
are excluded from the clinical trials.
Possible Raynaud’s Phenomenon
Gepants are likely a safer alternative to triptans in patients
with vascular disease, but further studies are needed. There
are reports of at least two cases of new onset Raynaud’s
phenomenon (RP) from gepants. In one participant, this
was induced from ubrogepant and rimegepant separately;
in another participant, RP was developed in response to
daily atogepant [63]. This phenomenon has been reported in
response to CGRP monoclonal antibodies. In a study of 169
participants on CGRP monoclonal antibodies, nine partici-
pants or 5.3% developed microvascular complications, rang-
ing from worsening facial telangiectasis to digital gangrene
and autonecrosis that required digit amputation; five out of
the nine participants had previously diagnosed RP [64]. It
is postulated that CGRP deficiency plays a role in RP with
CGRP deficiency in distal or acral skin [65].
Current Pain and Headache Reports (2023) 27:479–488
Severe RP has been associated with CGRP monoclonal
antibodies, but not well reported in gepants. In a paper ana-
lyzing the World Health Organization (WHO) Safety Data-
base from 1967 until January of 2022, CGRP receptor antag-
onists were found to be significantly more associated with
Raynaud’s syndrome than beta blockers and triptans, based
on a disproportionality analysis [66]. One case was reported
with ubrogepant, and one was reported with rimegepant. The
study authors suggested that the low reporting of gepants
could be related to their recent introduction and their inter-
mittent use as acute migraine treatments at the time. It would
be helpful to further elucidate risk factors for those redis-
posed to RP when taking CGRP antagonists.
Lack of Pediatric Indication
Although gepants are not approved in the pediatric popula-
tion, ongoing safety and tolerability studies for ubrogepant
and rimegepant may pave the way for approval in the future.
Pregnancy and Lactation
It is unclear if gepants would be safe in pregnancy. In animal
studies, CGRP has been shown to help regulate placental
blood flow, increase uterine relaxation, and maintain blood
pressure. For this reason, there is concern that antagonizing
CGRP receptor could potentially increase the risk of gesta-
tional hypertension and preeclampsia [67]. This has been
recognized by the makers of rimegepant, who are enrolling
participants into observational studies to study exposure in
pregnant and infant outcomes with anticipated completion
in 2034.
Beyond Migraine
In the years to come, there will be other studies with results
that could expand use of gepants in other areas that involve
CGRP-related pathophysiology, which could help migraine
patients suffering from other co-morbidities. Some of these
studies are ongoing. For example, rimegepant is currently
explored in the acute treatment of pain related to rhinosinusi-
tis, as well as other indications such as trigeminal neuralgia
and psoriasis. An ongoing phase 1 study is investigating the
effect of oral zavegepant 150 mg BID in asthmatics.
Conclusions
Gepants so far have a more favorable safety profile compared
to triptans. They have been shown to have a clinically sig-
nificant reduction in MMDs and 2-h pain freedom in about
19–20% of participants. Thus far, the FDA approved oral
gepants have not demonstrated significant cerebrovascular
485
or hepatoxic side effects when used in the appropriate con-
text. Rimegepant is the only gepant approved for both the
acute treatment of migraine and the preventive treatment of
episodic migraine. Atogepant is the only gepant approved for
prevention of both episodic and chronic migraine. Zavege-
pant is the only nasal gepant approved for acute treatment
of migraine. Ubrogepant is the only gepant approved for
acute treatment of migraine shown to terminate migraine
in the pre-headache prodrome pre-pain phase of a migraine
episode. None of the gepants appear to be associated with
medication overuse headache [68], and no studies thus far
have shown that gepants are associated with transformation
to daily headache. Raynaud’s remains a concern for gepants,
and constipation occurs in 8–10% of participants on atoge-
pant. Gepants may be a suitable option for patients planning
to conceive given their relatively shorter half-lives. Com-
pared to CGRP monoclonal antibodies, they can be more
rapidly eliminated in the event of pregnancy or other medical
circumstances.
Taken together, gepants change the paradigm of migraine
treatment in multiple ways:
1. They can be used preventively and acutely.
2. They are not associated with transformation to chronic
migraine and medication overuse headache.
3. They can be used pre-emptively in pre-headache.
4. Tolerability allows for earlier use in migraine episodes
generally without concern for either side effects or trans-
formation to higher frequency attacks.
5. They are safer alternative in those who have cerebrovas-
cular risk factors.
6. Gepants may be preferred in patients planning concep-
tion as they can be promptly stopped and rapidly elimi-
nated due to their relatively shorter half-lives.
Author contributions Dr. Tepper received grants for research (no
personal compensation) from Allergan/Abbvie, Amgen, Eli Lilly,
Lundbeck, Neurolief, Novartis, Satsuma, and Zosano. He acted as a
consultant and/or served on advisory boards with honoraria for Aeon,
Abbvie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics,
Becker Pharmaceutical Consulting, BioDelivery Sciences International,
Biohaven, ClearView Healthcare Partners, ClickTherapeutics,
CoolTech, CRG, Decision Resources, Defined Health, DRG, Eli Lilly,
ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health
Advances, Health Science Communications, HMP Communications,
Impel, Initiatior Pharma, InteractiveForums, Keyquest, Ki Health
Partners, Krog and Partners, Lundbeck, M3 Global Research, Magnolia
Innovation, MJH Holdings, Miravo Healthcare, Neurofront Therapeutics,
Neurolief, Novartis, P Value Communications, Pain Insights, Inc., Palion
Medical, Pulmatrix, Putnam Associates, Rehaler, SAI MedPartners,
Satsuma, Slingshot Insights, Spherix Global Insights, Strategy Inc,
Synapse Medical Communication, System Analytic, Taylor and
Francis, Tegus, Teva, Theranica, Tremeau, Trinity Partners, Unity HA,
Vial, XOC, and Zosano. He received salary from Dartmouth-Hitchcock
Medical Center and Thomas Jefferson University. He received CME
13
486
honoraria from American Academy of Neurology, American Headache
Society, Annenberg Center for Health Sciences, Catamount Medical
Education, Diamond Headache Clinic, Forefront Collaborative,
Haymarket Medical Education, HMP Global, Medical Education
Speakers Network, Medical Learning Institute Peerview, Migraine
Association of Ireland, Miller Medical Education, National Association
for Continuing Education, North American Center for CME, The Ohio
State University, Physicians’ Education Resource, PlatformQ Education,
Primed, Vindico Medical Education, and WebMD/Medscape.
Funding No financial assistance was obtained in writing this review.
Compliance with Ethical Standards
Conflict of Interest Drs. Li and Abreu have no conflict of interests.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any
of the authors.
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