By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first selective serotonin 1F (5-HT_1F) receptor agonist (“ditan”) for the acute treatment of migraine headaches. The drug’s selectivity may result in a safer cardiovascular profile than triptans. Lasmiditan is distributed as Reyvow.

INDICATIONS

Lasmiditan is indicated for the acute treatment of migraine with or without aura in adults.¹

DOSAGE

The recommended dose is 50 mg, 100 mg, or 200 mg taken orally as needed.¹ Lasmiditan is available as 50 mg and 100 mg tablets. No more than one dose should be taken in 24 hours.

POTENTIAL ADVANTAGES

Lasmiditan provides an alternative to the triptans for acute migraine. Due to the drug’s high affinity for the 1F receptor subtype and low affinity for the 1B receptor subtype, lasmiditan does not mediate significant vasoconstriction effects on cerebral or coronary vessels.²

POTENTIAL DISADVANTAGES

Lasmiditan is a central nervous system depressant.¹ Patients should not drive or operate machinery for at least eight hours after taking the drug. The most frequent (vs. placebo) adverse events include dizziness (9-17% vs. 3%), sedation (6-7% vs. 2%), paresthesia (3-9% vs. 2%), and fatigue (4-6% vs. 1%).¹ These events were mild or moderate in severity and self-limited.³

Serotonin syndrome has been reported with lasmiditan in clinical trials.¹ There is a low likelihood (approximately 1%) that lasmiditan could produce euphoria and hallucination. The drug has been approved but is awaiting DEA scheduling before it is made available in the United States. Lasmiditan is an inhibitor of P-gp and breast cancer-resistant protein. Concomitant use with substrates of these transporters should be avoided.¹

COMMENTS

The efficacy of lasmiditan was evaluated in two randomized, double-blind, placebo-controlled trials.^1,4,5 Investigators enrolled subjects with a history of migraine with and without aura. Study 1 subjects were randomized to lasmiditan 100 mg, 200 mg, or placebo. In study 2, subjects were randomized to 50 mg, 100 mg, 200 mg, or placebo. Efficacy assessments were conducted based on treating migraines with moderate to severe pain within four hours of onset of the attack.

The primary efficacy endpoint was the proportion of subjects achieving headache pain freedom and Most Bothersome Symptoms (MBS) at two hours after the first dose of lasmiditan compared to placebo. Pain freedom was defined as a reduction of moderate or severe headache pain to no pain, and MBS was defined as the absence of self-identified symptoms such as photophobia, phonophobia, or nausea. The population for analysis averaged 520 subjects per group.

The percent achieving pain freedom at two hours ranged from 28% to 39% for lasmiditan, compared to 15% to 21% for placebo. MBS success ranged from 41% to 49% compared to 30% to 33% for placebo. Response rates and the time course for onset generally were dose-dependent (i.e., higher dose, greater response rate, and earlier onset of response). Treatment effectiveness was not affected by taking preventive drugs.⁷ There is no clear benefit of a second dose as a rescue treatment.⁸

In a post-hoc, pooled analysis of these trials, efficacy and safety were evaluated in subjects with one or more cardiovascular risk factors (n = 3,500).⁶ The efficacy of lasmiditan was not affected by the degree of CV risk. Treatment-emergent cardiovascular adverse events were numerically higher for lasmiditan than placebo, but not statistically significant (0.9% vs. 0.4%). The most common cardiovascular adverse events were palpitation, tachycardia, and increased heart rate.

CLINICAL IMPLICATIONS

Triptans are considered first-line treatment for acute migraines in adults.⁹ However, generally, triptans are 5-HT_1B/1D receptor agonists, which mediate vasoconstriction, and many also are 5-HT_1F receptor agonists.² Lasmiditan is the first “non-vasoconstrictive,” central nervous system-penetrating, selective 5-HT_1F receptor agonist for treating acute migraine. It may offer a potentially safer alternative to triptans, particularly in patients with cardiovascular history or risk factors (for whom triptans are contraindicated) or those nonresponsive to triptans. Availability is pending DEA action on scheduling.

REFERENCES

1. Eli Lilly and Company. Reyvow Prescribing Information, October 2019. Available at: http://bit.ly/34H3cq4. Accessed Nov. 8, 2019.
2. Rubio-Beltrán E, Labastida-Ramírez A, Villalón CM, MaassenVanDenBrink A. Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol Ther 2018;186:88-97.
3. Krege JH, Rizzoli PB, Liffick E, et al. Safety findings from phase 3 lasmiditan studies for acute treatment of migraine: Results from SAMURAI and SPARTAN. Cephalalgia 2019;39:957-966.
4. Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain 2019;142:1894-1904.
5. Kuca B, Silberstein SD, Wietecha L, et al. Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study. Neurology 2018;91:e2222-e2232.
6. Shapiro RE, Hochstetler HM, Dennehy EB, et al. Lasmiditan for acute treatment of migraine in patients with cardiovascular risk factors: post-hoc analysis of pooled results from 2 randomized, double-blind, placebo-controlled, phase 3 trials. J Headache Pain 2019;20:90.
7. Loo LS, Ailani J, Schim J, et al. Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: Findings from SAMURAI and SPARTAN, two randomized phase 3 trials. J Headache Pain 2019;20:84.
8. Loo LS, Plato BM, Turner IM, et al. Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: Findings from the phase 3 trials (SAMURAI and SPARTAN). BMC Neurol 2019;19:191.
9. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: The American Headache Society evidence assessment of migraine pharmacotherapies. Headache 2015;55:3-20.