Short-term efficacy and safety of lasmiditan, a novel 5-HT_1F receptor agonist, for the acute treatment of migraine: a systematic review and meta-analysis

Migraine is a common neurological disease that was ranked by the Lancet Global Burden of Disease Study as the second highest cause of disability in 328 diseases from 195 countries between 1990 and 2016, and is becoming a larger component of the global burden of disease [1]. Statistically, 45.1 million of total years lived with disability are suffered from migraine [1], which has a significant impact on quality of life and increased use of health resources [2, 3]. It is characterized by moderate-severe, unilateral, throbbing headache attacks lasting from 4 to 72 h, accompanied by additional symptoms such as nausea, vomiting, phonophobia, and/or photophobia [4]. However, the exact etiology and pathogenesis of migraine currently is unclear. Thus, to find a safety, effective and highly specific medication remains a challenge and warrants further research.

In general, the choice of acute treatment is based mainly on two classes of medicines: nonspecific (analgesics and nonsteroidal antiinflammatory drugs, NSAIDs) and specific drugs (triptans and ergot derivatives) [5]. The triptans, regarded as the gold standard in the migraine therapy, are a class of selective and effective 5-hydroxytryptamine (HT)_1B/1D receptor agonists that have replaced ergot derivatives. However, 30% ~ 40% of treated patients do not respond to triptans that are also endowed with the risk of serious cardiovascular adverse events caused by vasoconstriction yielded by 5-HT_1B receptor activation [6, 7]. Therefore, a new acute therapy for migraine is urgently needed, especially for those patients unable to achieve optimal outcomes with current therapies.

Lasmiditan, also known as COL-144 and LY573144, is a novel 5-HT receptor agonist with high-affinity and selectivity for the 5-HT_1F receptor, which acts on the trigeminal system without causing vasoconstriction because of its low affinity for 5-HT_1B receptors [8]. Representing a new class of migraine medications, lasmiditan is believed to act both centrally and peripherally, and developed as an acute therapy for migraine to address significant unmet needs in patients with cardiovascular risk factors, those with stable cardiovascular disease, or patients who respond poorly to their current treatment.

The U.S. Food and Drug Administration approved lasmiditan for the acute treatment for migraine with or without aura in adults on 11 October 2019 [9]. Data from phase II and III studies showed significant efficacy and high incidence of treatment-emergent adverse reactions (TEAEs) of this molecule versus placebo in acute treatment for migraine. However, up to now, there was no systematic review that examined the efficacy and tolerability of lasmiditan. Therefore, in this paper, we performed this systematic review and meta-analysis to evaluate the safety and efficacy of lasmiditan in the treatment of acute migraine attacks.

With the growing knowledge of the pathogenesis on migraine, the expression of 5-HT_1F receptor mRNA in neurons of the trigeminal ganglia led to the suggestion that 5-HT_1F receptors could be a therapeutic target for migraine [20]. As expected, it became the potential new class of anti-migraine therapy with no vascular activity and the related issues on the vascular and neuronal aspects of migraine pathogenesis. So far two selective 5-HT_1F agonists, LY334370 and lasmiditan, have been studied in clinical trials for the acute treatment of migraine. LY334370 was efficient with a much higher rate of asthenia, dizziness, somnolence, and parestesia than placebo for attenuating migraine attacks through selective trigeminovascular neuronal inhibition [21]. Unfortunately, the LY334370 project withdrew because of toxicity in animals [22]. Admittedly, the efficacy of LY334370 and lasmiditan also proved that vasoconstriction was not essential for anti-migraine therapy.

The U.S. FDA approval was based on positive results from two pivotal phase III trials (SAMURAI and SPARTAN), in which lasmiditan signifcantly improved the proportions of patients achieving freedom from headache pain and freedom from the most bothersome symptoms (photophobia, phonophobia or nausea) compared with placebo [9]. The current study is the first meta-analysis, to the best of our knowledge, to evaluate the efficacy and safety of lasmiditan for the treatment of acute migraine attacks. The results suggested the use of lasmiditan (daily doses from ≤50 mg to 400 mg) for patients who had at least a 1-year history of disabling migraine with or without aura was associated with significantly more pain freedom and pain relief at 2 h. Furthermore, lasmiditan also showed benefits over placebo at 2 h in terms of the proportion of patients in global impression of change ratings and disability level ratings. The findings of this systematic review confirmed that lasmiditan was superior to placebo in relieving migraine, however, as feared earlier, there was some concern about the relatively high incidence of CNS-related AEs (especially dizziness, nausea, and fatigue) as the published reviews discussing by Peer C et al [23] and David K et al [24]. The CNS-related AEs were reported in all included studies, and remarkably increased with increasing doses compared with placebo. Most adverse events affected the CNS probably due to the drugs lipophilic structure which leads to high permeability through the blood brain barrier [25], which prompted that the future development of 5-HT_1F agonists could give more attention to the safety profile.

For the long-term efficacy and safety of lasmiditan, a phase III GLADIATOR study involved patients who had completed SPARTAN or SAMURAI [26], and received lasmiditan 100 mg or 200 mg to be used as their frst treatment (within 4 h of pain onset) for every new migraine attack with moderate to severe pain. The interim safety and efficacy results were consistent with the previous researches, which showed a benefit of lasmiditan for reducing both the headache pain and most bothersome symptoms of migraine attacks. It is interesting to note that TEAEs over time generally showed a decrease in the incidence of these events with subsequent treated migraine attacks, and no new serious safety findings were observed, with no deaths occurring and no other trends with regard to serious AEs reported during treatment with lasmiditan for up to 1 year. Despite the most frequently reported TEAEs were associated with the CNS, there were no serious accidents or injuries resulting from a CNS-related AEs during long-term intermittent treatment. Further research should be needed to support these results, and verify the efficacy and safety of lasmiditan.

Compared to previous studies [27, 28] aimed to summarize the evidence on lasmiditan for the acute treatment of migraine, this study provided a systematic and more detailed assessment on the efficacy and safety of lasmiditan. Indeed, this first meta-analysis covered a greater number of studies and larger sample size to obtain more precise estimates on the efficacy and safety. The results showed some new valuable information about lasmiditan. First, we proved that lasmiditan (daily doses from ≤50 mg to 400 mg) was effective for the acute treatment migraine with some dose-effect relationship. Then, we analyzed the safety profile of lasmiditan by comparing TEAEs across different doses, which appeared to be mostly dose-related in the increased risk. These more detailed findings will provide some references for clinical application of lasmiditan, specially for the subpopulation of patients with relative risk factors and/or disease.

This meta-analysis suggested that lasmiditan are effective for the acute treatment of migraine, however, with a higher incidence of CNS-related adverse reactions compared with placebo. It is critical to weigh the benefits against the risk of AEs in clinical application of lasmiditan. More long-term, open-label, multi-dose trials with larger sample sizes are needed before a definitive conclusion about the efficacy and safety of lasmiditan for migraine in the future.