Emerging therapies for opioid-induced constipation: what can we expect?

INTRODUCTION: The rise in opioid use for managing chronic and oncologic pain has led to a significant increase in opioid-induced constipation (OIC) that impacts patient quality of life and pain management. AREAS COVERED: In this study, emerging therapies for OIC were criticized for refining advancements and novel treatment options. Key topics included the efficacy of peripherally acting mu-opioid receptor antagonists (PAMORAs) such as methylnaltrexone, naloxegol, and naldemedine, which specifically target opioid-induced gut dysfunction. Other treatment options, including intestinal secretagogues like lubiprostone and linaclotide, selective 5-HT receptor agonists such as prucalopride, and emerging adjunctive therapies like transcutaneous electrical nerve stimulation (TENS) and electroacupuncture were mentioned. Current guidelines from the American Gastroenterological Association (AGA) and the European consensus were criticized. EXPERT OPINION: Experts stress the importance of a stepwise approach to managing OIC, considering patient-specific factors and the efficacy of various treatments. While PAMORAs have demonstrated effectiveness in improving bowel function, their high cost and lack of extensive head-to-head comparisons with traditional laxatives are significant concerns. Emerging therapies and adjunctive treatments offer promising results but require further validation through rigorous studies. Future research should focus on long-term outcomes, cost-effectiveness, and comparative effectiveness to better address the complex needs of patients with OIC and refine treatment protocols.

Safety and Efficacy of Calcitonin Gene-related Peptide Receptor Antagonists and Selective Serotonin Receptor Agonist in the Management of Migraine: A Systematic Review and Meta-analysis.

BACKGROUND: Recently, US Food and Drug Administration (FDA) has approved calcitonin gene-related peptide receptor antagonists (rimegepant, and ubrogepant), and selective serotonin receptor agonists (lasmiditan) in the management of migraine. However, the exact safety and efficacy profile of these drugs is unclear so far. METHODS: The study's primary objective was to determine the exact safety and efficacy profile. The overall estimate was calculated in terms of risk ratios using a suitable model. The subgroup analysis was also performed to check the effect of individual drugs on the outcome, whereas sensitivity analysis was performed to check the effects of outliers on the outcome. All the analyses were performed using Rev Man 5. The drugs have shown significant improvement in efficacy parameters (pain freedom, most bothersome symptoms, phonophobia, nausea, and photophobia). RESULTS: The subgroup analysis results have shown significant improvement in all efficacy parameters in the rimegepant and ubrogepant groups. The effect of ubrogepant on safety parameters was found to be non-significant, indicating a better safety profile of ubrogepant than lasmiditan. CONCLUSION: The sensitivity analysis results have shown no effect of outliers on the efficacy parameters. Based on the available evidence, recently approved drugs are effective in the treatment of migraine, however, associated with few adverse drug reactions.

Efficacy and tolerability of 100†mg of lasmiditan for migraine: A multi-center, prospective observational real-world study in Japan.

BACKGROUND: Real-world data on the effectiveness and safety of lasmiditan, a new medication for acute migraine attacks, is necessary. METHODS: We performed a prospective, observational, multi-center, real-world study. A total of 48 patients with migraine (44 females, 44.6 ± 12.9 years old) were included in this study. RESULTS: Twenty-three patients (47.9%) reported they were headache-free two hours after taking lasmiditan and were categorized into the responder group. In total, 44 patients (91.7%) experienced at least one side effect within two hours of taking the medication. Dizziness, somnolence, malaise, nausea, and palpitations were reported by 56.3% (n = 27), 45.8% (n = 22), 37.5% (n = 18), 20.8% (n = 10), and 14.6% (n = 7) of patients respectively. Of 48 patients, 20 (41.7%) indicated that they preferred lasmiditan to their previous acute treatment. There were no predictive factors for efficacy. CONCLUSION: This real-world study demonstrated the efficacy and safety of lasmiditan. More than 90% of patients experienced side effects from lasmiditan. Approximately 40% of patients preferred lasmiditan despite the occurrence of side effects.

Long-term treatment with lasmiditan in patients with migraine: post hoc analysis of treatment patterns and outcomes from the open-label extension of the CENTURION randomized trial.

BACKGROUND: The objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting. METHODS: This was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses. RESULTS: In total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change - Migraine Headache Condition (56.5% vs 33.4%-52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%-83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency. CONCLUSIONS: Based on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018-001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018.

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.

Safety profile of lasmiditan in patients with migraine in an Asian population.

BACKGROUND: MONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management. RESEARCH DESIGN AND METHODS: Safety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE-efficacy associations. RESULTS: Of 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy. CONCLUSIONS: In the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index <30 kg/m2) patients and Asian patients with migraine.

Safety Findings in Lasmiditan as a Novel Acute Treatment of Migraine in Chinese Patients: A Post Hoc Analysis of the Randomized Controlled Phase 3 CENTURION Trial.

INTRODUCTION: Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed. METHODS: Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed. RESULTS: A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy. CONCLUSION: In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population. TRIAL REGISTRATION: NCT03670810.

Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT_1F receptor) with a proven efficacy and safety in phase 2 and 3 studies. Owing to some differences in clinical practice between China and western countries, there is need to get additional evidence on safety of lasmiditan in the Chinese population to support its usage in clinical practice.This post hoc analysis was conducted to present the detailed safety profile of lasmiditan in the Chinese population using data from the CENTURION study. Approximately half of the analyzed population was not covered in the published primary cohort.The results show that in the Chinese population of the study, most of the treatment-emergent adverse events (TEAEs) were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort with no new safety concerns observed in the Chinese population. The overall safety profile of lasmiditan in the Chinese population was generally consistent with the primary cohort. The results provide additional evidence and emphasize that lasmiditan may be considered as a useful acute treatment option with acceptable safety profile for patients with migraine in China.

Lasmiditan for single migraine attack in Japanese patients with cardiovascular risk factors: subgroup analysis of a phase 2 randomized placebo-controlled trial.

BACKGROUND: Some migraine treatments are contraindicated for patients with cardiovascular disease (CVD) or risk factors (CVRFs). We report safety and efficacy of lasmiditan, a new oral acute migraine treatment with no cardiovascular contraindication, in Japanese patients with CVRFs. RESEARCH DESIGN AND METHODS: MONONOFU was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of Japanese patients with migraine (met International Headache Society criteria, Migraine Disability Assessment score ≥11, disabling migraine for ≥1 year). Eligible patients were randomized (7:3:7:6) to placebo or lasmiditan 50, 100, 200 mg. This prespecified analysis described CVDs, CVRFs, and cardiovascular treatment-emergent adverse events (TEAEs). Efficacy (proportion pain-free, experienced pain relief, most bothersome symptom-free, or disability-free 2 hours post-dose) was evaluated within CVRF subgroups (≤1, ≥2). RESULTS: Of 846 randomized patients, 691 were analyzed (CVRF≤1: 375; CVRF≥2: 316). The proportion of lasmiditan-treated patients with ≥1 TEAE was not related to CVRF numbers. Eighteen (3.8%) lasmiditan-treated and three (1.4%) placebo-treated patients reported likely cardiovascular TEAEs. Lasmiditan was more effective than placebo at relieving pain, symptoms, and disability in both CVRF subgroups. There was no consistent relationship between CVRF subgroups and efficacy. CONCLUSIONS: Lasmiditan was well tolerated and effective in Japanese patients with migraine and CVRFs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03962738.

Migraine history and response to lasmiditan across racial and ethnic groups.

OBJECTIVE: The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT1F) receptor agonist, in racial and ethnic subgroups. METHODS: Descriptive data from racial (White [W](n = 3471) and Black or African American [AA](n = 792)) and ethnic (Hispanic or Latinx [HL](n = 775) and Non-Hispanic or Latinx [Non-HL](n = 3637)) populations are presented on pooled data from two double-blind, placebo-controlled, randomized Phase 3 studies (SAMURAI [NCT02439320] and SPARTAN [NCT2605174]). Patients were treated with lasmiditan (50 (SPARTAN only), 100, or 200 mg) or placebo for a single migraine attack of moderate-to-severe intensity. Efficacy data were recorded in an electronic diary at baseline, 30, 60, 90, and 120 min. Safety was evaluated and reported by occurrences of adverse events. RESULTS: Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes. CONCLUSIONS: There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.

Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries.

BACKGROUND: Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamine2C receptor antagonist agomelatine is used to treat adults, and could offer a new therapeutic option for paediatric patients. Therefore, we aimed to investigate the short-term antidepressant efficacy and safety of agomelatine in children and adolescents with major depressive disorder. METHODS: We performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23. FINDINGS: Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours. INTERPRETATION: This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder. FUNDING: Servier. VIDEO ABSTRACT.

The Effect and Safety of 5-HT1F Receptor Agonist Lasmiditan on Migraine: A Systematic Review and Meta-Analysis.

BACKGROUND: Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks. OBJECTIVE: To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks. METHODS: The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model. RESULTS: Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92), P = 0.007; 200 mg: RR = 0.81, 95% CI (0.66, 0.99), P = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75, 95% CI (0.81, 9.37), P = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83, 95% CI (0.74, 0.94), P = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88, 95% CI (0.81, 0.96), P = 0.006). CONCLUSIONS: Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Efficacy and Safety of Lasmiditan for Acute Treatment of Migraine in Adults: A Meta-Analysis.

Monotherapy with triptans in acute migraine is ineffective in many patients and contraindicated in certain cardiovascular diseases where alternative therapeutic options are necessary to explore. This meta-analysis has evaluated the efficacy and safety of lasmiditan for the treatment of acute migraine in adults. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from 4 relevant articles. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed in the selection, analysis, and reporting of findings. A random-effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta-regression for probable variables affecting effect size. Subgroup analysis was done depending on the dose of lasmiditan. Lasmiditan use was associated with a significantly higher percentage of patients with pain freedom (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.72-2.39; P < .00001), sustained pain freedom (OR, 1.93; 95%CI, 1.55-2.39; P <.00001), headache response (OR, 2.05; 95%CI, 1.77-2.36; P < .00001), clinical disability level (OR, 1.36; 95%CI, 1.20-1.55; P < .00001), patients' global impression (OR, 1.88; 95%CI, 1.69-2.10; P < .00001), and significantly lower use of rescue medication (OR, 0.49; 95%CI, 0.38-0.63; P < .00001) compared to placebo. Lasmiditan use was also associated with a higher likelihood of adverse effects like dizziness (OR, 6.54; 95%CI, 4.24-10.07; P < .00001), paresthesia (OR, 4.28; 95%CI, 2.97-6.17; P < .00001), and fatigue (OR, 5.67; 95%CI, 3.78-8.52; P < .00001) compared to placebo. Subgroup analysis showed a dose-dependent effect of lasmiditan on pain freedom, sustained pain freedom, patient's global impression, and occurrence of adverse drug reactions. Prediction probability for effect estimate favoring placebo was calculated to be 0.0017%. Lasmiditan has shown a favorable effect in terms of efficacy and safety in the treatment of an acute attack of migraine in comparison to placebo. Further studies are needed to evaluate long-term safety, efficacy, and use in specific subgroups of patients. PROSPERO Registration Number: CRD42020177838.

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine.

Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).

YH12852, a Potent and Selective Receptor Agonist of 5-hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation.

Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5-hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low-dose cohort (MLD), healthy subjects randomly received once-daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well-tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.

Discovery of Novel pERK1/2- or ß-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and ß-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated ß-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials.

OBJECTIVE: Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT1F receptor agonist approved in the United States for the acute treatment of migraine. METHODS: In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). RESULTS: Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. CONCLUSIONS: The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

Lasmiditan for Acute Treatment of Migraine in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT1F receptor agonist. OBJECTIVE: The objective of this study was to systematically evaluate the efficacy and safety of lasmiditan for the acute treatment of migraine in adult patients. METHODS: We systematically searched PUBMED, EMBASE, and Cochrane Library databases. Any relevant articles published before 3 March, 2020 were collected. Inclusion criteria were: (1) randomized clinical trials; (2) enrolled adult participants diagnosed with migraine; (3) compared lasmiditan at 100 mg or 200 mg with placebo; (4) enrolled more than 100 participants; and (5) provided any available data for predefined primary or secondary outcomes. RESULTS: Three high-quality, multi-centered randomized clinical trials with 4506 patients in total were included. We found that the use of lasmiditan was related to a significantly increased rate of pain freedom at 2 h post-dose with 31.60% patients achieving freedom of pain in the lasmiditan group compared with 17.55% patients in the placebo group (relative risk [RR] 1.80 [95% confidence interval (CI) 1.34-2.42]), with no significant heterogeneity. In addition, lasmiditan is reported to significantly increase the rate of absence of the most bothersome symptoms at 2 h compared with the placebo group with no significant heterogeneity (lasmiditan, 42.82%; placebo, 30.38%; RR 1.44 [95% CI 1.03-2.01], I2 = 0%). With regard to the safety endpoints, compared with the placebo group, participants in the lasmiditan group had a higher rate of fatigue, paresthesia, and somnolence (fatigue: lasmiditan, 1.94%; placebo, 0.24%; RR 7.96 [95% CI 0.4-158.86]; paresthesia: lasmiditan, 6.91%; placebo, 1.56%; RR 4.46 [95% CI 1.54-12.93], somnolence: lasmiditan, 5.9%; placebo, 2.15%; RR 2.76 [95% CI, 1.49-5.11]) with low heterogeneity. A subgroup analysis demonstrated that without safety differences, participants who received the 200-mg dose had a higher percentage of freedom of pain at 2 h and sustained pain relief at 2-24 h compared with the 100-mg dose (freedom of pain at 2 h: lasmiditan, 34.53%; placebo, 28.67%; RR 1.2 [95% CI 1.04-1.38]; lasmiditan, 20.62%; placebo, 16.33%; RR 1.26 [95% CI 1.19-1.34]), with low heterogeneity for both outcomes (I2 = 0%). CONCLUSIONS: In this meta-analysis, the use of lasmiditan as an acute treatment for episodic migraine in adults led to a greater percentage of freedom of pain and the absence of the most bothersome symptoms at 2 h post-dose. Lasmiditan 200 mg had superior efficacy to 100-mg dose without a significantly increased risk for adverse events.

Targeting the 5-HT system: Potential side effects.

Targeting the serotonin (5-HT) system is no simple task: there are at least 15 5-HT receptors, in addition to a number of transporters and metabolizing enzymes. Multiple 5-HT receptor variants exist due to genetic variations and/or post translational modifications, splice variants or editing variants. Some receptors may form homo and heteromers. The 5-HT system is targeted by multiple drugs to treat a variety of diseases. Given the homology amongst the 5-HT and neighbouring receptor classes, only few drugs are actually selective for a single target. In fact, many 5-HT drugs act on a combination of targets, i.e. several receptors and/or transporters or enzymes. For instance, a number of antidepressants or antipsychotics act on 5-HT and other transmitter systems. Recently developed drugs may show target selectivity by design, based on the current state of knowledge, whereas many older compounds hit multiple targets since they were developed using phenotypic screens, as was done well into the 1980's. Ergot analogues, antipsychotics or antidepressants, fall into this category. As our knowledge developed over the last 25-30 years, some targets have very well-defined liabilities: for instance, 5HT2B or 5-HT2A receptor agonists, will produce valvulopathies or hallucinations, respectively, whereas 5-HT3 receptor antagonists, may lead to constipation. This short review will be limited in scope as there are multiple targets and even more compounds to discuss. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.