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New drug: lasmiditan for migraine attacks


Two new drugs for the acute treatment of migraine attacks were authorised in 2022. They concern the ‘calcitonin gene-related peptide’ (CGRP) antagonist rimegepant, which was previously discussed in Ge-Bu, and the 5HT1F agonist lasmiditan. New agents can prove to be a welcome addition, as the current treatment with triptans does not work for all patients, cause adverse events or are contraindicated in case of cardiovascular disorders. Research has shown that lasmiditan can effectively halt the pain and the most bothersome symptom of migraine within 2 hours. Research has also shown, however, that it very often produces central adverse effects. The question is whether the effectiveness and adverse events profiles of lasmiditan offer any advantages over the profiles of the currently used triptans.

What is Ge-Bu’s opinion?
  • The percentage of patients who are free of pain 2 hours after a migraine attack is 10% to 21% higher among patients using lasmiditan than among those using a placebo. The ‘number needed to treat’ is 5 to 10.
  • A network meta-analysis using only indirect comparisons appears to show that the efficacy of lasmiditan is comparable to that of rimegepant, but lower than that of sumatriptan.
  • Lasmiditan has central adverse effects, including dizziness (14% to 24%) and somnolence (5.5% to 8.5%). It does not cause coronary vasoconstriction and is therefore, unlike the triptans, not contraindicated for patients with cardiovascular disorders.
  • Prescribing lasmiditan can be considered if a patient’s current migraine medication is ineffective, is not tolerated or is contraindicated. The relatively common central adverse events may be bothersome. 

The acute treatment of migraine attacks received a strong boost in 2022, with the authorisation of two new drugs. Ge-Bu previously published an article on rimegepant, a calcitonin gene-related peptide (CGRP) antagonist to treat migraine attacks.1 Since then, the 5HT1F agonist lasmiditan has been added. Unlike the triptans, which are not only 5HT1B/1D receptor agonists but are also moderate 5HT1F receptor agonists, lasmiditan is a highly selective 5HT1F receptor agonist. This results in reduced release of CGRP without direct vasoconstriction, reducing the pain of migraine. The number of migraine patients who are free of pain 2 hours after an attack of migraine is significantly higher among those taking lasmiditan than among those using placebo, with a number needed to treat of 5 to 10. In addition, the percentage of patients whose most bothersome symptom has disappeared after 2 hours is also significantly higher with lasmiditan than with placebo. Indirect comparisons with the triptans appear to show that lasmiditan is less effective. The central adverse events, like dizziness and somnolence, can be bothersome.

Lasmiditan is the only 5HT1F agonist investigated in phase 3 studies to far. It efficacy has been evaluated in three randomised placebo-controlled registration studies among patients who have three to eight migraine attacks a month.2,3,4 The majority (84%) of the participants in these three studies, entitled SAMURAI, SPARTAN and CENTURION, respectively, were women, with an average age of 42 years. They had an average of five migraine attacks a month. Their most bothersome migraine symptoms included photophobia, nausea and phonophobia. 

SAMURAI study

Study design

Patients included in the SAMURAI study were randomised to three groups which were treated with 100 mg or 200 mg lasmiditan or placebo. Patients with coronary heart disease, clinically relevant arrhythmia or untreated hypertension were excluded. The primary outcome measure was being free of pain 2 hours after taking 200 mg lasmiditan. The main secondary outcome measures were being free of pain 2 hours after taking 100 mg lasmiditan and the disappearance of the most bothersome symptom (MBS) of migraine after 2 hours.2

Results

A total of 2231 patients were randomised, 1856 of whom actually took the drug. They were divided over a lasmiditan 100-mg group (630 patients), a lasmiditan 200 mg group (609 patients) and a placebo group (617 patients). Of these patients, 77.9% had not only migraine but also at least one cardiovascular risk factor. The outcomes were determined in the modified intention-to-treat (mITT) population (1545 patients). The mITT consisted of the participants who had taken the medication within 4 hours after the start of a moderately to highly intense migraine attack and who had entered at least one efficacy item in their electronic diary. In the lasmiditan 200 mg group, 167 of the 518 patients (32.2%) were free of pain 2 hours after taking the drug (the primary outcome measure), compared to 80 of the 524 patients (15.3%) in the placebo group (odds ratio [OR] 2.6 [95% confidence interval (CI) 2.0 to 3.6]; NNT = 6). An overview of all results is presented in table 1 and table 2.

SPARTAN study

The SPARTAN study involved patients in four groups being treated with 50 mg, 100 mg or 200 mg lasmiditan or placebo. Unlike the SAMURAI study, this study did not exclude patients with a coronary heart disease, clinically relevant arrhythmia or untreated hypertension or patients with a cardiovascular risk factor (age, cholesterol, systolic blood pressure, diabetes or smoking). The primary outcome measures were being free of pain after 2 hours and the resolution of the most bothersome symptom of migraine after 2 hours.3

Results

A total of 2869 patients were randomised, 2583 of whom had taken a tablet. They were treated with lasmiditan 50 mg (654 patients), lasmiditan 100 mg (635 patients), lasmiditan 200 mg (649 patients) or placebo (645 patients). Almost 80% had a cardiovascular risk factor, and 6% had a cardiovascular disorder. The results were determined in the mITT population (2156 patients). In the lasmiditan 50 mg group, 159 of the 556 patients (28.6%) were free of pain 2 hours after taking the drug, compared to 115 of the 540 patients (21.3%) in the placebo group (OR 1.5 [95% CI 1.1 to 1.9]; NNT = 14). The corresponding figures for the lasmiditan 100 mg group were 167 of the 532 patients (31.4%; OR 1.7 [1.3 to 2.2]; NNT = 10) and for the lasmiditan 200 mg group 205 of the 528 patients (38.8%; OR 2.3 [1.8 to 3.1]; NNT = 6). 

CENTURION study

Study design

The CENTURION study was designed to assess the efficacy of lasmiditan across four migraine attacks, rather than just one, as was done in the SAMURAI and SPARTAN studies. Migraine patients, including those with a cardiovascular risk factor or disorder, were randomised to a group treated with 100 mg lasmiditan, one treated with 200 mg lasmiditan or a control group. The control group received a placebo, and for the third or fourth attack lasmiditan 50 mg instead of the placebo. The two primary outcome measures were being free of pain 2 hours after the first migraine attack and being free of pain after 2 hours in at least two out of three migraine attacks. One of the secondary outcome measures was the resolution of the most bothersome migraine symptom after 2 hours.4

Results

A total of 1613 patients were randomised, 1296 of whom treated the first migraine attack in accordance with protocol. 419 patients received 100 mg lasmiditan, 434 patients 200 mg lasmiditan and 443 were randomised to the control group. Of the participating patients, 59% had a cardiovascular disorder or risk factor. The numbers of patients who were free of pain after 2 hours were 108 of the 419 patients (25.8%) in the lasmiditan 100 mg group (OR 3.8 [95% CI 2.6 to 5.7]; NNT = 6) and 127 of the 434 patients (29.3%) in the lasmiditan 200 mg group (OR 4.6 [3.1 to 6.8]; NNT = 5), compared to 37 of the 443 patients (8.4%) in the placebo group. The CENTURION study also showed that the percentage of patients who were free of pain 2 hours after two out of their three migraine attacks was significantly higher in the lasmiditan 100 mg group (49 of the 340 patients [14.4%]; OR 3.8 [2.1 to 6.8]) and the lasmiditan 200 mg group (82 of the 336 patients [24.4%]; OR 7.2 [4.1 to 12.7]) than in the placebo group (16 of the 373 patients [4.3%]).

Table 1. Percentage of patients free of pain after 2 hours in the SAMURAI, SPARTAN and CENTURION studies

Free of pain after 2 hours

Lasmiditan 50 mg OR (95% CI)

Lasmiditan 100 mg OR (95% CI)

Lasmiditan 200 mg OR (95% CI)

Placebo

NNT Lasmiditan 100 mg

NNT Lasmiditan 200 mg

SAMURAI

-

28.2%

 2.2 (1.6-3.0)

32.2%

2.6 (2.0-3.6)

15.3%

8

6

SPARTAN

28.6%

1.5 (1.1-1.9)

31.4%

1.7 (1.3-2.2)

38.8%

2.3 (1.8-3.1)

21.3%

 10

6

CENTURION

-

25.8%

3.8 (2.6-5.7)

29.3%

4.6 (3.1-6.8)

8.4%

6

5

CBI: confidence interval, NNT: number needed to treat, OR: odds ratio

Table 2. Percentage of patients free of their most bothersome symptom (MBS) of migraine after 2 hours in the SAMURAI, SPARTAN and CENTURION studies

Free of MBS after 2 hours

Lasmiditan 50 mg OR (95% CI)

Lasmiditan 100 mg OR (95% CI)

Lasmiditan 200 mg OR (95% CI)

Placebo

SAMURAI

-

40.9%

1.7 (1.3-2.2)

40.7%

1.6 (1.3-2.1)

29.5%

SPARTAN

40.8%

1.4 (1.1-1.8)

44.2%

1.6 (1.2-2.0)

48.7%

1.9 (1.4-2.4)

33.5%

CENTURION

-

40.4%

1.7 (1.3-2,4)

39.0%

1.6 (1.2-2.2)

28.0%

CI: confidence interval, OR: odds ratio

Odds ratio or relative risk?

It is common practice in randomised placebo-controlled trials to calculate the relative risk (RR) of the intervention.5 The authors of the lasmiditan studies opted for determining the odds ratio (OR). Since the effect size of lasmiditan is relatively large (about 30%), calculating the OR yields a higher value than the RR. This results in a more favourable representation of the effect of lasmiditan. The authors do not offer an argument for using OR instead of RR. 


A network meta-analysis discussed previously in Ge-Bu compared lasmiditan with the triptans, such as the most frequently prescribed sumatriptan and rizatriptan, as well as the small-molecule CGRP antagonists, such as rimegepant.6,1 This network meta-analysis also included four studies of lasmiditan, a proof of concept trial, a phase 2 study and the SAMURAI and SPARTAN studies. 

Results

Table 3 shows the odds ratios for the primary outcome measure, i.e. being free of pain after 2 hours, for lasmiditan, sumatriptan, rizatriptan and rimegepant, compared to placebo and compared to lasmiditan 100 mg. 

Table 3. Study results for the primary outcome measure of being free of pain after 2 hours

Migraine drug

Free of pain after 2 hours OR (95% CI) compared to placebo

Free of pain after 2 hours OR (95% CI) compared to lasmiditan 100 mg

Lasmiditan 50 mg

1.62 (1.13-2.34)

0.86 (0.57-1.30) ns

Lasmiditan 100 mg

1.91 (1.42-2.57)

-

Lasmiditan 200 mg

2.52 (1.87-3.38)

No data

Sumatriptan 50 mg

3.46 (2.83-4.23)

1.93 (1.33-2.80)

Sumatriptan 100 mg

4.37 (3.57-5.36)

2.48 (1.71-3.59)

Rizatriptan 10 mg

4.78 (3.79-6.01)

2.55 (1.68-3.87)

Rimegepant 75 mg

1.79 (1.37-2.33)

1.25 (0.95-1.64) ns

OR: odds ratio, CI: confidence interval, ns: non-significant

The odds ratios for the primary outcome measure of being free of pain after 2 hours, compared to placebo, are statistically significantly higher than 1. This implies that the probability of a patient perceiving no more pain 2 hours after taking a migraine drug is significantly greater than after taking a placebo. The indirect comparison with lasmiditan 100 mg shows that there is no significant difference regarding the probability of being pain-free 2 hours with lasmiditan 50 mg or rimegepant 75 mg. The probability of sumatriptan and rizatriptan being effective is significantly higher than that of lasmiditan, but this conclusion is also based on an indirect comparison.


Study design

The SAMURAI, SPARTAN and CENTURION studies did not use the occurrence of adverse events as an outcome measure, but did record these adverse events. The open-label GLADIATOR follow-up study investigated the long-term adverse events of lasmiditan.7,8,9 The network meta-analysis studied the number of adverse events as a secondary outcome measure.6

The open-label GLADIATOR study included patients from the SAMURAI and SPARTAN studies, who were randomised to 100 mg or 200 mg lasmiditan and were followed for one year. The primary goal was to assess the safety of lasmiditan and to find out what adverse events arise from its long-term use.7,8,9 

Results

The GLADIATOR study randomised 2171 patients, and 2030 patients from this cohort had treated at least one migraine attack with 100 mg lasmiditan (991 patients) or 200 mg (1039 patients). A total of 19,879 migraine attacks were treated. The majority of the patients were women (85%), with an average age of 43 years. Of these patients, 82% had at least one cardiovascular risk factor. The study had a high dropout rate (52%). The main reasons for discontinuing participation in the study were the burden of keeping up an electronic diary every day (22%) and the adverse events experienced (13%). The numbers of adverse events that occurred in the lasmiditan 100-mg and 200-mg groups were combined. The most frequently reported adverse events were dizziness and somnolence (table 4). Table 4 also shows the cardiovascular adverse events; the most common of these were palpitations.7,8,9 

Table 4. Most frequent adverse events and cardiovascular adverse events when using lasmiditan 100 or 200 mg

Adverse events

Dizziness (placebo) %

Somnolence (placebo) %

Cardiovascular (placebo) %

SAMURAI

14.4 (3.4)

5.5 (2.3)

0.7 (0.3)

SPARTAN

18.1 (2.5)

5.5 (2.0)

0.6 (0.2)

CENTURION

24.4 (4.6)

5.9 (1.4)

0

GLADIATOR

18.5

8.5

0


Network meta-analysis

Results regarding the number of adverse events found in the network meta-analysis are presented in table 5. 

Table 5. Odds ratios of the number of adverse events associated with the most frequently prescribed triptans and the new migraine drugs, compared with placebo

Migraine drug

OR (95% CI) adverse events vs. placebo

Lasmiditan 50 mg

2.95 (1.81-4.81)

Lasmiditan 100 mg

4.27 (2.84-6.44)

Lasmiditan 200 mg

5.66 (3.71-8.63)

Sumatriptan 50 mg

1.77 (1.39-2.36)

Sumatriptan 100 mg

1.71 (1.32-2.22)

Rizatriptan 10 mg

1.89 (1.36-2.45)

Rimegepant 75 mg

1.25 (0.85-1.84) ns

OR: odds ratio, CI: confidence interval, ns: non-significant

The odds ratios for the number of adverse events associated with lasmiditan show a dose-dependent significant difference compared to placebo. Dizziness (14% to 24%) is the most frequently reported adverse event. It usually starts after 30 to 40 minutes and continues for 1.5 to 2 hours. Another frequently reported event is somnolence (5.5% to 8.5%), which is why patients are not allowed to drive a vehicle for 8 hours after taking the drug. The great majority of the adverse events are mild to moderate and are of a transient nature. In addition, the incidence of adverse events recorded in the studies appears to decrease with long-term use. This might result from patients who experience an adverse event discontinuing their participation in the study. Among patients using lasmiditan 100 mg for five or more migraine attacks, the adverse events decreased from 20.5% at the first attack to 10.9% at the fifth attack. The corresponding figures for lasmiditan 200 mg were 27.5% and 14.5%, respectively.[8][Brandes 2020] Of all the treatments investigated in the network meta-analysis, adverse events are most likely to occur with lasmiditan. Hardly any cardiovascular problems were reported.10,11,6


Information about the prevalence, symptoms and pathophysiology of migraine can be found in the Ge-Bu article ‘Nieuwe geneesmiddelen voor migraineprofylaxe’ (New drugs for migraine prophylaxis).12 Further background information about the current treatment of migraine attacks and the conduct of migraine research has been published in the Ge-Bu article ‘Nieuw geneesmiddel: rimegepant bij migraineaanvallen’ (New drug: Rimegepant for migraine attacks’.1

Mode of action 

It still remains unclear why a migrain attack starts. What is known by now is that the ‘calcitonin gene-related peptide’ (CGRP) concentration is increased during a migraine attack. CGRP causes neurogenic inflammation (dilatation of intracranial arteries and extravasation) and activates nociceptors on the trigeminal nerve. Via transmission of impulses in central and peripheral neurons, this causes the perception of pain in migraine. The presynaptic membrane in the synapses of these neurons contains 5HT1F receptors. Activation of these receptors by serotonin or an 5HT1F agonist like lasmiditan inhibits the release of CGRP.13 

The triptans are 5HT1B/1D agonists, but they also act as non-selective agonists for the 5HT1F receptor. In addition to inhibition of the CGRP release, the migraine-mitigating effect is also achieved by activation of the 5HT1B receptor in the intracranial blood vessels, resulting in vasoconstriction. The smooth muscles of the coronary vessels also feature 5HT1B receptors. Triptans act as agonistics on these receptors, which also results in vasoconstriction. This is why triptans are contraindicated for patients with cardiovascular disorders like a history of myocardial infarction. The high selectivity of lasmiditan for the 5HT1F receptor means that there is no contraindication for this drug for patients with cardiovascular disorders.13,10

Lasmiditan

Lasmiditan is a lipophilic, selective 5HT1F receptor agonist with a more than 440 times higher affinity fort he 5HT1F receptor than for the 5HT1B and 5HT1D receptors.10,13 It has been authorised for the ‘acute treatment of the headache phase of a migraine attack, with or without aura, in adults’.14 The recommended starting dosage is 100 mg, which can, if necessary, be reduced to 50 mg or increased to 200 mg. The maximum dosage is 200 mg per 24 hours. The patient is not allowed to drive a vehicle for 8 hours after taking the drug.14

Lasmiditan (Rayvow®) is a film-coated tablet, available in strengths of 50 mg, 100 mg and 200 mg. After oral intake, it is rapidly absorbed and crosses the blood-brain barrier. The peak plasma concentration is reached after 1.8 hours. The drug is mostly metabolised by ketone reduction to pharmacologically inactive metabolites. Lasmiditan is not metabolised via cytochrome P450. Its half-life is 5.7 hours.14 Its price is not yet known. Lasmiditan has not yet been included in migraine guidelines. 

Study details

SAMURAI 2
Study name: SAMURAI (A Study of two doses of lAsMiditan (100 mg and 200 mg) compared to placebo in the acUte treatment of migRAIne)
Design: randomised, double-blind, placebo-controlled phase 3 study carried out at multiple research centres in the United States
Inclusion criteria: patients aged over 18 years who have had migraine for more than 1 year, have three to eight migraine attacks of moderate to high intensity per month; stable migraine prophylaxis allowed
Main exclusion criterion: known cardiovascular disorder (risk factors for such disorders were not an exclusion criterion)
Intervention: lasmiditan 200-mg or 100-mg tablet versus placebo used for one migraine attack 
Primary endpoint and duration: free of pain 2 hours after using lasmiditan 200 mg; 8 weeks
Intended number of patients and power: 1710 patients; over 90% power with 2.5% one-sided significance
Randomisation: 1:1:1, using interactive response technology and stratified for use or not of concomitant preventive medication
Blinding: double-blind
Population analysed: modified intention-to-treat (mITT, i.e. patients who had taken the medication within 4 hours after the start of a migraine attack and had entered at least one efficacy item in their electronic diary)
Number of patients included and patient characteristics: 2231 randomised, 1856 of whom had taken a dose, 83,6% women, average age 42.0 years, average of 5.1 migraine attacks per month, mITT 1545 patients 
Trial registration: NCT02439320
Funding: CoLucid Pharmaceuticals (Eli Lilly)
Conflicts of interest: 6 of the 6 authors
SPARTAN 3
Study name: SPARTAN (A Study of three doses of lasmiditan (50 mg, 100 mg and 200 mg) compared to Placebo in the Acute tReaTment of migrAiNe)
Design: randomised, double-blind, placebo-controlled phase 3 study, carried out at multiple research centres in the United States, the United Kingdom and Germany
Inclusion criteria: patients aged over 18 years who have had migraine for more than 1 year, have three to eight migraine attacks of moderate to high intensity per month; stable migraine prophylaxis allowed, coronary heart disease, clinically relevant arrhythmia or untreated hypertension or cardiovascular risk factor allowed
Intervention: lasmiditan 200 mg, 100-mg or 50-mg tablet versus placebo used for one migraine attack
Primary endpoints and duration: free of pain after 2 hours and free of the most bothersome migraine symptom after 2 hours; 8 weeks
Intended number of patients and power: 2280 patients; over 90% power with 2.5% one-sided significance
Randomisation: 1:1:1:1, using interactive response technology and stratified for use or not of concomitant preventive medication
Blinding: double-blind
Population analysed: modified intention-to-treat (i.e. patients who had taken the medication within 4 hours after the start of a migraine attack and had entered at least one efficacy item in the electronic diary)
Number of patients included and patient characteristics: 2869 randomised, 2583 of whom had taken a dose, 84.2% women, average age 42.7 years, average of 5.3 migraine attacks per month, mITT 2156 patients 
Trial registration: NCT02605174
Funding: CoLucid Pharmaceuticals (Eli Lilly)
Conflicts of interest: 7 of the 7 authors
CENTURION 4
Study name: CENTURION (acronym not explained)
Design: randomised double-blind placebo-controlled phase 3 study carried out at multiple research centres in Europe, North-America and Asia 
Inclusion criteria: patients aged over 18 years who have had migraine for more than 1 year, have three to eight migraine attacks of moderate to high intensity per month; stable migraine prophylaxis allowed, coronary heart disease, clinically relevant arrhythmia or untreated hypertension or cardiovascular risk factor allowed 
Intervention: for four migraine attacks: lasmiditan 200-mg or 100-mg tablet versus placebo (for three attacks, and 50 mg lasmiditan for the third or fourth attack, 1:1) 
Primary endpoints and duration: free of pain 2 hours after the first migraine attack and free of pain after 2 hours with at least two of the three migraine attacks; 4 months
Intended number of patients and power: not reported; over 90% power
Randomisation: 1:1:1, using interactive response technology and stratification by country
Blinding: double-blind
Population analysed: intention-to-treat (patients who had taken at least one dose after a migraine attack involving at least mild pain and had then entered at least one efficacy item in their electronic diary within 2 hours)
Number of patients included and patient characteristics: 1613 randomised, 1471 of whom had taken a dose, 84% women, average age 42 years, average of 4.9 migraine attacks per month 
Trial registration: NCT03670810
Funding: Eli Lilly
Conflicts of interest: 10 of the 10 authors
GLADIATOR 7,8
Study name: GLADIATOR (an open-label, lonG-term, safety study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of migRaine)
Design: randomised open-label phase 3 study carried out in multiple research centres in the United States, United Kingdom and Germany 
Inclusion criteria: patients from the SAMURAI or SPARTAN study
Intervention: treatment with lasmiditan 100-mg or 200-mg tablet at each migraine attack with moderate to severe pain, for 1 year 
Primary endpoint and duration: number and nature of the long-term adverse effects; 1 year
Intended number of patients and power: at least 300 patients with at least two migraine attacks per month over 6 months, and at least 100 patients with at least two migraine attacks per months over 12 months; no power calculation reported
Randomisation: 1:1, stratified by use of migraine prophylaxis
Blinding: open-label
Population analysed: safety population (patients who had used at least one dose of lasmiditan)
Number of patients included and patient characteristics: total of 2171 (2030 in the safety population), 85.3% women, average age 43.3 years, average of 5.2 migraine attacks per month 
Trial registration: NCT02565186
Funding: Eli Lilly
Conflicts of interest: 8 of the 8 authors

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Authors

  • Erik P. Schwarz