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

Migraine is a neurologic disease characterized by severe, intermittent headache attacks with associated symptoms including nausea, vomiting, phonophobia, and photophobia that can be chronic and disabling [1]. The disease can interfere significantly with occupational, educational, household, family, and social responsibilities [2]. It is the second largest cause of years lost to disability [3].

Migraine is an independent risk factor for cardiovascular (CV) disease [4, 5] and is associated with a number of CV events, including ischemic stroke, transient ischemic attack, ischemic heart disease, and myocardial infarction, as well as increased morbidity and mortality [6‐11]. Although both migraine with and without aura are known to be associated with CV disease, these associations are more significant in patients with migraine with aura [5, 11‐13]. A recent meta-analysis demonstrated that the presence of aura significantly affects the risk of stroke (adjusted hazard ratio [aHR] aura 1.56; 95% confidence interval [CI] 1.30–1.87 vs. aHR no aura 1.11; 95% CI 0.94–1.31; p_interaction = 0.01) [5]. In addition, statistical heterogeneity was lower for all CV and cerebrovascular outcomes when results were stratified by the presence of aura [5]. Existing options for acute migraine treatment may be contraindicated in patients with CV history or risk [14, 15]. For example, nonsteroidal anti-inflammatory drugs are associated with an increased risk of CV, thrombotic, and upper gastrointestinal events [16‐18]. Due to vasoconstriction associated with the 5-hydroxytryptamine receptor 1B (5-HT_1B) activity, triptans are contraindicated in patients with ischemic coronary artery disease (CAD), coronary artery vasospasm, Wolff-Parkinson-White syndrome, peripheral vascular disease, ischemic bowel disease, and uncontrolled hypertension and in patients with a history of cerebrovascular ischemic events [19‐25]. Approximately 2 million women and 665,000 men in the United States have episodic migraine and a history of ≥1 CV event, condition, or procedure that may limit the use of triptans [26].

The desire to discover effective migraine treatments without vasoconstrictive properties led to the development of selective 5-hydroxytryptamine receptor 1F (5-HT_1F) agonists and other molecules [27‐33]. Lasmiditan selectively targets 5-HT_1F receptors on neurons in the central and peripheral trigeminal system, decreasing neuropeptide release and inhibiting pain pathways, including the trigeminal nerve [34, 35]. Preclinical studies have demonstrated that messenger RNA for 5-HT_1F receptors is highly expressed in human middle cerebral arteries [36] and human coronary arteries [37], but in vitro studies suggest that 5-HT_1F receptors do not mediate significant vasoconstriction effects in human cerebral or coronary vessels [37‐40]. Data from nonclinical animal and in vitro studies indicate that lasmiditan does not cause vasoconstriction in coronary, carotid, and internal mammary arteries [35, 41, 42].

The efficacy and safety of oral lasmiditan in the acute treatment of migraine attacks have been demonstrated in 2 randomized, double-blind, placebo-controlled, Phase 3 studies, SAMURAI and SPARTAN [43, 44]. This publication reports the pooled safety and efficacy of lasmiditan in a subpopulation of patients with CV risk factors (CVRFs).

Options for acute treatment of migraine attacks are limited in patients with prior history of CV and cerebrovascular diseases and CVRFs, which are a significant percentage of the migraine patient population especially with increasing age. Migraine itself is a risk factor for CV disease and CV events, and these associations are more significant in patients with aura. In addition, patients may have other risk factors including hypertension and diabetes. Finding a treatment that does not exacerbate these risks could improve safety over existing treatments such as triptans, which are contraindicated in patients with CV history or risk.

Lasmiditan is a centrally penetrant, non-vasoconstrictive, selective 5-HT_1F receptor agonist being developed for the acute treatment of migraine. Lasmiditan inhibits trigeminovascular nociception by activation of 5-HT_1F receptors [36]. The purpose of this analysis was to examine the safety and efficacy of lasmiditan in patients with CVRFs from two Phase 3 studies, SAMURAI and SPARTAN.

This pooled Phase 3 population included a well-balanced population across lasmiditan- and placebo-treated patients with respect to the presence of baseline CCRH (approximately 20%) and 1 or more CVRFs (79% with ≥1, 41% with ≥2, and 15% with ≥3 CVRFs) in addition to their migraine history. The rates of risk factors appear to be generally representative of the overall migraine population; for example, in the American Migraine Prevalence and Prevention study, patients with migraine with ≥1, ≥ 2, and ≥ 3 risk factors are numbered 70%, 40%, and 19%, respectively [26].

Headache pain freedom and MBS freedom at 2 h examined by subgroups of 0 or 1 compared to ≥2 CVRFs were not significantly different in any dose regimen of lasmiditan, indicating that lasmiditan efficacy is not affected by the presence of CVRFs. In general, a small number of CV AEs including TEAEs were reported in the placebo-controlled studies. There were no ischemic CV TEAEs reported. There was no statistical difference between placebo and lasmiditan in the frequency of likely CV TEAEs either in the absence or presence of CVRFs at either an SMQ or an individual PT level. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations. The subjective AE descriptor palpitations (which includes tachycardia and increased heart rate) is considered an adverse drug reaction with lasmiditan; however, the reported incidence was < 1%. Since concomitant vital signs or ECGs were not recorded during these symptoms, it is not known whether they were associated with true increases or decreases in heart rate. In clinical pharmacology studies using objective measures, lasmiditan was associated with decreases in heart rate of − 5 to − 10 beats per minute following doses of 50 to 200 mg (data unpublished). Additionally, the symptom of palpitations could reflect CV changes or actually wholly non-cardiac sources, such as anxiety or panic. In most of the cases, there was a report of other concurrent TEAEs, mostly neurological. Although the mechanism of action is unknown for which lasmiditan may cause palpitations or a decrease in heart rate, caution is advised for concomitant use of lasmiditan with other drugs that may lower heart rate.

Limitations of these analyses include the small sample size in patients with CCRH, the single migraine attack design, the medical review of potential CV AEs was performed by unblinded Lilly physicians, and the lack of vital sign and ECG measurements around the time of dosing. Additionally, potential rare events require large sample sizes and longer duration of observation than was available in these single-attack studies. Despite the limitations, these studies provide insight into the efficacy and safety of lasmiditan in patients with CVRFs. Results of multiple-attack studies (such as NCT03670810 and NCT02565186) will provide insight into efficacy and safety over time.

We found that the proportion of patients achieving headache pain freedom and MBS freedom at 2 h were similar within subgroups of patients with 0 or 1 CVRF(s) and with ≥2 CVRFs, indicating that lasmiditan efficacy is not affected by the presence of CVRFs. We also found no statistical difference between placebo and lasmiditan in the frequency of likely CV TEAEs either in the absence or presence of any CVRFs in these single-attack studies. The lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Longer-term studies are needed to evaluate efficacy and safety over time.