Low incidence of CV AEs with lasmiditan in migraine

Cardiovascular (CV) event incidence was low among patients taking lasmiditan for migraine, according to interim analysis of the phase III GLADIATOR* study presented at AHS 2020.

The open-label GLADIATOR trial included individuals with migraine who had received lasmiditan 50, 100, or 200 mg, or placebo, in the double-blind, single-attack, phase III SPARTAN or SAMURAI** trials. They were re-randomized 1:1 to receive lasmiditan 100 or 200 mg, either as a single dose (within 4 hours of pain onset) or if required, two doses (2–24 hour interval; n=1,978). Eighty-one percent of SPARTAN and SAMURAI participants had CV risk factors. A total of 19,058 migraine attacks were treated over a median 288 days in GLADIATOR.

Overall, CV adverse event (AE) rate was low during all three time periods assessed (treatment-emergent [TE]: <48 hours post-dose; intermediate: 48 hours–1 week post-dose; remote: >1 week post-dose). Eight palpitation incidents occurred during the TE period (80.4 per 1,000 patient-years) and one in the remote period. There were two incidents each of increased heart rate in the TE and remote periods, and two incidents each of decreased heart rate and dyspnoea, both in the TE period.

There were three, two, and six incidents of increased blood pressure in the TE, intermediate, and remote periods, respectively, and three, nine, and 12 incidents of hypertension (34.6 and 15.4 per 1,000 patient-years in the latter two).

“Lasmiditan, a selective serotonin (5-HT) 1F receptor agonist, lacks the vasoconstrictive activity of other acute migraine treatments,” noted the researchers. In this analysis, vasoconstriction-related CV events (eg, angina) were rare, with none occurring in the TE period.

Dose-dependent outcomes

A separate analysis examined the effect of increasing or decreasing lasmiditan dose in GLADIATOR from SPARTAN/SAMURAI.

Two hours after the first lasmiditan dose in GLADIATOR, taken after the first migraine attack, more patients who received a higher dose than in SPARTAN/SAMURAI were pain-free. In contrast, a decrease in dose in GLADIATOR compared with SPARTAN/SAMURAI led to a lower percentage of patients who were pain-free. For example, 30 percent of patients who received lasmiditan 100 mg in SPARTAN/SAMURAI were pain-free after 2 hours; this increased to 36 percent among those who received 200 mg in GLADIATOR.

TEAE incidence – occurring within 48 hours of the first dose for the first migraine attack – tended to increase with an increased dose. For example, TEAE incidence was 15 percent in patients who received lasmiditan 50 mg in SPARTAN/SAMURAI and 22 percent upon increase to 100 mg in GLADIATOR and increased from 17 to 22 percent when dose increased from 50 to 200 mg. Likewise, a decrease in dose in GLADIATOR led to a decrease in TEAEs (from 29 to 18 percent when dose was reduced from 200 to 100 mg). TEAE incidence did not differ with an increase from 100 to 200 mg.

“[T]he study was designed to evaluate the safety and efficacy of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year [and] to help provide insights for clinicians in choosing the most appropriate dose for a patient,” said the researchers.

“Increasing the dose may result in improvement in efficacy (pain freedom at 2 hours) and an increase in AE reporting,” they noted.