Profile of Lasmiditan in the Acute Treatment of Migraine in Adults: Design, Development, and Place in Therapy.

Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of men in the United States. The pathophysiology of migraine is a major focus of research, and medications have been developed to interrupt the processes that generate headache and other bothersome symptoms of migraine attacks. The triptan class of medications acts as a direct agonist at the 5-HT1B/D receptor but its use is limited by contraindications for those with coronary or cerebrovascular disease. Lasmiditan is a first-in-class agonist at the 5-HT1F serotonin receptor that does not appear to generate vasoconstriction. This article reviews the design, development, and place in therapy for lasmiditan. A narrative review of the literature using the Ovid MEDLINE database was performed. The rationale behind the development of lasmiditan and pre-clinical, proof-of-concept, Phase II, pivotal, Phase III trials and post-hoc data is covered. Additionally, the efficacy and safety of lasmiditan when compared to other acute treatments in migraine is described, including lasmiditan's side effect profile and status as a Schedule V substance. Further, head-to-head studies of lasmiditan compared with other acute treatments are required.

Long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine attacks.

BACKGROUND: Long-term data helps assess the consistency of efficacy, tolerability, and safety of acute treatment over repeated use for different attacks. Real-world studies help assess tolerability, safety, and efficacy in patients with possibly refractory chronic migraine, more comorbidities, other diseases such as cardiovascular diseases, and polypharmacy. METHODS: This is a narrative review of the long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine. Both manuscripts and abstracts were reviewed. RESULTS: The efficacy and tolerability of lasmiditan, ubrogepant, and rimegepant are maintained over time. No significant cardiovascular adverse events were thought to be related to any of these medications. The rare instances of palpitations and/or tachycardia occurred within 48 hours of lasmiditan. One participant with a history of supraventricular tachycardia had sinus tachycardia thought to be related to ubrogepant which did not recur despite continued use. One case of thrombocytopenia and two cases of increased aspartate aminotransferase and alanine transaminase were thought to be possibly related, but the alanine transaminase and aspartate aminotransferase levels normalized despite continued use of ubrogepant. A case of first-degree atrioventricular block was considered possibly related to rimegepant. Acute use of rimegepant was associated with a decrease in monthly migraine days over time. The three medications were associated with improvement in function and/or productivity. CONCLUSION: Long-term and real-world data of tolerability, safety and efficacy of lasmiditan, ubrogepant, and rimegepant is thus far consistent with prior studies, but more longitudinal data that clarifies long-term safety as well as consistency and predictors of response is needed.

[Integrating new migraine treatments into clinical practice (part 1) : management of acute migraine attack]. / Intégration des nouveaux anti-migraineux dans notre pratique clinique . Partie 1 : traitement de la crise de migraine.

Although migraine is one of the most common chronic diseases and is the subject of numerous studies, there is still a considerable proportion of patients who are not satisfied with their acute treatment. Left without any real new therapeutic option to offer patients since sumatriptan was introduced on the Belgian market 30 years ago, neurologists have recently seen a change in the therapeutic landscape with the advent of new specific acute treatments for migraine: gepants and ditans. Being the only ones currently available in Belgium, gepants (including the newly marketed rimegepant) bring added value to traditional treatments such as non-steroidal anti-inflammatory drugs and triptans. This is why it seemed useful to review the different therapeutic options available in Belgium today by including these new treatments and to propose a rational pharmacological approach to relieve acute migraine attack.

Bien que la migraine soit une des maladies chroniques les plus fréquentes et fasse l'objet de nombreuses recherches, il existe malheureusement encore une proportion importante de patients insatisfaits de leur traitement anti-douleur. Sans nouvelle vraie option thérapeutique à proposer aux patients depuis la mise sur le marché belge du sumatriptan voici 30 ans, le neurologue a vu récemment le paysage thérapeutique se modifier avec l'arrivée de nouveaux traitements spécifiques de la crise de migraine : les gépants et les ditans. Seuls disponibles pour le moment en Belgique, les gépants (avec notamment le rimégépant nouvellement commercialisé) apportent une plus-value aux traitements traditionnels que sont les anti-inflammatoires non stéroïdiens et les triptans. C'est la raison pour laquelle il nous a semblé utile de refaire le point sur les différentes options thérapeutiques disponibles aujourd'hui en Belgique en intégrant ces nouveaux traitements et de proposer une approche pharmacologique rationnelle pour soulager la douleur de la crise de migraine.

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.

BACKGROUND: Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. MAIN BODY: The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient's well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. CONCLUSIONS: The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.

Cardiovascular Disease and Migraine: Are the New Treatments Safe?

PURPOSE OF REVIEW: The authors present data on cardiovascular safety for the new acute and preventive migraine treatments including ditans, gepants, and calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) alongside older medications like triptans and ergotamines. RECENT FINDINGS: The authors conclude that there are no cardiovascular safety concerns for lasmiditan, and that it could be used in those with cardiovascular disease. In fact, the literature even suggests that triptans are safer in cardiovascular disease than their contraindications may suggest. At this time, there is insufficient evidence that gepants and CGRP mAbs should be contraindicated in those with cardiovascular disease including stroke or myocardial infarction, though erenumab has now been associated with hypertension. Vasodilation may be an important CGRP-mediated mechanism mid-ischemia especially in patients with small vessel disease; hence, CGRP antagonists should be use with caution in this context. Long-term data is still needed, and prescribers should ensure patients are aware of the limitations of our knowledge at this time, while still offering these effective and well-tolerated treatment options.

Tolerability and Safety of Lasmiditan Treatment in Elderly Patients With Migraine: Post Hoc Analyses From Randomized Studies.

PURPOSE: Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population. METHODS: These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing). FINDINGS: Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period. IMPLICATIONS: The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).

Optimal Dosing of Lasmiditan in the Management of Acute Migraine Attack: A Systematic Review and Meta-analysis.

BACKGROUND: The current target of migraine treatment is focused on Triptans. Lasmiditan, a non-vasoconstrictive and highly selective 5HT1F receptor agonist is a novel therapeutic discovery for migraine for patients with cardiovascular (CV) risk factors or stable cardiovascular diseases and who fail to respond to the existing treatment. OBJECTIVE: To identify an optimal dosing of Lasmiditan 100 mg versus 200 mg for the treatment of acute migraine attacks in adult patients with cardiovascular risk factors. METHODS: Systematic searches were run in databases such as Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Google scholar, and PUBMED. Out of 83 study records identified, two studies were included for quantitative analysis. RESULTS: There was a significant headache pain freedom at 2 h [Odds Ratio (OR): 0.77; 95% Confidence interval (CI): 0.64-0.92] and sustained pain freedom at 24 h (OR): 0.75; 95% CI: 0.61-0.93] in patients taking Lasmiditan 200 mg compared to those taking Lasmiditan 100 mg. The results were statistically insignificant for parameters like most bothersome symptoms (MBS) free at 2 h, headache relief at 2 h, disability level at 2 h, and global impression of change at 2 h. A combined analysis of these parameters showed a remarkable difference between both the groups favoring Lasmiditan 200 mg [OR: 0.88; 95% CI: 0.81-0.95]. CONCLUSION: An oral dosing of Lasmiditan 200 mg is ideal for the treatment of acute migraine in adult patients with CV risk factors for attaining headache pain freedom at 2 h and sustained pain freedom at 24 compared to Lasmiditan 100 mg.

Future prophylactic treatments in migraine: Beyond anti-CGRP monoclonal antibodies and gepants.

Migraine is ranked as a leading cause of years lived with disability among all neurological disorders. Therapies targeting the calcitonin gene-related peptide (CGRP) signaling pathway, including monoclonal antibodies against the receptor or ligand and small molecule CGRP receptor antagonists (gepants), are today approved for migraine prophylaxis with additional compounds expected to be introduced to the market soon. In this review, we consider other putative prophylactic migraine drugs in development, including compounds targeting G-protein coupled receptors, glutamate, ion channels, and neuromodulatory devices. Emergence of these new interventions could complement our current treatment armamentarium for migraine management.

Efficacy and safety of Di-Tan Decoction for treating post-stroke neurological disorders: a systematic review and Meta-analysis of randomized clinical trials.

The management of post-stroke complications plays an important role in the quality of life. Di-Tan Decoction (DTD; ) is a widely used traditional Chinese medicine. This study incorporated systematic review and meta-analysis to evaluate the efficacy of DTD in post-stroke neurological disorders. Randomized clinical trials (RCTs) were searched from English, Chinese and Korean electronic medical databases, by including the keywords "Di-Tan Tang", "Di-Tan Decoction", "Scour Phlegm Decoction", "stroke", and "RCT. Each RCT included control (placebo, conventional therapy, or Western medicine) and experimental (DTD treatment) groups. For patients inflicted with stroke for 1-6 weeks, the outcomes of post-stroke neurological disorders were measured by scales for post-stroke symptoms and were classified as "completely healed", "markedly effective", "effective" and "ineffective". Totally, 11 RCTs (n = 490 controls and n = 502 DTD subjects) were selected from 210 articles identified in the initial search. A meta-analysis of evaluation criteria in post-stroke symptoms revealed that the overall odds ratio (ORs) for alleviating post-stroke neurological disorders were 0.30-fold lower (95% CI = 0.21-0.43) in the DTD group than the control (Western medicine) group (P < 0.000 01). Moreover, regardless of the type of stroke diagnostic scale applied (including NFA, HDS, and NIHSS), the overall post-stroke symptoms determined were less severe in the DTD group (n = 219) than the control group (n = 217). No adverse effects of DTD were observed in the 11 RCTs reviewed. All 11 studies used an appropriate method for randomization of subjects to evaluate the risk of bias (ROB), and 7 studies included allocation concealment as well as blinding of patients and practitioners. High-risk ROB was included in 6 RCTs. No significant publication bias was derived from the funnel plot. Our results indicate that the administration of DTD alone, and DTD in combination with Western medicine, exert greater efficacy for post-stroke complication therapy, than Western medicine administered alone. More rigorous and regulated studies are required to confirm the therapeutic efficacy of DTD for post-stroke neurological disorders. disorders.

Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study.

BACKGROUND: Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment of migraine. Here we analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study. METHODS: Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis. RESULTS: The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were - 12.5 and - 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks. CONCLUSIONS: Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months. TRIAL REGISTRATION: clinicaltrials.govNCT02565186; first posted October 1, 2015.

The potential of lasmiditan in migraine.

Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT1F) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2 h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatment-related side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans.

Lasmiditan for the acute treatment of migraine: Subgroup analyses by prior response to triptans.

BACKGROUND: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. METHODS: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). RESULTS: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. CONCLUSIONS: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. TRIAL REGISTRATION: SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Onset of Efficacy Following Oral Treatment With Lasmiditan for the Acute Treatment of Migraine: Integrated Results From 2 Randomized Double-Blind Placebo-Controlled Phase 3 Clinical Studies.

OBJECTIVE: To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine-associated symptoms. BACKGROUND: Lasmiditan is a novel selective 5-hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose. METHODS: Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine-related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed. RESULTS: Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100- and 200-mg lasmiditan-treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100- and 200-mg lasmiditan-treated groups. A significantly higher percentage of patients in the 200-mg lasmiditan-treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200-mg lasmiditan-treated group achieved freedom from migraine-related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001). CONCLUSIONS: Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first assessment at 30 minutes after 100- or 200-mg lasmiditan treatment.

Novel Medications for the Treatment of Migraine.

OBJECTIVE: To describe the new classes of medication for headache management and their roles in clinical practice. BACKGROUND: Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications - the gepants and the CGRP monoclonal antibodies (mAbs) - for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5-HT1F receptor to provide acute treatment without vasoconstrictive effects. METHODS: This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications. RESULTS: At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019. CONCLUSIONS: The development of new migraine-specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.

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.

BACKGROUND: In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs. METHODS: SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects. RESULTS: In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations. CONCLUSIONS: When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, 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. Future studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.

Interim results of a prospective, randomized, open-label, Phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study).

OBJECTIVES: To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. METHODS: In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. RESULTS: As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. CONCLUSIONS: The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186.

Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials.

OBJECTIVE: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications. BACKGROUND: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives. METHODS: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes. RESULTS: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications. CONCLUSIONS: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications. TRIAL REGISTRATION: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.

Traditional and Novel Migraine Therapy in the Aging Population.

Migraine is a common disabling disorder that affects 36 million Americans. The clinical features of migraine are less typical in the people above age 60, making the diagnosis and treatment difficult in this group. In this review, we will discuss migraine-specific drugs and their use in populations about age 60 who suffer from migraine. This discussion will include an overview of traditional treatments for the acute and preventive treatment of migraine, and considerations for their use in patient populations above age 60. In addition, we will discuss newer agents that show a more promising safety profile.

Therapeutic novelties in migraine: new drugs, new hope?

BACKGROUND: In the past decade, migraine research has identified novel drug targets. In this review, we discuss recent data on emerging anti-migraine therapies. MAIN BODY: The development of ditans, gepants and anti-calcitonin gene-related peptide monoclonal antibodies for the treatment of migraine is one of the greatest advances in the migraine field. Lasmiditan, rimegepant and ubrogepant will extend our therapeutic armamentarium for managing acute migraine attacks when triptans are not effective or contraindicated due to cardiovascular disorders. The monoclonal antibodies are migraine specific prophylactic drugs with high responder rates and favorable adverse event profiles. Furthermore, they offer convenient treatment regimens of 4- or 12-week intervals. CONCLUSION: Collectively, novel migraine therapies represent a major progress in migraine treatment and will undoubtedly transform headache medicine.