Research Outlines Safety, Tolerability of Lasmiditan for Migraine

Abstracts presented at this year’s Migraine Trust International Symposium (MTIS) show how investigators analyzed the efficacy, tolerability, and safety profile of lasmiditan (Reyvow), a prescription drug used to treat migraine attacks. The virtual conference took place from October 3-9, 2020.

Lasmiditan in Pediatric Patients

Currently, lasmiditan is only indicated for use in adults who suffer migraine with or without aura. However, results from a phase 1 open-label single-dose pharmacokinetic (PK) study found safety and tolerability of the treatment were similar among patients 6 to <18 years compared with that observed in adults¹. In addition, the PK results supported weight-based doing of lasmiditan in pediatric patients.

Patients were divided into cohorts based on weight and received different doses of the selective serotonin receptor agonist. Cohort 1 (n = 11) comprised individuals weighing 15 to ≤40 kg who received 100 mg of lasmiditan. Those in cohort 2 (n = 7) weighed >40 to ≤55 k, and received a dose of 200 mg. “This weight-based dosing was expected to elicit exposures in pediatric patients comparable to adults receiving a 200-mg dose,” the researchers said. Patients were followed up with around 14 days after dosing, and 1 patient discontinued due to adverse events (AEs).

No deaths or serious AEs were reported, while frequency and severity of AEs (somnolence, dizziness, and fatigue) were similar to those experienced by adults. Time courses of lasmiditan concentrations were also similar between cohorts 1 and 2. Plasma concentrations peaked at a median C_max time of 1.5 to 2.0 hours post dose and then declined, with a geometric mean terminal half-life of approximately 4.0 hours, similar to adults, the researchers said. They concluded the findings support further investigation of lasmiditan as a potential treatment for migraine in pediatric populations.

Tolerability of Lasmiditan in Elderly Migraineurs

An additional abstract included a pooled analysis of 2 phase 3 studies of lasmiditan evaluating the treatment’s tolerability in elderly (aged ≥65 years) and nonelderly patients.² Specifically, the researchers investigated treatment-emergent AEs (TEAEs) that occurred within 48 hours of the first does in each cohort of patients.

Results from 2 randomized, double-blind, controlled studies (SAMURAI and SPARTAN) showed the overall incidence of TEAEs with lasmiditan was similar in elderly and nonelderly migraineurs, although numerical differences in the incidence of some specific TEAEs were found.

In each study, adults took placebo or lasmiditan 50, 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. A total of 3177 lasmiditan-treated patients were included in the analysis, among which 132 (4.2%) were elderly. From this overall group, 1262 received a placebo and 54 (4.3%) of them were elderly. Overall, 34.8% of elderly patients experienced at least 1 TEAE compared with 35.7% of nonelderly patients.

“No significant treatment-by-age subgroup interactions were seen in patients who reported at least 1 TEAE overall or for any individual TEAE,” the researchers said. Notably, 18.9% of elderly lasmiditan-treated patients experienced dizziness compared with 14.5% of nonelderly patients, and 2.3% of elderly patients experienced vertigo compared with 0.5% of younger patients. “However, no trend was identified, nor any safety signals observed in the elderly age group,” the researchers concluded.

Cardiovascular Safety of Lasmiditan

An interim analysis of results from the phase 3 GLADIATOR study found no vasoconstriction-related cardiovascular (CV) events occurred during the treatment-emergent period of lasmiditan, while CV safety of the treatment was generally consistent with data from single-attack studies.³

The researchers randomized GLADIATOR patients 1:1 to either receive lasmiditan 100/200 mg taken as 1 dose (within 4 hours of moderate/severe pain onset) or 2 doses (within 2-24 hours). All patients had previously participated in phase 3 placebo-controlled, single-attack lasmiditan studies that included participants with CV risk factors such as coronary artery disease, arrhythmia, or uncontrolled hypertension.

“CV adverse event rates were calculated for 3 time periods—treatment-emergent (<48 hours post dose), intermediate (48 hours-1 week post dose), remote (>1 week post dose)—as some CV events were likely not reported as treatment emergent/were identified later,” the researchers wrote. In addition, any CV events that occurred more than 48 hours post dose were analyzed to determine whether they increased in treatment-emergent/intermediate periods compared with the remote period.

A total of 1978 patients received ≥1 dose of lasmiditan, and 19,058 migraine attacks were treated. The median study duration was 288 days. The researchers found:

• 81% patients had ≥1 CV risk factor, 0.3% had coronary artery disease, and 35% had low high-density lipoprotein cholesterol
• No vasoconstriction-related CV events occurred in the treatment-emergent period; such events were rarely observed (between 1­-3 occurred, all in remote period, limiting clinical interpretation)
• Treatment-related CV events (palpitations, tachycardia) were more frequent in the treatment-emergent period versus the intermediate and remote periods

References

1. Tsai M, Nery ESM, Kerr L, et al. A phase 1, open-label, single-dose pharmacokinetic study of lasmiditan in paediatric patients with migraine. Presented at: Migraine Trust International Symposium; October 3-9, 2020. Abstract MTV20-DP-029. https://bit.ly/2SsCQ71

2. Buchanan A, Martin V, Ahmed Z, et al. Tolerability of lasmiditan in elderly patients with migraine. Presented at: Migraine Trust International Symposium; October 3-9, 2020. Abstract MTV20-DP-040. https://bit.ly/2GpSGwM​

3. Buchanan A, Baygani SK, Rosen N, Matthew PG, Hochstelter H, Khanna R. Long-term cardiovascular safety of lasmiditan for the acute treatment of migraine for up to one year: interim results of an open-label phase 3 study (GLADIATOR). Presented at: Migraine Trust International Symposium; October 3-9, 2020. Abstract MTV20-DP-039. https://bit.ly/2SqbluU