Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

The safety and efficacy of the 5-HT 1F receptor

agonist lasmiditan in the acute treatment of
migraine

Bianca Raffaelli, Heike Israel, Lars Neeb & Uwe Reuter

To cite this article: Bianca Raffaelli, Heike Israel, Lars Neeb & Uwe Reuter (2017): The safety
and efficacy of the 5-HT 1F receptor agonist lasmiditan in the acute treatment of migraine, Expert
Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2017.1361406

To link to this article: http://dx.doi.org/10.1080/14656566.2017.1361406

Accepted author version posted online: 27

Jul 2017.

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 The safety and efficacy of the 5-HT 1F receptor agonist lasmiditan in the acute
treatment of migraine

Bianca Raffaelli, MD1; Heike Israel, MD1; Lars Neeb MD1, Uwe Reuter, MD MBA1*
1
Department of Neurology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

Corresponding author:

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Prof. Dr. Uwe Reuter, MBA

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Hochschulambulanz und Klinik für Neurologie

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Charité - Universitätsmedizin Berlin
Charitéplatz 1

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10117 Berlin
E-mail: uwe.reuter@charite.de
Phone: +49(0)30-450-560274
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Fax: +49(0)30-450-560 932
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Funding:
This paper was not funded
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Declaration of interest:
U Reuter has received honoraria for the participation in advisory boards, oral presentations or
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contributions to clinical trials from Pharm Allergan, Amgen, Autonomic technologies, CoLucid,
ElectroCore, EliLilly, Haas & Health, Novartis, TEVA. U Reuter was an advisor to CoLucid until
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September 2016 and has participated in several clinical trials with Lasmiditan.
H Israel and L Neeb have received honoraria from Pharm Allergan, Eli Lilly (LN), Novartis (LN) and
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Autonomic technologies. 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.
Abstract

Introduction: Migraine is among the most disabling disorders worldwide, with a significant
therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are
contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties.
Further limitations include side effects, inconsistency in therapeutic action and possible non-response.
Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid
of vasoconstriction.

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Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan

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as a possible acute migraine treatment. We analyze all currently available results in Phase I to III
studies.

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Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular, for patients at
cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache

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response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not
essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal
contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the
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blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate
severity. The results of long-term Phase III studies will determine if these adverse events represent a
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limitation in clinical practice.

Keywords: 5-HT1F receptor; clinical trials; lasmiditan; migraine; serotonin; vasoconstriction.

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 1. Introduction
Migraine is a common neurological disorder, affecting over 13% of adults worldwide [1, 2]. It is
characterized by recurrent headache attacks lasting 4 to 72 hours [3]. Typical attack features are
unilateral localization, pulsating character, moderate or severe intensity, aggravation by routine
physical activity and accompanying vegetative symptoms such as nausea and/or vomiting,
phonophobia and photophobia [3]. Migraine is one of the twenty most disabling diseases worldwide

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and ranks number 7 for years lived with disability attributed to headache. The disease has an important

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socioeconomic impact [4, 5]. Direct and indirect costs of migraine sum up to over €70 billion together
in Europe and the United States [6, 7]. Given the high prevalence and the high burden of disease, the

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development of efficacious pharmacotherapies for the treatment of migraine appears to be of pivotal
importance [8].

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The most frequent acute anti-migraine therapies are non-specific drugs such as NSAIDs or other non-
narcotics like paracetamol [9]. If the response to these non-specific drugs is not sufficient, particularly
in moderate or severe attacks, selective 5-HT1B/1D receptor antagonists, so called triptans, are drugs of
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choice [10]. Triptans were introduced into the market in the early 1990s and represented a major
breakthrough in acute anti-migraine therapy [11]. Currently there are seven triptans available:
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sumatriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan and zolmitriptan [12]. All
triptans were tested superior to placebo and can be considered safe and effective drugs for the vast
majority of migraine patients [13]. Although they have some differences with respect to certain
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properties, such as onset of action or half-life time, they share the same mechanism of action [14].
Triptans bind mostly to 5-HT1B and 5-HT1D receptors on smooth muscle cells in cerebral arteries,
leading to vasoconstriction, and inhibit the release of inflammatory mediators such as CGRP [14].
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So far, no more recent substance class has succeeded in passing all developmental stages [13].
Therefore, most clinical studies focus on the improvement of triptan therapy [15]. These trials
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incorporate the addition of an NSAID to a triptan or novel triptan formulations, e.g. transdermal
application for acute migraine, currently removed from the US market due to the analysis of skin
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reactions [15, 16]. While the trials help clinicians to identify the optimal attack treatment with a
triptan, these modifications in drug application do not improve the tolerability and adverse event
profile of a triptan [15]. In particular, the activation of the 5-HT1B receptor can cause vasoconstriction
of arteries and veins in several experimental surrogate models and may cause ischemia in the
susceptible patient with pre-existing conditions.
Rare cases of stroke, myocardial infarction, and arrhythmia were reported in temporal relation to
triptan therapy [17–19]. Therefore, cardiovascular safety is one of the major concerns in triptan
therapy [15]. Patients with myocardial infarction, coronary artery disease, stroke, vasculitis and
uncontrolled hypertension are not eligible for triptan therapy. Also, in subjects with hemiplegic
migraine or with prolonged migraine aura triptans are not entirely recommended. In a large meta-
analysis, also frequent NSAID intake was proven to increase the risk of acute myocardial infarction,
especially during the first month of use and with higher doses [20]. Thus, the acute therapy of
migraine patients with cardiovascular risk factors represents a substantial challenge for the treating
physician.
Most disturbing symptoms related to triptan intake include paraesthesia, muscle pain, chest tightness
in up to 24% of patients with oral triptans and 40% after subcutaneously application [21]. Moreover,
up to 25% of patients do not respond to any triptan treatment, while others complain about their lack

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of consistency over time [13]. In line with these findings, Lipton and colleagues showed in the

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American migraine program project that up to 40% of migraineurs have unmet therapeutic needs [22].
Headache related disability (19%) and dissatisfaction with current migraine medications (15%) were

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the two most frequently mentioned reasons in this study [22].
New acute drug antimigraine treatments are currently not available. Small molecule CGRP receptor

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antagonists such as telcagepant or BIBN 44370TA were promising and efficacious attack therapies
some years ago, with a favorable adverse event profile when compared to triptans [23-25]. However,
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CYP3A4 interaction in the metabolizing process of these substances with transaminase elevation after
repetitive treatment led to the termination of several small molecule development programs [26].
The CGRP receptor antagonist ubrogepant and the 5-HT1F receptor agonist lasmiditan are the most
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promising acute anti-migraine treatments currently being tested in clinical trials [27-29].

2. Lasmiditan overview
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The 5-HT1F receptor agonist lasmiditan acts on 5-HT1F receptors expressed on secondary trigeminal
neurons within the brainstem and the trigeminal ganglion as well as in cortex layers 4-5 and in the
cerebellum [30]. Therefore, 5-HT1F receptor agonists may possess a central and peripheral mode of
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action [30]. In animal experiments, activation of 5-HT1F receptors resulted in the blockade of plasma
extravasation and inhibition of central and peripheral neuronal activity [31]. These findings led to the
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hypothesis that selective 5-HT1F receptor agonists may be sufficient in aborting migraine attacks [31].
It is relevant to note that 5-HT1F receptors cannot be found in endothelial or smooth muscle cells of
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cerebral vessels and are therefore not involved in the vasoconstriction process [32].
In 2001, one of the first prototypes of 5-HT1F receptor agonist, called LY 334370, was proven
effective in proof-of-concept clinical trials [33]. While the substance has a 100-fold higher selectivity
for 5-HT1F receptors over 5-HT1B and 5-HT1D receptors, LY334370 showed a significant affinity for 5-
HT1A receptors and a partial affinity to 5-HT1B receptors. Therefore vasoconstriction as mechanism of
action in higher doses could not be excluded [33]. LY 334370 was not further developed due the
appearance of liver toxicity in dogs [11]. However, this adverse event was probably both species and
drug specific, as it did not occur in testing other animals with LY 334370 or other 5-HT1F receptor
agonists [11].
Lasmiditan, formerly known as COL-144 and LY573144, is a new, highly selective 5-HT1F receptor
agonist, which is devoid of vasoconstriction and belongs to a novel class of drugs called neutrally
acting anti-migraine agents (NAAMAs) [13]. The chemical structure of lasmiditan differs clearly from
the triptans, as it does not contain an indole core but presents a pyridinoyl-piperidine scaffold instead
[34].
3. Pharmacodynamics

The binding affinity of lasmiditan at the 5-HT1F receptor is 470-fold higher than at 5-HT1B and 5-HT1D
receptors, which avoids cross reactivity and thus minimizes interactions and vascular complications

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[35]. In in vitro assays, its inhibitory constant (Ki) at the 5-HT1F receptor was 2.21 (±0.22) nM,
compared to 1043 (±124) nM at the 5-HT1B receptor and 1357 (±156) nM at the 5-HT1D receptor [35].

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Lasmiditan is a high lipophilic substance, able to penetrate the blood brain barrier and is therefore
supposed to act on both peripheral and centrally located receptors [35]. In rodent models, it potently

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blocked neurogenic inflammation, through suppression of dural plasma protein extravasation and also
inhibits central c-Fos expression in the trigeminal nucleus caudatus [35]. In a rabbit saphenous vein
model, lasmiditan did not cause vessel contraction, as opposed to sumatriptan, which led to a 50%
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vasoconstriction [35]. Saphenous vein contraction can be considered as a surrogate model for vessel
contraction in human coronary arteries, confirming the already supposed vascular neutrality of
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lasmiditan [35].

4. Pharmacokinetics
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Lasmiditan has a mean oral bioavailability of approximately 40%. The maximum plasma
concentrations were reached between 1.5 and 2.5 hours (tmax) after administration of the lasmiditan in a
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rapid disintegration tablet [36].

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5. Clinical efficacy
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5.1 Phase I/II studies

Between 2003 and 2015, five lasmiditan trials have completed phase I, four of them for the oral
formulation and one of them for the intravenous one (Table 1). Phase I peer-reviewed primary
publications do not exist (see 6.1 for further discussion) [37]. In each of these studies, lasmiditan was
tested on 40 to 55 healthy subjects to evaluate safety, bioavailability, tolerability and
pharmacokinetics. The effective dose, defined as at least as effective as sumatriptan, was calculated to
be 170 mg and above for the oral formulation [37, 38].
Two Phase II studies were conducted between 2007 and 2009, the first for the intravenous
formulation, and the second for the oral one [36, 39]. The intravenous formulation of lasmiditan was
studied in a randomized, multicenter, placebo-controlled, double-blind, proof-of-concept and dose-
finding trial with 130 migraine patients [39]. Subjects were between 18 and 65 years old, in good
general health, had at least a one-year history of migraine, reported one to eight migraine attacks a
month and did not use any prophylactic medication. The study design allowed the up or down titration
of the study drug (adaptive-treatment design), depending on efficacy and adverse events. Subjects with
moderate to severe acute migraine were allocated to either placebo or lasmiditan i.v. in doses 2.5 to 45
mg and received an identical infusion of 60 ml over 20 minutes. Primary endpoint was headache
response after two hours meaning significant pain improvement to mild pain or none. A typical

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migraine study population on the study drug showed a superior headache response (54.2-75%) to

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placebo (45.2%). A dose response relationship was detected with increasing doses of lasmiditan
leading to better response rates (p=0.021). The study was not designed to detect a statistical difference

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for a specific dose. The therapeutic gain, i.e. placebo-subtracted response, averaged 19% [-4-42%].
Accordingly, patients' global impression improved significantly with increasing dose, while the use of

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rescue medication decreased. The onset of pain relief occurred after 20 to 40 minutes. Based on these
early results, lasmiditan could potentially serve as an acute i.v. anti-migraine drug in emergency room
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situations. This was the first proof of concept study in a large migraine population for 5-HT1F receptor
mediated acute anti migraine effectiveness.
The Phase II trial with oral formulation was a double blind, placebo controlled, multicenter, parallel
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group, randomized study in Europe for the treatment of acute migraine of moderate to severe pain
intensity [36]. Similar to the intravenous study, patients between 18 and 65 years were included with a
history of 1 to 8 migraine attacks per month. Previous prophylactic drugs were discontinued at least
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two weeks before screening. 534 patients were screened and 390 terminated the study. Lasmiditan was
tested in a rapid disintegration tablet for the primary endpoint, defined as dose response relationship
for the improvement of headache after 2 hours, in doses of 50, 100, 200 and 400 mg (total n= 310
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subjects) versus placebo (n=81) in an identical formulation. Subjects were randomized in a 1:1:1:1:1
ratio. Lasmiditan doses were chosen based on a pharmacokinetics/pharmacodynamics (PK/PD) model
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with the expectation that 50 mg would have minimal efficacy and 400 mg the highest efficacy and the
most rapid onset. The oral bioavailability of the disintegrating tablet was calculated as 40% with a
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rapid absorption and maximum plasma concentration was reached between 1.5 and 2.5 hours (Pilgrim
et al. 2009). The primary endpoint was clearly reached in this study and several secondary endpoints
also showed beneficial effects for the investigational product. Lasmiditan showed a linear association
for headache response and dose with the highest response rate of 64.7% [52.2-75.9] for the 400 mg
dose, which was also statistically superior to placebo. Headache responses after 2 hours were 50.7%
[38.4-63], 64.2% [52.8-74.6], 43% [31.9-54.7] and 25.9% [18.8-36.9] for 200 mg, 100 mg and 50 mg
lasmiditan versus placebo. All results reached statistical significance (p<0.03). Onset of action started
after 30 minutes in the 400 mg group, after 60 minutes all but the 50 mg lasmiditan dose were superior
to placebo and after 90 minutes all groups reached statistical significance versus placebo.
According to the IHS, absence of pain after 2 hours provides the most clinically relevant information
[40]. Lasmiditan also had a linear trend for dose and pain freedom (p=0.0006). Doses of 200 mg (19%;
10.6-30.5) and 400 mg (28%; 18.0-40.7) were statistically superior to placebo (7.4%; 2.8-15.4). The
placebo response in this trial seem to be somewhat lower than in triptan trials, while the pain freedom
rate for the 400 mg dose is comparable to sumatriptan and zolmitriptan tablets in standard doses [14].
The difference between the 200 mg dose and placebo suggests a comparability to almotriptan pain
freedom rates after 2 hours [14]. These results are also in line with the calculation from Tfelt Hansen
and Olesen who assume that the number needed to treat (NNT) for lasmiditan is comparable to

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sumatriptan 100 mg tablets [40]. Improvements in headache severity, clinical disability and patients’

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global impression were all superior for the study drug 100 mg and 400 mg doses, while the 200 mg
tablet failed to show superiority for global impression, probably due to random variation in migraine

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severity and response in the different lasmiditan groups. All migraine accompanying symptom like
nausea, vomitus, phono-, and photophobia were clearly improved after two hours, the strongest effect

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was achieved for phono- and photophobia in the 100 and 400 mg doses.
The highest therapeutic gain, i.e. placebo-subtracted response, was reached for oral lasmiditan 400 mg
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with 38% [28-51%]. 400 mg of oral lasmiditan correspond to an intravenous dose of 160 mg, but the
maximum dose reached in the intravenous trial was 45 mg [36, 39].
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5.2. Phase III studies
Currently, Phase III trials are under way. One trial is completed and some key data were presented
during the IHC conference in Glasgow 2016.
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The first Phase III trial for oral lasmiditan was called SAMURAI (Id number NCT02439320) and was
conducted from April 2015 to August 2016 [7, 41]. SAMURAI was a placebo-controlled, randomized,
double blind, parallel group trial, analyzing the effect of 100 mg and 200 mg lasmiditan versus
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placebo on one acute migraine attack in 2,231 patients. Inclusion criteria were history of disabling
migraine of at least one year, defined as MIDAS >11, and 3-8 migraine attacks per month. While most
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trials include subjects up to an age of 65 years, this trial had no upper age limit. The cohort consisted
mainly of Caucasian women with a mean age of 41.6 years. Over 81% of patients had cardiovascular
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conditions or cardiovascular risk factors. Cardiovascular risk factors included obesity, family history
of coronary artery disease, smoking, hypertension, post-menopausal women, men over 40 years of
age, hyperlipidemia and type-2 diabetes. Data were collected using electronic diaries during one acute
migraine attack. A second dose of the study drug was allowed between 2 and 24 hours after the first
one if pain freedom was not achieved or headache reoccurred. Primary endpoint of this trial was pain
freedom after 2 hours. The key secondary endpoint was defined as freedom from the most bothersome
associated migraine symptom, as identified by the subject, among nausea, photo- and phonophobia.
The most bothersome symptom is a novel endpoint in migraine therapy. First results were presented in
September 2016 at the 5th European Headache and Migraine Trust International Congress (EHMTIC
2016) in Glasgow, but have not been published in full paper to our best knowledge. Both doses
achieved the primary and key secondary endpoint with statistical significance (p<0.001) [7]. Other
secondary endpoints reaching statistical significance were pain relief after 2 hours, pain freedom after
lasmiditan use as rescue medication, reduction of migraine related disability and improvement in the
Patient Global Impression of Change (Table 2) [41].
A second Phase III trial, called COL MIG-302 or SPARTAN (Id number NCT02605174) was
conducted at approximately 140 sites in the United States, United Kingdom and Germany. It started in
April 2016 and the recruitment was closed in April 2017 with 2,968 randomized patients. SPARTAN

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is a prospective, randomized, double-blind study that aim to compare three doses of lasmiditan (50

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mg, 100 mg, 200 mg) with placebo in the acute treatment of one migraine attack. The primary and key
secondary endpoints match the one of SAMURAI. Results are still pending and are expected for the

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second half of 2017 [7].
An open-label Phase III trial called COL MIG-305 or GLADIATOR (Id number NCT 02565186) was

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started in October 2015 to evaluate the safety and efficacy of long-term intermittent use of lasmiditan
100 mg and 200 mg for the acute treatment of migraine. Patients will be treated over a one-year period
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for up to eight migraine attacks per month. Migraine patients who have completed SAMURAI or
SPARTAN are eligible for GLADIATOR. Up to 2,580 patients are expected to enroll in
GLADIATOR, the estimated study completion date is May 2018 [7].
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6. Clinical safety and tolerability

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6.1. Phase I/II studies

The adverse event profile of lasmiditan is different from typical triptan side effects, which are
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paresthesia, neck pain or stiffness and warm sensations in the head, neck, chest, and limbs [12]. CNS
adverse reactions such as asthenia, somnolence or dizziness are less frequent but of higher relevance
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[12]. Sumatriptan 100 mg has a placebo subtracted adverse events rate of 13%. In the initial
publication i.v. sumatriptan was associated with adverse events in 60% of subjects; however, this was
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an uncontrolled trial [12]. Almotriptan 12.5 mg and Naratriptan 2.5 mg were proven to have a better
tolerability, while Zolmitriptan 5 mg had the highest placebo subtracted adverse events rate with 24%
[12].
Although extensive data for Phase I studies with lasmiditan are not published in peer-reviewed form,
its cardiac safety was confirmed, as no arrhythmia or any pro-arrhythmic effects were observed [37].
In a comparator trial with the antibiotic moxifloxacin, lasmiditan 100 and 400 mg did not cause any
significant QT prolongation, whereas moxifloxacin showed its already known QT prolonging effect
[37]. In Phase I studies with maximum dose of 400 mg, drowsiness, dizziness and paraesthesia were
reported as most frequent adverse events [37].
The most common adverse event in the Phase II trial with the intravenous lasmiditan formulation was
transient mild paresthesia [39]. The feelings of heaviness, fatigue, relaxation and dizziness were also
observed. In total 65% of subjects with lasmiditan and 43% on placebo reports adverse events. The
placebo-subtracted adverse events rate for intravenous lasmiditan 20 mg was 25% with a number
needed to harm (NNH) of 4. All adverse events were mild, no serious adverse events were observed.
ECG, vital signs and laboratory testing were all within in normal range. No triptan-like chest
symptoms like chest tightness or pain were reported.
In the larger Phase 2 trial with the oral formulation, emerging adverse events increased with increasing

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doses of lasmiditan (53/82 [65%], 59/82 [72%], 61/71 [86%], 59/70 [84%] for 50, 100, 200, and 400

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mg lasmiditan) [36]. In contrast, 19 out of 86 subjects [22%] on placebo reported a treatment emerging
adverse event. The placebo-subtracted adverse events rate for the oral formulation of 400 mg was

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62% with a NNH of 1.6. Most adverse events affected the CNS, particularly dizziness or paresthesia,
or the vestibular system, probably due to the drugs lipophilic structure which leads to high

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permeability through the blood brain barrier. There was one hospital admission due to dizziness after
200 mg study drug. The female subject could be discharged after a cardiac and neurological work up
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which did not reveal any pathological findings. Most adverse events were of mild or moderate
intensity. However, 20% - 44% of subjects on lasmiditan 50-400 mg reported an adverse event of
severe intensity, while in the placebo group only 6% of subjects reported severe adverse events.
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Importantly, neither cardiac adverse events were reported nor chest pain or chest tightening. ECG,
vital parameters and biochemistry did not show pathological findings.
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6.2 Phase III studies

In the first Phase III trial, lasmiditan was tolerated well [7, 41]. Importantly, again no cardiovascular
adverse events were reported neither when taken as first nor as second dose, confirming the general
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cardiovascular safety. As in the Phase II study, most adverse events concerned the CNS or the
vestibular system. Dizziness was the most frequent adverse events, being reported in 11.9% of the
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cases for 100 mg and 15.4% for 200 mg versus 3.1% for placebo. Other common adverse events were
paresthesia, somnolence, nausea and fatigue. Adverse events were reported in 91% of the cases to be
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mild or moderate in nature. No treatment-related serious adverse event occurred. Dizziness and vertigo
were less frequently seen in the phase III trial compared to the phase II study period.

7. Conclusion
Since the introduction of triptans in the 1990s, there has been no new approved drug for the acute
therapy of migraine attacks [15]. Triptans are generally efficacious and safe drugs, but their adverse
events profile makes them unsuitable for patients with preexistent cardio- and cerebrovascular diseases
[13]. Even in patients with no contraindications for triptan therapy, many report unmet therapeutic
needs due to side effects or lack of response. Therefore, novel effective attack therapies are required
[42, 43].
Lasmiditan, a specific 5-HT1F receptor, has been shown efficacious in several clinical phase II and II
trials with an adverse event profile probably related to the CNS due to its fast penetration through the
blood brain barrier. Based on its lack of vasoconstriction this substance could serve as a treatment
option for subjects with a cardiovascular risk profile. The results of the first phase III study, in line
with all prior clinical and pre-clinical study results, support this hypothesis.
8. Expert opinion

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Migraine is believed to be a disorder in which the brain, meningeal blood vessels and the trigeminal

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nerve system play a crucial role [44]. The current view on migraine pathophysiology can be
summarized as follows: Migraine headache is caused by activation and sensitization of trigeminal

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nociceptors innervating the large vessels in the meninges. This results in neuropeptide release, among
others CGRP, a potent vasodilatator [44]. These processes lead to subsequent excitation of secondary

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and tertiary central trigeminal neurons, which activate various subcortical and cortical areas, resulting
in pain and other typical migraine symptoms. Whether a central component is more important than a
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peripheral component or vice versa has been matter of debate for many years and still unsolved [44].
Triptans were developed in the early 1990s, as vasodilatation of cerebral blood vessel was considered
the main cause of migraine and it was supposed that vasoconstriction would alleviate migraine
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headache [45]. In recent decades, vasodilation has come to be considered as an epiphenomenon in
migraine pathogenesis, occurring after trigeminal activation and neuropeptide release. Thus, a theory
focusing purely on vascular factors has been largely rejected [44]. In addition to vasoconstriction, it
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has been shown that triptans may also alleviate the pain though inhibition of neuropeptide release from
trigeminal neurons and block the spreading of pain signals within the trigeminal cervical complex
[46]. The efficacy of lasmiditan proves that vasoconstriction is not essential for anti-migraine therapy
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and offers further support for the neurogenic theory of migraine [47]. The inhibition of neuropeptide
release may also contribute to the effect of lasmiditan.
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Migraine may be aborted by inhibiting central or peripheral nervous system mechanisms [35]. Future
research will tell us more about lasmiditan's ability to penetrate the blood brain barrier easily and will
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also help to analyze central 5-HT1F receptor binding as a potential site of antimigraine action. In
contrast, most recent studies with monoclonal antibodies against CGRP or the CGRP receptor support
the hypothesis that a peripheral mechanism is sufficient to block the development of migraine
headaches [23-25]. Because of their size these monoclonal antibodies have limited ability to penetrate
the blood brain barrier under physiological conditions. While a transporter mechanism for the uptake
of monoclonal antibodies into the CNS cannot be ruled out, there is on the other hand no evidence for
such [48]. In addition, the adverse event profile for these drugs does not indicate a central mechanism
of action [48]. In line, the acute anti-migraine drug telcagepant was not found during and outside
migraine attacks in significant concentrations in the brain in a PET study, underlining the importance
of a peripheral component for anti-migraine drug action [49]. Taken together, these study results
indicate that both central and peripheral components play an important role in migraine
pathophysiology. It remains unclear, whether inhibition of central or peripheral mechanism represents
the better target for acute anti-migraine therapy. However, vasoconstriction is not necessary to abort
acute migraine.
Lasmiditan is currently being tested in large Phase III clinical trials [7]. Phase II studies and the first
Phase III trial show a significant better pain relief and pain freedom after two hours in comparison to
placebo [7, 36, 39]. Several secondary endpoints such as freedom from other bothersome migraine

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symptoms and reduction of migraine disability reached statistical significance. In all studies, no

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cardiovascular adverse events occurred and other triptan-specific side effects like chest, neck or jaw
heaviness were uncommon. Lasmiditan could thus represent a benefit in clinical practice as potential

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alternative in patients non responding to triptans or where the use of triptans is limited by
cardiovascular risk factors or side effects. The adverse events profile of lasmiditan deserves further

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research but will finally be determined in clinical practice [50, 51].
Another interesting aspect is the possible use of lasmiditan as an anti-migraine drug in urgent care.
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Emergency room treatment for migraine is limited to subcutaneous sumatriptan, DHE and opioids in
the US, while the intravenous formula of acetylsalicylic acid is available in Europe but not in the US.
All currently available substances have several well-known disadvantages [52]. Half of the patients
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who were treated with subcutaneous sumatriptan in the emergency department reported side effects,
most common rash at injection size, chest tightness, generalized weakness, muscle and neck stiffness,
dizziness and paresthesia [52]. Lasmiditan might offer a valid alternative for acute migraine treatment
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in urgent care.
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References
* = of interest

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** = of considerable interest

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 Drug name Lasmiditan
Phase Phase III
Indication Migraine
Pharmacology description 5 Hydroxytryptamine 1F receptor agonist
Route of administration Injectable (intravenous), oral (sublingual/ swallowed)

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Drug Summary Box

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Chem
mical structure

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Pivottal trial(s) [7, 36, 39]
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Table 1: Lasmiditan clinical trials (modified from [37])

No. of
ditan
Study Formulation Phase Objectives Date Reference
exposed
subjects
Safety,
No name Intravenous I 40 tolerability, 2003 -
pharmacokinetics
Safety,
Oral solution
COL-MIG 102 I 44 tolerability, 2008 -
and sublingual

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pharmacokinetics

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Oral solution Bioavailability and
COL-MIG 103 I 44 2008 -
and oral tablet pharmacokinetics
Bioavailability

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COL-MIG 104 Oral tablet I 30 under fed/fasted 2015 -
conditions
Exclusion QT
COL-MIG 105 Oral tablet I 55 2011 -

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prolongation
Efficacy and dose-
COL-MIG 201 Intravenous II 88 response 2007 [39]
relationship
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Oral
Efficacy and
COL-MIG 202 disintegrating II 305 2009 [36]
safety
tablet
COL-MIG 301 Efficacy and
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Oral tablet III 1.483 2016 [7,41]
(SAMURAI) safety
COL-MIG 303 Efficacy and
Oral tablet III 2.226 2016 -
(SPARTAN) safety
COL-MIG 305 Long-term 2016
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Oral tablet III 2.580 -

(GLADIATOR) efficacy and safety (ongoing)
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Table 2: Primary and some secondary endpoints from SAMURAI. Data taken from [7] and [41].

Lasmiditan 100 Lasmiditan 200

Endpoint Placebo
mg mg
% of patients migraine headache pain free at two
28.2 % 32.2 % 15.3%
hours
% of patients free from most bothersome symptom at
40.9% 40.7% 29.5%
two hours
% of patients migraine headache pain relief at two

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59.4% 59.5% 42.2%
hours

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Global Impression of Change much of very much
37.2% 37.8% 21.8%
better at two hours
No migraine disability at two hours 32.2% 32.4% 21.5%

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Utilization rate of a second dose of study drug 46.0% 39.0% 65.0%

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