Expert Review of Pharmacoeconomics & Outcomes

Research

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierp20

Comparative efficacy and safety of rimegepant,

ubrogepant, and lasmiditan for acute treatment of
migraine: a network meta-analysis

Karissa Johnston, Evan Popoff, Alison Deighton, Parisa Dabirvaziri, Linda

Harris, Alexandra Thiry, Robert Croop, Vladimir Coric, Gilbert L’Italien &
James Moren

To cite this article: Karissa Johnston, Evan Popoff, Alison Deighton, Parisa Dabirvaziri, Linda
Harris, Alexandra Thiry, Robert Croop, Vladimir Coric, Gilbert L’Italien & James Moren (2021):
Comparative efficacy and safety of rimegepant, ubrogepant, and lasmiditan for acute treatment of
migraine: a network meta-analysis, Expert Review of Pharmacoeconomics & Outcomes Research,
DOI: 10.1080/14737167.2021.1945444

To link to this article: https://doi.org/10.1080/14737167.2021.1945444

© 2021 The Author(s). Published by Informa View supplementary material

UK Limited, trading as Taylor & Francis
Group.

Published online: 02 Jul 2021. Submit your article to this journal

Article views: 272 View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierp20
EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
https://doi.org/10.1080/14737167.2021.1945444

META-ANALYSIS

Comparative efficacy and safety of rimegepant, ubrogepant, and lasmiditan for

acute treatment of migraine: a network meta-analysis
Karissa Johnstona, Evan Popoffa, Alison Deightona, Parisa Dabirvaziria, Linda Harrisb, Alexandra Thiryb, Robert Croopb,
Vladimir Coricb, Gilbert L’Italienb and James Morenc
a
Broadstreet Health Economics & Outcomes Research, Vancouver, BC, Canada; bBiohaven Pharmaceuticals, New Haven, CT, USA; cIsland Hospital,
Anacortes, Washington, USA

ABSTRACT ARTICLE HISTORY

Objective: In the absence of head-to-head comparisons, the objective of this study was to conduct Received 13 April 2021
a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of rimegepant, Accepted 16 June 2021
ubrogepant, and lasmiditan for the acute treatment of migraine.
KEYWORDS
Methods: A systematic literature review was conducted to identify randomized controlled trials (RCTs)
Acute migraine; network
of rimegepant, ubrogepant, and lasmiditan in adults with acute migraine. Outcomes included sustained meta-analysis; rimegepant;
pain freedom and -relief 2–48 hours post-dose, and adverse events. No RCTs were identified that lasmiditan; ubrogepant;
directly compared these interventions. Therefore, a fixed-effects Bayesian NMA was conducted by CGRP
identifying a connected (via comparison to placebo) network of RCTs.
Results: Five RCTs were identified as follows: rimegepant study 303 (n = 1,466), ubrogepant ACHIEVE
I and II (n = 1,672 and n = 1,686, respectively), and lasmiditan SAMURAI and SPARTAN (n = 2,231 and
n = 3,005, respectively). Efficacy outcomes (pain freedom and relief at 2, 24, 48 hours) tended to be
highest for lasmiditan 200 mg and rimegepant followed lower doses of lasmiditan and all doses of
ubrogepant. However, lasmiditan 200 mg was also associated with higher rates of adverse events,
particularly somnolence and dizziness.
Conclusions: Lasmiditan, rimegepant, and ubrogepant all performed significantly better than placebo
with respect to pain freedom and pain relief. Efficacy results were similar for rimegepant and lasmiditan
with rimegepant having higher rates of pain freedom and relief than lower doses of lasmiditan, while
somnolence and dizziness outcomes were lower for rimegepant than higher doses of lasmiditan.

1. Introduction challenging to optimize treatment for individuals with

migraine due to variations in the characteristics, frequency,
Migraine is a common, chronic disease with a substantial
and severity of migraines between people, as well as within
functional, social, and financial burden [1–5]. People with
the same person over time [1]. The choice of treatment
migraine utilize more healthcare resources, are less productive
depends on migraine characteristics such as severity, symp­
and more likely to experience work loss, have increased odds
toms, and accompanying disability, as well as patient pre­
of filing disability claims, and have a lower quality of life
ference and characteristics such as pregnancy, response to
during and between migraines (interictal) compared to people
previous treatments, and comorbidities and concomitant
without migraine [6–8]. The likelihood of migraine having
treatments that could result in contraindications [1].
a detrimental effect on family members, relationships, careers,
Although treatment is individualized, first-line treatments
and financial security increase with increased migraine fre­
for mild to moderate migraine include oral non-steroidal
quency [2]. It is therefore important to manage migraine
anti-inflammatory drugs (NSAIDs), acetaminophen, or com­
effectively [9].
bination analgesics containing caffeine [1,12]. Treatments
Management approaches include education to make life­
for moderate to severe migraine, or for people with an
style changes and avoid or manage triggers, cognitive beha­
inadequate response to mild or moderate migraine treat­
vioral therapy, and acute and preventive pharmacological
ments, include migraine-specific treatments such as
treatments that are able to address migraine pain and its
5-hydroxytryptamine (5-HT)1B/1D receptor agonists (trip­
consequences [1,10,11]. The goals of acute treatment for
tans) or dihydroergotamine (DHE) [1,12]. Triptans have
migraine are to rapidly achieve and maintain freedom
a better efficacy and adverse effect profile than DHE, and
from pain and other symptoms, to restore functional ability,
triptans are recommended as a first-line therapy for the
and to minimize the use of rescue medications, repeat
acute treatment of moderate to severe migraine attacks,
doses, adverse effects, and other resources [1]. It is

CONTACT Karissa Johnston kjohnston@broadstreetheor.com Broadstreet Health Economics & Outcomes Research, Vancouver, BC 203-343 Railway St. V6A
1A4
Supplemental data for this article can be accessed here.
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
2 K. JOHNSTON ET AL.

Table 1. PICOS Criteria.

Article Highlights Population Adults (≥18 years old) with acute migraine, and at least
a 1-year history of migraine (with or without aura),
● Systematic literature review and network meta analysis methods were and ineligible for/refractory to triptans and NSAIDS
used to estimate relative efficacy and safety across three novel acute
treatments for migraine. Interventions/ ● rimegepant 75 mg
● The evidence base comprised a connected network based on five Comparators ● ubrogepant 25 mg, 50 mg, 100 mg
placebo-controlled Phase III trials (Study 303 for rimegepant, ACHIEVE ● lasmiditan 50 mg, 100 mg, 200 mg
I and II for ubrogepant, and SAMURAI and SPARTIN for lasmiditan.
● All treatments had superior efficacy to placebo. Outcomes Clinical outcomes
● Rimegepant and lasmiditan were associated with similar outcomes,
although the greatest efficacy for lasmiditan was observed at higher Treatment efficacy:
doses, which were also associated with an increased risk of safety ● Sustained Pain Freedom
endpoints (specifically, somnolence and dizziness). ● Sustained Pain Relief
● Freedom from most bothersome symptoms

Treatment safety:
● Adverse events
whereas DHE is recommended as a second-line therapy Study design Randomized controlled trials
[1,12,13]. NSAIDS: Non-steroidal anti-inflammatory drugs, PICOS: Population, Intervention,
Several novel treatments have been developed and Comparator, Outcomes, Study design
recently approved by the US Food and Drug Administration
(FDA) for the acute treatment of migraine [14–21]. These novel
treatments include the calcitonin gene-related peptide (CGRP)
estimate relative efficacy and safety between treatments that
receptor antagonists rimegepant [16] and ubrogepant [15,18]
have not been compared head to head.
and the selective 5HT1F-receptor agonist lasmiditan [14,17,19].
CGRP receptor antagonists block CGRP receptor and reduces
inflammation, vasodilation, and pain [13]. Due to the more
specific mechanism of action of CGRP receptor antagonists on
2. Methods
the trigeminovascular system, these treatments have fewer 2.1. Data sources, searches, and study selection
adverse effects compared to older treatments [20,22]. Of par­
A systematic literature review (SLR) was conducted accord­
ticular note, first-generation gepants, which were first intro­
ing to Preferred Reporting Items for Systematic Reviews and
duced more than 15 years ago, were not utilized due to liver
Meta-Analyses (PRISMA) guidelines [39] and a prespecified
toxicity, while the second-generation gepants rimegepant and
protocol to identify, among others, relevant RCTs for com­
ubrogepant are not associated with liver safety concerns [23].
paring the efficacy and safety of rimegepant, ubrogepant,
Lasmiditan is a highly selective agonist that binds to the 5-
and lasmiditan. Of note, this search was part of a broader
HT1F receptor with high affinity, and activation of this receptor
search to identify a range of studies related to the burden
blocks trigeminal neuron activation which inhibits ‘the acute
of migraine in addition to RCTs of efficacy and safety, and
migraine pathway;’ [13,14]; lasmiditan has been shown to be
as such a sensitive search strategy was employed, resulting
efficacious in reducing migraine pain relief and pain freedom
in a large number of hits in addition to those relevant to
[24] and reductions in disability following long-term treatment
the NMA described here. Outcome measures were not
[25]. However, because lasmiditan crosses the blood–brain
included as indexing terms in the search strategy but were
barrier, there is the potential for greater adverse effects than
incorporated into the selection criteria which were based on
CGRP receptor antagonists [17,26]. The safety and efficacy of
patient population, interventions/comparators, outcome
these treatments have been demonstrated in randomized,
measures, and study design selection (PICOS). Embase and
double-blind, placebo controlled trials (NCT03461757 [27,28],
Medline were searched from database inception to present
NCT02828020 [29,30] and NCT02867709 [31,32], and
on 22 July 2019 using a combination of free-text words,
NCT02439320 [33,34] and NCT02605174 [35,36]), but they
indexing terms (e.g. MeSH) and their relationship using
have not been compared head-to-head [37]. When direct
Boolean operators (e.g. ‘and,’ ‘or,’ ‘not’). The search was
comparisons are not available, indirect comparisons via
limited to articles in English. Additional sources were iden­
a network meta-analysis (NMA) can assist in generating evi­
tified through hand searches. The focus of the SLR was
dence for decision-making [38]. The objective of this study
broader than the NMA, and tables of the search terms and
was to conduct an NMA study to indirectly compare the
PICOS criteria for the full SLR can be found in the online
relative efficacy and safety of rimegepant, ubrogepant, and
resources/supplementary material. The PICOS criteria that
lasmiditan for the acute treatment of migraine. Novel treat­
were used for the NMA are listed in Table 1. In brief, the
ments may be able to fill an unmet need for patients that are
population of interest was adults 18 years and older with
not well managed with historic treatment options, and
acute migraine who are ineligible for or refractory to first-
a comparison of the efficacy and safety of novel treatments
line treatments such as NSAIDS and triptans; the interven­
can help to guide decision-making for patients and clinicians
tions that were compared were rimegepant orally disinte­
to select the optimal treatment for patients’ needs. Ideally,
grating tablets (ODT), oral ubrogepant, and oral lasmiditan;
head-to-head trial data would be available for all pairwise
outcomes included sustained pain freedom and sustained
comparisons, but in the absence of this, NMA can be used to
pain relief 2–48 hours post-dose, freedom from most
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
bothersome symptoms, and safety outcomes including
adverse events such as somnolence, paresthesia, dizziness,
and nausea; and only RCTs providing direct or indirect
evidence between treatments of interest were considered.
Outcomes were chosen because they are frequently used as
primary endpoints in clinical trials. Pain freedom was
defined as having no pain 2 hours after treatment and
sustained pain freedom meant maintaining being pain free
without relapse or the use of rescue medications for up to
Figure 1. PRISMA Flow Diagram.
Figure 2. Network of Evidence.
3
24- or 48-hours post-dose. Pain relief is defined as improve­
ment from moderate to severe pain before treatment, to
mild or no pain after a specific interval.
2.2. Screening, data extraction, and quality assessment
Two reviewers independently reviewed the titles and abstracts
of the identified studies against the PICOS criteria to deter­
mine relevancy, and after exclusions reviewed the full text of
4 K. JOHNSTON ET AL.
retained articles. A third reviewer resolved any conflicts
between the two reviewers. Study quality assessment was
performed by one reviewer using the Cochrane Risk of Bias
Tool (see supplementary materials) [40]. Articles that passed
the full-text review were used for data extraction, and the total
number of papers that were excluded, as well as the reason for
their exclusion was recorded. Study selection for the NMA is
illustrated in Figure 1 and based on PRISMA [39].
From the SLR, a connected network of trials was identified
to compare the treatments indirectly (Figure 2). All trials were
placebo-controlled, which allowed for all comparators of inter­
est to be connected through placebo.
2.3. Model specifications, fitting, and data analysis
All NMA models were fit using a Bayesian framework. These
methods are in accordance with the guidelines set forth by
the NICE Decision Support Unit (DSU) [41]. All analyses were
conducted using R (V3.6.1) and JAGS (V4.3.0). Binomial like­
lihood models incorporating a logit link were used for all
outcomes. No additional regression adjustments such as base­
line risk or the adjustment for specific baseline characteristics
were made. As the network of evidence was sparse in terms of
the number of included trials, fixed-effect models were
decided upon a priori as there was insufficient evidence to
effectively estimate heterogeneity between studies using
a random-effects model.
2.4. Interpretation of results
Results are expressed in terms of risk differences (95% credible
interval [CrI]) of competing interventions, i.e. the incremental
proportion of respondents achieving the outcome of interest
across treatments. Results are presented using the surface
under the cumulative ranking curve (SUCRA), to provide
clearer interpretation on the presence of multiple
Figure 3. Baseline characteristics of the trials included in the evidence base.
interventions and outcomes [42]. A higher numerical value
(closer to 100) indicates a higher likelihood that the interven­
tion is ranked at the top (best = 1) [42]. For each intervention,
the entire risk-benefit profile must be considered. That is,
some interventions may rank higher with regard to efficacy,
but this must be balanced with possible lower rankings with
regard to safety, and vice versa [42].
3. Results
3.1. Search results
The search strategy yielded 5,769 abstracts for review. After
526 duplicates were removed, 5,243 abstracts were reviewed
for inclusion, of which 743 underwent full-text review. Four
additional duplicates were found and removed during full-text
review and further 737 articles were excluded after applying
the NMA PICOS criteria. Three additional articles were found
via hand searches. These included full-text articles of the
included studies, which were only available in abstract form
(i.e. not yet indexed) at the time of search strategy execution
[28,30,32].
3.2. Study characteristics
In total, five randomized placebo-controlled trials contributed
data to the network and were included in the NMA. These
were Study 303 for rimegepant (n = 1,466) [28], ACHIEVE
I (n = 1,672) [30] and ACHIEVE II (n = 1,686) [32] for ubroge­
pant, and SAMURAI (n = 2,231) [34] and SPARTAN (n = 3,005)
[36] for lasmiditan. All trials were phase III, multicenter trials
from the US, with the exception of SPARTAN which was
a multi-country trial from the US, UK, and Germany. All trials
assessed the acute treatment of a single migraine attack over
a period of 4 to 11 weeks.
Table 2. Raw Efficacy and Safety Data by Study and Outcome used in the Analysis/Model.
Study ACHIEVE I ACHIEVE II RIM 303 SAMURAI SPARTAN
Outcome
n/N(%) PL UBR 50 UBR 100 PL UBR 25 UBR 50 PL RIM 75 PL LAS 100 LAS 200 PL LAS 50 LAS 100 LAS 200
EFFICACY OUTCOMES
Pain free 2 h 54/ 81/ 95/ 65/ 90/ 101/ 74/ 142/ 80/ 142/ 167/ 115/ 159/ 167/ 205/
456 422 448 456 435 464 682 669 524 503 518 540 556 532 528
(11.8%) (19.2%) (21.2%) (14.3% (20.7%) (21.8%) (10.9%) (21.2%) (15.3% (28.2%) (32.2%) (21.3%) (20.7%) (31.4%) (38.8%)
Pain relief 2 h 224/ 256/ 275/ 220/ 263/ 291/ 295/ 397/ 234/ 334/ 330/ 274/ 353/ 370/ 367/
456 422 448 456 435 464 682 669 554 562 555 575 598 571 565
(49.1%) (13.3%) (61.4%) (48.2%) (60.5%) (62.7%) (42.3%) (59.3%) (42.2%) (59.4%) (59.5%) (47.7%) (59.0% (64.8%) (65.0%)
Sustained pain freedom 39/ 53/ 68/ 37/ 55/ 66/ 38/ 105/ 42/ 83/ 103/ 77/ 103/ 102/ 128/
2–24 h 452 418 441 451 432 457 682 669 554 562 555 576 598 571 565
(8.6%) (12.7%) (15.4%) (8.2%) (12.7%) (14.4%) (5.6%) (15.7%) (7.6%) (14.8%) (18.6%) (13.4%) (17.2%) (17.9%) (22.6%)
Sustained pain freedom N/A N/A N/A N/A N/A N/A 37/ 90/ 42/ 84/ 91/ 68/ 89/ 86/ 111/
2–48 h 682 669 554 562 555 576 598 571 565
(5.4%) (13.4%) (7.6%) (14.9%) (16.4%) (1.0%) (14.9%) (15.1%) (19.6%)
Sustained pain relief 2– 93/ 150/ 165/ 93/ 138/ 165/ 189/ 320/ N/A N/A N/A N/A N/A N/A N/A
24 h 447 413 434 443 424 449 682 669
(20.8%) (36.3%) (38.0%) (21.0%) (32.5%) (36.7%) (27.7%) (47.8%)
Freedom from MBS at 2 h 126/ 162/ 169/ 125/ 148/ 180/ 183/ 235/ 144/ 192/ 196/ 172/ 209/ 221/ 235/
454 420 448 456 434 463 682 669 488 469 481 514 512 500 483
(27.7%) (38.6%) (37.7%) (27.4%) (34.1%) (38.9%) (26.8%) (35.1%) (29.5%) (40.9%) (40.7%) (33.5%) (40.7%) (44.2% (48.6%)
Freedom from 143/ 172/ 205/ 162/ 171/ 203/ 221/ 274/ 294/ 388/ 379/ 309/ 368/ 380/ 391/
photophobia at 2 h 456 423 448 456 435 464 682 669 554 562 555 576 598 571 565
(31.4%) (40.7%) (45.8%) (35.5%) (39.3%) (43.8%) (32.4%) (41.0%) (53.1%) (69.0%) (68.3%) (53.6%) (61.5%) (66.5%) (69.2%)
Freedom from 215/ 245/ 244/ 211/ 233/ 251/ 370/ 406/ 374/ 426/ 419/ 368/ 428/ 428/ 431/
phonophobia at 2 h 456 423 448 456 435 464 682 669 554 562 555 576 598 571 565
(47.1%) (57.9%) (54.5%) (46.3%) (53.6%) (54.1%) (54.2%) (60.7%) (67.5%) (75.8%) (75.5%) (63.9%) (71.6%) (75.0%) (76.3%)
Freedom from nausea at 284/ 297/ 310/ 319/ 307/ 331/ 446/ 474/ 427/ 448/ 449/ 465/ 473/ 468/ 460/
2h 456 423 448 456 435 464 682 669 554 562 555 576 598 571 565
(62.3%) (70.2%) (69.2%) (70.0%) (70.6%) (71.3%) (65.4%) (70.8%) (77.1%) (79.7%) (80.9%) (80.7%) (79.1%) (82.0%) (81.4%)
SAFETY OUTCOMES
Somnolence 4/ 3/ 12/ N/A N/A N/A 1/ 693 2/ 14/ 36/ 33/ 13/ 35/ 29/ 42/
485 466 485 (0.1%) 682 617 630 609 645 654 635 649
(0.8%) (0.6%) (2.5%) (0.3%) (2.3%) (5.7%) (5.4%) (2.0%) (5.3%) (4.6%) (6.5%)
Dizziness N/A N/A N/A 8/ 10/ 7/ 7/ 6/ 21/ 79/ 99/ 16/ 56/ 115/ 117/
499 478 488 693 682 617 630 609 645 654 635 649
(1.6%) (2.1%) (1.4%) (1.0%) (0.9%) (3.4%) (12.5%) (16.3%) (2.5%) (8.6%) (18.2%) (18.0%)
Nausea 8/ 8/ 20/ 10/ 12/ 10/ 3/ 11/ 12/ 19/ 32/ 8/ 18/ 21/ 17/
485 466 485 499 478 488 693 682 617 630 609 645 654 635 649
(1.6%) (1.7%) (4.1%) (2.0%) (2.5%) (2.0%) (0.4%) (1.6%) (1.9%) (3.0%) (5.2%) (1.2%) (2.7%) (3.3%) (2.6%)
h = hours; LAS = lasmiditan; MBS = most bothersome symptoms; n = number of events; N = number of people per treatment arm; N/A = not applicable; PL = placebo; RIM = rimegepant; UBR = ubrogepant
EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
5
 6

Table 3. Results of fixed-effect models for pain relief and pain freedom at various intervals.
2 hours – fixed-effects model
PL −11.36 −17.16 −17.28 −11.57 −13.17 −13.07 −16.02
(−16.43, −6.13) (−21.03, −13.16) (−21.13, −13.31) (−17.58, −5.38) (−17.64, −8.63) (−18.95, −6.99) (−21.02, −10.79)
6.59 LAS_50 −5.82 −5.95 −0.26 −1.85 −1.75 −4.67
(2.67, 11.12) (−11.01, −0.65) (−11.09, −0.81) (−8.26, 7.80) (−8.79, 5.02) (−9.67, 6.14) (−11.80, 2.65)
9.89 3.29 LAS_100 −0.13 5.62 3.99 4.09 1.14
(6.30, 13.96) (−0.88, 7.47) (−4.11, 3.86) (−1.60, 12.94) (−2.02, 9.99) (−3.09, 11.24) (−5.25, 7.65)
K. JOHNSTON ET AL.

15.10 8.47 5.18 LAS_200 5.70 4.12 4.20 1.27

(11.08, 19.62) (4.13, 12.86) (1.60, 8.87) (−1.51, 13.11) (−1.90, 10.13) (−2.87, 11.29) (−5.15, 7.76)
6.80 0.21 −3.09 −8.24 UBR_25 −1.62 −1.52 −4.46
(1.80, 12.85) (−6.51, 7.39) (−9.46, 3.87) (−14.96, −1.11) (−7.73, 4.52) (−9.44, 6.47) (−12.34, 3.52)
8.09 1.48 −1.81 −6.98 1.28 UBR_50 0.08 −2.83
(3.98, 12.90) (−4.52, 7.63) (−7.59, 4.13) (−13.09, −0.85) (−4.12, 6.40) (−6.00, 6.17) (−9.61, 4.05)
10.61 4.00 0.70 −4.48 3.75 2.50 UBR_100 −2.92
(4.90, 17.23) (−3.14, 11.68) (−6.23, 8.16) (−11.69, 3.24) (−3.52, 11.23) (−3.13, 8.46) (−10.77, 4.88)
12.91 6.29 3.01 −2.18 6.08 4.80 2.31 RIM_75
(7.33, 19.55) (−0.83, 14.00) (−3.83, 10.51) (−9.31, 5.46) (−2.15, 14.37) (−2.62, 12.55) (−6.37, 11.00)

2–24 hours – fixed-effects model

PL – – – −12.33 16.75 −18.47 −18.97
(−19.14, −6.20) (−22.03, −11.75) (−25.33, −11.92) (−24.64, −13.61)
3.91 LAS_50 – – – – – –
(1.02, 7.59)
4.94 1.03 LAS_100 – – – – –
(2.29, 8.24) (−2.16, 4.13)
8.67 4.75 3.71 LAS_200 – – – –
(5.52, 12.55) (1.45, 8.16) (1.00, 6.65)
3.99 0.10 −0.93 −4.65 UBR_25 −4.40 −6.10 −6.61
(0.18, 9.15) (−5.20, 5.87) (−5.98, 4.71) (−10.12, 1.18) (−10.51, 1.94) (−14.34, 2.29) (−14.86, 1.99)
5.25 1.34 0.28 −3.41 1.24 UBR_50 −1.72 −2.23
(1.99, 9.46) (−3.49, 6.44) (−4.29, 5.23) (−8.42, 1.77) (−3.15, 5.32) (−8.10, 4.58) (−9.63, 5.35)
7.58 3.67 2.63 −1.09 3.56 2.32 UBR_100 −0.51
(3.04, 13.63) (−2.11, 10.34) (−2.95, 9.16) (−6.99, 5.60) (−2.42, 9.81) (−2.24, 7.43) (−9.08, 8.12)
14.34 10.41 9.39 5.72 10.28 9.06 6.74 RIM_75
(8.25, 22.31) (3.40, 18.76) (2.58, 17.56) (−1.37, 13.96) (2.43, 19.07) (1.79, 17.56) (−1.79, 15.82)

2–48 hours – fixed-effects model

PL
3.34 LAS_50
(0.54, 7.04)
4.52 1.17 LAS_100
(1.94, 7.81) (−2.01, 4.20)
7.18 3.81 2.65 LAS_200
(4.18, 10.93) (0.56, 7.14) (−0.01, 5.47)
– – – – UBR_25
– – – – – UBR_50
– – – – – – UBR_100
11.21 7.84 6.65 4.01 – – – RIM_75
(5.73, 18.63) (1.41, 15.62) (0.43, 14.31) (−2.42, 11.82)
Note: Pain-freedom is represented on the lower diagonal (white), while pain-relief is represented on the upper diagonal (gray).
Each cell represents the risk difference and 95% credible interval of the row treatment versus the column treatment.
Bolded values are statistically significant at a 5% level of significance
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 7

Figure 4. Network meta-analysis results for efficacy (treatment vs. placebo).

Trial baseline characteristics are compared in Figure 3. The 3.3. Efficacy outcomes
trials were generally well balanced in terms of the baseline
Pain relief at 24 hours was not reported in lasmiditan stu­
characteristics for sex (82% to 88.2% female), and age (mean
dies, pain freedom at 48 hours was not reported in ubro­
age ranging from 40.2 to 42.7 years), and most bothersome
gepant studies, and pain relief data were not available for
symptom (photophobia), but the SAMURAI and rimegepant
any comparison at 48 hours. Data were available for each
303 studies had fewer white participants compared with the
treatment for each other outcome. All active comparators
other trials. More participants reported a history of migraine
demonstrated a significant increase in pain relief and pain
with an aura in the lasmiditan trials (32% to 36%) compared to
freedom compared to placebo at 2 hours and 2–24 hours
the rimegepant 303 (30%) and ACHIEVE II trails (24%). These
where data were available (Table 3 and Figure 4). Rate of
data were not reported for ACHIEVE I. Participants in the
pain freedom at 2 hours were highest for lasmiditan 200 mg
lasmiditan trials, for which an inclusion criterion was
(risk difference vs. placebo 15.1% [95% CrI: 11.1, 19.6%]),
a Migraine Disability Assessment (MIDAS) score ≥ 11, experi­
followed by rimegepant. For sustained pain freedom at 2–
enced more migraine attacks per month (mean >5) at baseline
24 hours, risk difference vs. placebo was highest for rime­
compared to ACHIEVE II and Rimegepant 303 (mean<5), while
gepant (14.3% [8.2–22.3%]), followed by lasmiditan 200 mg
ACHIEVE I did not report on attack severity.
(8.7% [5.5–12.5%]) and ubrogepant 100 mg (7.6% [3.0%-
The raw efficacy and safety data that were used in the
13.6%]). Regarding 2–24 hour pain freedom, lasmiditan
model and analysis are presented study and outcome in
200 mg was favored compared to the two lower doses of
Table 2.
8 K. JOHNSTON ET AL.
Figure 5. Network meta-analysis results for freedom from outcomes: fixed-effects models.
lasmiditan; in addition, rimegepant was superior to lasmidi­
tan 50 mg (10.4% [CrI 3.4–18.8%]) and 100 mg (9.4% [2.6–
17.6%]), as well as ubrogepant 25 mg and 50 mg (Table 3).
Rimegepant was favored with regard to pain freedom vs.
placebo and the two lower doses of lasmiditan at 2–
48 hours post-dose (ubrogepant data not available for this
outcome).
In terms of the ‘freedom from’ outcomes (Figure 5), all
active comparators were favored over placebo for all out­
comes (although not all estimates were statistically signifi­
cant), except for lasmiditan 50 mg which had a worse
outcome for freedom from nausea 2 hours post-dose com­
pared to placebo. The lowest doses of ubrogepant (25 mg)
and lasmiditan (50 mg) performed worse than the higher
doses of those treatments with regard to freedom from MBS
at 2 hours, while the highest doses of ubrogepant (100 mg)
and lasmiditan (100 mg and 200 mg) performed the best
degree of freedom with regard to photophobia at 2 hours.
Rimegepant was comparable to all other treatments for all
other outcomes except for the high doses of lasmiditan for
freedom from photophobia, where it was shown to be
inferior.
3.4. Safety outcomes
Data were available for all treatments for each specific adverse
event outcome examined. Ubrogepant 25 mg and 50 mg had
comparable results regarding somnolence and dizziness com­
pared to placebo for all adverse event outcomes. Rimegepant
was comparable to placebo regarding dizziness and somno­
lence. Placebo was superior to all other active comparators for
all other adverse event outcomes (Figure 6). The higher doses
of lasmiditan had the worst dizziness outcomes, ubrogepant
100 mg fared the worst on somnolence, and rimegepant had
the worst nausea outcome.
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH 9

Figure 6. Network meta-analysis results for safety.

When estimates are very uncertain, raw rankings can be
biased. To get around this limitation, the SUCRA captures this
uncertainty by taking into account the full area under the
ranking curves [42]. The rankings and SUCRA percentages of
the interventions by study and outcomes are presented in
Table 4. Therefore, although lasmiditan 200 mg ranks highest
on most efficacy outcomes, it must be balanced with the fact
that it ranked lowest or second lowest with regard to safety
outcomes of somnolence, dizziness, and nausea. Rimegepant
ranked high on both efficacy and safety outcomes, except for
nausea. Ubrogepant 50 mg fared better on safety outcomes
compared to rimegepant, but worse when it came to efficacy
outcomes.
4. Discussion
This NMA compared the safety and efficacy of rimegepant,
ubrogepant, and lasmiditan for the acute treatment of
migraine, and found significant differences between these
treatments. All active comparators were superior to placebo
with regard to pain freedom and pain relief 2 to 24 hours
post-dose. Rimegepant and all doses of ubrogepant were
comparable for 2–24 hour pain relief, but rimegepant was
superior to the lower doses of lasmiditan and ubrogepant for
2 to 24 hour pain freedom. Lasmiditan was superior to rime­
gepant for freedom from photophobia after 2 hours, while
rimegepant was superior to all doses of lasmiditan regarding
dizziness. A recent NMA of these three treatments by the
Institute for Clinical and Economic Review (ICER) presented
similar findings [37]. In that analysis, rimegepant, ubrogepant,
and lasmiditan were all found to be associated with improved
function and decreased migraine symptoms compared to
placebo, for a subset of the outcomes considered here [37].
These findings are similar to the results of the SUCRA rankings
in the current study. Cost-effectiveness was not considered in

Table 4. Surface under the cumulative ranking curve (SUCRA).

Treatment Arm
Outcome: Ranking (%) PL LAS 50 LAS 100 LAS 200 RIM 75 UBR 25 UBR 50 UBR 100
Pain free 2 h 8 (0) 7 (29%) 4 (59%) 1 (94%) 2 (79%) 6 (32%) 5 (42%) 3 (65%)
Pain relief 2 h 8 (0) 7 (32%) 2 (83%) 1 (84%) 3 (72%) 6 (35%) 4 (47%) 5 (47%)
Sustained pain freedom 2–24 h 8 (0) 7 (31%) 5 (43%) 2 (79%) 1 (98%) 6 (33%) 4 (46%) 3 (69%)
Sustained pain freedom 2–48 h 5 (0) 4 (31%) 3 (45%) 2 (77%) 1 (96%) N/A N/A N/A
Sustained pain relief 2–24 h 5 (0) N/A N/A N/A 1 (80%) 4 (31%) 3 (62%) 2 (80%)
Freedom from MBS at 2 h 8 (0) 7 (30%) 3 (66%) 1 (86%) 5 (48%) 6 (32%) 2 (74%) 4 (63%)
Freedom from photophobia at 2 h 8 (1%) 6 (39%) 2 (82%) 1 (90%) 5 (44%) 7 (18%) 4 (45%) 3 (80%)
Freedom from phonophobia at 2 h 8 (0) 5 (44%) 2 (82%) 1 (88%) 6 (37%) 4 (49%) 3 (62%) 7 (37%)
Freedom from nausea at 2 h 7 (17%) 8 (12%) 5 (49%) 4 (55%) 1 (77%) 6 (44%) 3 (71%) 2 (75%)
Somnolence 2 (85%) 5 (37%) 4 (44%) 7 (26%) 3 (44%) N/A 1 (87%) 6 (27%)
Dizziness 3 (75%) 5 (35%) 6 (15%) 7 (62%) 2 (80%) 4 (62%) 1 (81%) N/A
Nausea 1 (89%) 5 (41%) 4 (45%) 7 (26%) 8 (14%) 3 (72%) 2 (85%) 6 (28%)
h = hours; LAS = lasmiditan; MBS = most bothersome symptoms; n = number of people per treatment arm; PL = placebo; r = number of events; RIM = rimegepant;
UBR = ubrogepant
10 K. JOHNSTON ET AL.
the current study and the cost-effectiveness of the respective
treatments may ultimately play a role in decision making.
Limitations of this study include limited events that hindered
the precise estimates of safety outcomes, as well as a lack of
long-term efficacy and safety data. While lasmiditan and ubro­
gepant were both assessed in independent confirmatory trials,
rimegepant was not, although no methodological or bias-
related concerns have been raised regarding the single rimege­
pant trial. Long-term safety data has been collected in 52-week
open-label studies of rimegepant [43], ubrogepant [44], and
lasmiditan [25]. A limitation of indirect comparisons via NMA is
that it creates more uncertainty than when treatments are
compared directly [37]. However, this NMA was based on
a connected network of acute migraine RCTs that were well-
balanced with regard to subject characteristics, and this
improves the validity of conducting an indirect comparison.
However, external validity may have been compromised due
to the homogenous populations that were selected for the RCTs
that were included in this NMA, as is usual for studies that are
used for regulatory purposes [45]. The internal validity of the
analyses is contingent on three factors: 1) the appropriate iden­
tification of the studies that make up the evidence network, 2)
the quality of the individual RCTs, and 3) the extent of con­
founding bias due to similarity and consistency violations. In this
instance, RCTs were identified via SLR, and both quality-
assessment of included trials and comparison of baseline char­
acteristics implied appropriateness of NMA conduct.
SUCRA rankings have several limitations, including that they
do not take differences in effect magnitude between interven­
tions into account, and its inability to capture the possibility that
the differences between interventions are due to chance [42].
However, the results have also been reported in terms of risk
difference in this paper. Another strength is that NMAs are able
to combine evidence, whether direct or indirect, and ‘increase
the precision of effect estimates’ to show the relative value or
advantages of interventions that have not been compared
directly in head-to-head trials [42]. Future research could com­
pare the interventions directly, and cost-effectiveness analysis
may be able to improve decision-making for healthcare provi­
ders, payers, and patients. The unpredictability, severity, and
frequency of migraines have a tremendously negative effect
on patients’ quality of life, their careers, income, and families,
and there is currently a substantial unmet need for safe and
effective treatments [37]. Therefore, it is important to compare
available treatments to determine which treatments may offer
a net benefit. The current NMA provides insight into the com­
parative efficacy and safety of rimegepant, ubrogepant, and
lasmiditan. All three of these acute migraine treatments offer
convenience because they are orally administered, but rimege­
pant offer benefits in terms of efficacy compared to lower doses
of the comparators, and safety benefits compared to higher
doses of the comparators.
5. Conclusions
All active comparators were more effective compared to pla­
cebo, but placebo had fewer adverse events in general. Active
comparators were comparable, but rimegepant was more effi­
cacious in giving subjects sustained freedom from pain com­
pared to lower doses of lasmiditan and ubrogepant. Subjects
experienced increased dizziness with higher doses of lasmiditan.
Rimegepant 75 mg ODT may provide efficacy benefits versus
lower doses of comparators and safety benefits versus higher
doses of active comparators for the acute treatment of migraine.
6. Clinical implications
● The relative efficacy of newer acute treatments for
migraine is uncertain because most randomized trials
compare these interventions to placebo.
● In the absence of direct comparison trials, randomized
placebo-controlled trials of rimegepant, ubrogepant, and
lasmiditan were included in a network meta-analysis to
indirectly compare the relative efficacy and safety of
these interventions for the acute treatment of migraine.
● All active comparators were superior to placebo with
regard to pain freedom and pain relief 2 to 24 hours
post-dose.
● Rimegepant and all doses of ubrogepant were compar­
able for 2–24 hours pain relief, but rimegepant was
superior to the lower doses of lasmiditan and ubroge­
pant for 2-to-24-hour pain freedom.
● Rimegepant 75 mg ODT showed safety benefits com­
pared to the higher doses of the active comparators,
except for nausea.
Declaration of interest
KJ, EP, AD, and PD are employees of Broadstreet HEOR, which received
funds from Biohaven for this work. LH, AT, RC, VC, and GL are employed by
and own stock/stock options in Biohaven Pharmaceuticals. The authors
have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
Reviewers disclosure
Peer reviewers on this manuscript have no relevant financial relationships
or otherwise to disclose.
Author contribution statement
KJ, EP, AD, PD, LH, and GL contributed significantly to the conception and
design of the work, the analysis, interpretation, and drafting of the most
recently submitted version. AT, RC, VC, and JM contributed significantly to
the conception of the work, the interpretation, and drafting of the most
recently submitted version.
All authors agreed to be personally accountable for the author’s own
contributions and to ensure that questions related to the accuracy or
integrity of any part of the work, even ones in which the author was not
 EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH
personally involved, are appropriately investigated, resolved, and the
resolution documented in the literature.
Funding
This study was funded by Biohaven Pharmaceuticals.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. American Headache Society. AHS consensus statement: the American
headache society position statement on integrating new migraine
treatments into clinical practice. Headache. 2019;59:1–18.
2. Buse D, Fanning K, Reed M, et al. Life with migraine: effects on
relationships, career, and finances from the Chronic Migraine
Epidemiology and Outcomes (CaMEO) Study. Headache. 2019;59
(8):1286–1299.
3. Messali A, Sanderson J, Blumenfeld A, et al. Direct and indirect
costs of chronic and episodic migraine in the United States: a
web-based survey. Headache. 2016;56(2):306–322.
4. Raval A, Shah A. National trends in direct health care expenditures
among US adults with migraine: 2004 to 2013. J Pain. 2017;18
(1):96–107.
5. Ford J, Ye W, Nichols R, et al. Treatment patterns and predictors of
costs among patients with migraine: evidence from the United States
medical expenditure panel survey. J Med Econ. 2017;22(9):849–858.
6. Blumefeld A, Varon S, Wilcox T, et al. Disability, HRQoL and
resource use among chronic and episodic migraineurs: results
from the International Burden of Migraine Study (IBMS).
Cephalalgia. 2011;31(3):301–315.
7. Bonafede M, Sapra S, Shah N, et al. Direct and Indirect healthcare
resource utilization and costs among migraine patients in the
United States. Headache. 2018;58(5):700–714.
8. Buse D, Rupnow M, Lipton R. Assessing and managing all aspects
of migraine: migraine attacks, migraine-related functional impair­
ment, common comorbidities, and quality of life. Mayo Clin Proc.
2009;84(5):422–435.
9. Lombard L, Farrar M, Ye W, et al. A global real-world assessment of
the impact on health-related quality of life and work productivity
of migraine in patients with insufficient versus good esponse to
triptan medication. J Headache Pain. 2020;21(1):41.
10. Marmura M, Silberstein S, Schwedt T. The acute treatment of migraine
in adults: the american headache society evidence assessment of
migraine pharmacotherapies. Headache. 2015;55(1):3–20.
11. Silberstein S, Holland S, Freitag F, et al. Evidence-based guideline
update: pharmacologic treatment for episodic migraine prevention
in adults. Report of the Quality Standards Subcommittee of the
American Academy of Neurology and the American Headache
Society. Neurology. 2012;78(17):1337–1345.
12. Mayans L, Walling A. Acute migraine headache: treatment
strategies. Am Fam Physician. 2018;97(4):243–251.
13. Peters G. Migraine overview and summary of current and merging
treatment options. Am J Manag Care. 2019;25(2 Suppl):S23–S34.
14. Eli Lilly and Company. REYVOW (lasmiditan) tablets Prescribing
Information. Indianapolis, IN.: U.S. Food and Drug Administration;
2019. (Ed.^(Eds).
15. Allergan USA. UBRELVY (ubrogepant) tablets Prescribing Information.
Madison, NJ.: U.S. Food and Drug Administration; 2019. (Ed.^(Eds).
11
16. Biohaven Pharmaceuticals. NURTEC ODT (rimegepant) orally disin­
tegrating tablets Prescribing Information. New Haven, CT: U.S. Food
and Drug Administration; (Ed.^(Eds), 2020.
17. Clemow DB, Johnson KW, Hochstetler HM, et al. Lasmiditan
mechanism of action - review of a selective 5-HT(1F) agonist.
J Headache Pain. 2020;21(1):71–71.
18. Curto M, Capi M, Cipolla F, et al. Ubrogepant for the treatment of
migraine. Expert Opin Pharmacother. 2020;21(7):755–759.
19. Curto M, Cipolla F, Cisale GY, et al. Profiling lasmiditan as a treatment
option for migraine. Expert Opin Pharmacother. 2020;21(2):147–153.
20. De Matteis E, Guglielmetti M, Ornello R, et al. Targeting CGRP for
migraine treatment: mechanisms, antibodies, small molecules,
perspectives. Expert Rev Neurother. 2020;20(6):627–641.
21. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new
drugs, new hope? J Headache Pain. 2019;20(1):37.
22. Edvinsson L, Haanes K, Warfvinge K, et al. CGRP as the target of
new migraine therapies - successful translation from bench to
clinic. Nat Rev Neurol. 2018;14(6):338–350.
23. Tepper D. Gepants. Headache. 2020;60(5):1037–1039.
24. Hou M, Xing H, Li C, et al. Short-term efficacy and safety of
lasmiditan, a novel 5-HT(1F) receptor agonist, for the acute treat­
ment of migraine: a systematic review and meta-analysis.
J Headache Pain. 2020;21(1):66.
25. Lipton R, Lombard L, Ruff D, et al. Trajectory of migraine-related
disability following long-term treatment with lasmiditan: results of
the GLADIATOR study. J Headache Pain. 2020;21(1):20.
26. Reuter U, Israel H, Neeb L. The pharmacological profile and clinical
prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute
treatment of migraine. Ther Adv Neurol Disord. 2015;8(1):46–54.
27. ClinicalTrials.gov. BHV3000-303: phase 3, Double-Blind, Randomized,
Placebo Controlled, Safety and Efficacy Trial of BHV-3000
(Rimegepant) Orally Disintegrating Tablet (ODT) for the Acute
Treatment of Migraine. NCT03461757. (Ed.^(Eds) (2020)
28. Croop R, Goadsby P, Stock D, et al. Efficacy, safety, and tolerability
of rimegepant orally disintegrating tablet for the acute treatment
of migraine: a randomised, phase 3, double-blind,
placebo-controlled trial. Lancet. 2019;394(10200):737–745.
•• This reference describes the clinical trial data for rimegepant
that was used within the network meta-analysis.
29. ClinicalTrials.gov. Efficacy, Safety, and Tolerability Study of Oral
Ubrogepant in the Acute Treatment of Migraine (ACHIEVE I).
NCT02828020. (Ed.^(Eds) (2019)
30. Dodick D, Lipton R, Ailani J, et al. Ubrogepant for the Treatment of
Migraine. N Engl J Med. 2019;381(23):2230–2241.
•• This reference describes the ACHIEVE I clinical trial data for
ubrogepant that was used within the network meta-analysis.
31. ClinicalTrials.gov. Efficacy, Safety, and Tolerability of Oral
Ubrogepant in the Acute Treatment of Migraine (ACHIEVE II).
NCT02867709. (Ed.^(Eds) (2019)
32. Lipton R, Dodick D, Ailani J, et al. Effect of ubrogepant vs placebo
on pain and the most bothersome associated symptom in the
acute treatment of migraine the ACHIEVE II randomized clinical
trial. JAMA. 2019;322(19):1887–1898.
•• This reference describes the ACHIEVE II clinical trial data for
ubrogepant that was used within the network meta-analysis.
33. ClinicalTrials.gov. Lasmiditan compared to placebo in the acute
treatment of migraine: (SAMURAI). NCT02439320. (Ed.^(Eds) (2019)
34. Kuca B, Silberstein S, Wietecha L, et al. Lasmiditan is an effective
acute treatment for migraine: a phase 3 randomized study.
Neurology. 2018;91(24):e2222–e2232.
12 K. JOHNSTON ET AL.
•• This reference describes the SAMURAI clinical trial data for
lasmiditan that was used within the network meta-analysis.
35. ClinicalTrials.gov. Three doses of Lasmiditan (50 mg, 100 mg and
200 mg) compared to placebo in the acute treatment of migraine
(SPARTAN). NCT02605174. (Ed.^(Eds) (2019)
36. Goadsby P, Wietecha L, Dennehy E, et al. Phase 3 randomized,
placebo-controlled, double-blind study of lasmiditan for acute
treatment of migraine. Brain. 2019;142(7):1894–1904.
•• This reference describes the SPARTAN clinical trial data for
lasmiditan that was used within the network meta-analysis.
37. Atlas S, Touchette D, Agboola F, et al. Acute Treatments for
Migraine: effectiveness and Value. Institute for Clinical and
Economic Review, February. (Ed.^(Eds) (2020)
38. Hoaglin D, Hawkins N, Jansen J, et al. Conducting indirect-treatment-
comparison and Network-Meta-Analysis studies: report of the ISPOR
task force on indirect treatment comparisons good research practices:
part 2. Value Health. 2011;14(4):429–437.
39. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. BMJ.
2009;339(jul21 1):b2535.
40. Higgins J, Altman D, Gotzche P, et al. The Cochrane Collaboration’s
tool for assessing risk of bias in randomised trials. BMJ. 2011;343
(oct18 2):d5928.
41. Dias S, Welton N, Sutton A, et al. NICE DSU Technical Support
Document 2: A Generalised Linear Modelling Framework for
Pairwise and Network Meta-Analysis of Randomised Controlled
Trials. Unit, DS (Ed.^(Eds) (2011)
•• This is a key methodological reference providing best practice
guidance for network meta-analysis of clinical trial data.
42. Mbuagbaw L, Rochwerg B, Jaeschke R, et al. Approaches to inter­
preting and choosing the best treatments in network
meta-analyses. Syst Rev. 2017;6(1):79.
•• This methodological paper describes the SUCRA methodology
for assessing the likelihood of each treatment being ranked
first.
43. Croop R, Berman G, Kudrow D, et al. Long-Term safety of rimege­
pant 75 mg for the acute treatment of migraine (Study 201) (4829).
Neurology. 2020;94 (15 Supplement).
44. Ailani J, Lipton R, Hutchinson S, et al. Long-Term safety
evaluation of ubrogepant for the acute treatment of migraine:
phase 3, randomized, 52-week extension trial. Headache. 2020;60
(1):141–152.
45. Jansen J, Fleurence R, Devine B, et al. Interpreting indirect treat­
ment comparisons and Network Meta-analysis for health-care deci­
sion making: report of the ISPOR task force on indirect treatment
comparisons good research practices: part 1. Value Health. 2011;14
(4):417–428.