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Background: Novel abortive treatments for migraine, ditans and gepants, have promising implications in triptan-insufficient responders with minimal existing comparative data. Our study aims to synthesize evidence through a systematic review and network meta-analysis to assess the comparative efficacy of lasmiditan, rimegepant and ubrogepant in triptan-insufficient responders. Method: We searched PubMed, Embase, CENTRAL, and EBSCO Open Dissertations up to May 2024. We included randomized controlled trials (RCTs) that compared novel abortive treatments, including lasmiditan, rimegepant, and ubrogepant, in migraine patients who self-reported insufficient response to triptans. Outcomes are represented using relative risks with corresponding 95% confidence intervals (CI). The surface under the cumulative ranking curve (SUCRA) was used to rank each medication. Results: A total of five phase 3 RCTs involving 3,004 patients were included in the analysis. All three agents were significantly superior to placebo for two-hour pain freedom (RR = 1.93, 95% CI [1.52, 2.46]), freedom from the most bothersome symptoms at two hours (RR = 1.55, 95% CI [1.37, 1.75]), and pain relief at two hours (RR = 1.46, 95% CI [1.35, 1.58]). No statistically significant differences in efficacy outcomes were observed among the three agents. However, lasmiditan 200 mg had the highest cumulative probability for two-hour pain freedom and relief (SUCRA 0.9, 0.8, respective), while rimegepant led in relieving the most bothersome symptoms (SUCRA 0.7). Conclusion: Lasmiditan, rimegepant, and ubrogepant are effective for acute treatment of migraine in triptan-insufficient responders, with high-dose lasmiditan showing the highest efficacy for pain control. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to comprehensively assess the safety of rimegepant administration in real-world clinical settings. Methods: Data from the Food and Drug Administration Adverse Event Reporting System (FAERS) spanning the second quarter of 2020 through the first quarter of 2023 were retrospectively analyzed in this pharmacovigilance investigation. This study focuses on employing subgroup analysis to monitor rimegepant drug safety. Descriptive analysis was employed to examine clinical characteristics and concomitant medication of adverse event reports associated with rimegepant, including report season, reporter country, sex, age, weight, dose, and frequency, onset time, et al. Correlation analysis, including techniques such as violin plots, was utilized to explore relationships between clinical characteristics in greater detail. Additionally, four disproportionality analysis methods were applied to assess adverse event signals associated with rimegepant. Results: A total of 5,416,969 adverse event reports extracted from the FAERS database, 10, 194 adverse events were identified as the "primary suspect" (PS) drug attributed to rimegepant. Rimegepant-associated adverse events involved 27 System Organ Classes (SOCs), and the significant SOC meeting all four detection criteria was "general disorders and administration site conditions" (SOC: 10018065). Additionally, new significant adverse events were discovered, including "vomiting projectile" (PT: 10047708), "eructation" (PT: 10015137), "motion sickness" (PT: 10027990), "feeling drunk" (PT: 10016330), "reaction to food additive" (PT: 10037977), etc. Descriptive analysis indicated that the majority of reporters were consumers (88.1%), with most reports involving female patients. Significant differences were observed between female and male patients across age categories, and the concomitant use of rimegepant with other medications was complex. Conclusion: This study has preliminarily identified potential new adverse events associated with rimegepant, such as those involving the gastrointestinal system, nervous system, and immune system, which warrant further research to determine their exact mechanisms and risk factors. Additionally, significant differences in rimegepant-related adverse events were observed across different age groups and sexes, and the complexity of concomitant medication use should be given special attention in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular (CV) risk factors can limit treatment options for migraine. Rimegepant is an orally administered small-molecule calcitonin gene-related peptide receptor antagonist that does not induce vasoconstriction. The aim of these post hoc subgroup analyses was to assess the safety of rimegepant according to CV risk. Methods: In a multicenter, long-term, open-label, phase II/III safety study, participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg, orally, to treat migraine up to once daily for up to 52 weeks. Uncontrolled, unstable, or recently diagnosed CV disease was part of the exclusion criteria. Safety was assessed across subgroups according to number of CV risk factors (0, 1, or ≥ 2) and Framingham Risk Score (< 10% or ≥ 10%). Results: Of 1800 treated participants, 28.8% had one CV risk factor and 12.1% had ≥ 2 CV risk factors; 7.0% had Framingham Risk Score ≥ 10%. Across the subgroups with 0, 1, and ≥ 2 CV risk factors and Framingham Risk Score < 10% and ≥ 10%, respectively, proportions of participants reporting adverse events (AEs; 59.6%, 61.4%, 62.2%, 59.9%, 67.5%) and serious AEs (2.7%, 2.5%, 2.3%, 2.6%, 2.4%) were consistent, and AEs leading to study drug discontinuation were low (1.9%, 3.1%, 5.5%, 2.5%, 4.8%). Conclusions: Rimegepant showed favorable safety and tolerability in adults with migraine and CV risk factors, including those with moderate to high CV risk. Trial Registration: ClinicalTrials.gov NCT03266588. Plain Language Summary: Older patients with migraine often have cardiovascular (CV) disease – such as a prior heart attack – or risk factors for CV disease. Examples of CV risk factors are high blood pressure, diabetes, smoking, high cholesterol, and a family history of heart disease. The choice of treatments for migraine is limited by safety concerns for patients who have CV risk factors. Newer treatments for migraine – including rimegepant – work differently than older drugs, by targeting calcitonin gene-related peptide. The safety of rimegepant for patients with migraine and CV risk factors can be studied in a clinical trial. In a long-term trial, patients with migraine took rimegepant tablets to treat migraine attacks, up to once a day, for up to 52 weeks. Some of the patients in the study had CV risk factors. We analyzed the results of the study by grouping the patients based on how many CV risk factors they had. We found that the side effects of rimegepant were similar across the groups. This showed that rimegepant was safe and well tolerated in adults with migraine and CV risk factors. [ABSTRACT FROM AUTHOR]

Background: Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. Methods: This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. Results: By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild. Conclusions: In the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant. Trial registration: Clinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01. [ABSTRACT FROM AUTHOR]

Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients. [ABSTRACT FROM AUTHOR]

This commentary addresses the use of rimegepant for situational prevention in migraine management. While the approach of using prophylactic treatments during high-risk periods is not new, its application with rimegepant described by Lipton et al. raises ethical and clinical concerns. These include the challenge of defining high-risk periods, the potential for overmedication, and the risk of medication overuse headache (MOH). The current evidence on MOH with gepants is inconclusive, and recommendations on dosing may be insufficient. Additionally, the long-term safety of calcitonin gene-related peptide (CGRP) antagonists remains uncertain, especially regarding cardiovascular and other systemic effects. The commentary emphasizes the need for caution and thorough investigation into the long-term risks and benefits of situational prevention with rimegepant before widespread adoption. [ABSTRACT FROM AUTHOR]

Background Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. Methods Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. Results Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. Conclusions A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. [ABSTRACT FROM AUTHOR]

Introduction: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine. Methods: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months. Results: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups. Conclusions: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies. Trial registration: ClinTrials.gov—NCT05127486 (I5Q-MC-CGBD). Plain Language Summary: Galcanezumab and rimegepant are preventive treatments for episodic migraine. The goal of this study was to compare the efficacy of galcanezumab and rimegepant in reducing the number of monthly migraine headaches and to determine if galcanezumab was better than rimegepant. The study provides important information to doctors and their patients when making treatment decisions. People with episodic migraine were assigned to the galcanezumab (given as an injection under the skin) or rimegepant (given as a tablet that dissolves in the mouth) group and treated for 3 months. The doctor and the patient did not know which group they were assigned to, and to keep it unknown to both, people in the galcanezumab group got an injection with real medicine and a fake tablet, and people in the rimegepant group got a tablet with real medicine and a fake injection. The researchers wanted to know how many people in each group had at least a 50% reduction in their monthly migraine headaches. Of the 580 people in the study, 287 were assigned to galcanezumab and 293 to rimegepant. In both groups, most were female and white. After 3 months of treatment, 62% of the people in the galcanezumab group and 61% of people in the rimegepant group had at least a 50% reduction in monthly migraine headaches. Both treatments were effective, but galcanezumab was not better than rimegepant. About 20% of the people in each treatment group had a side effect from the medication, and most were mild or moderate in severity. [ABSTRACT FROM AUTHOR]

Purpose of Review: Despite the unmet therapeutic needs of patients with chronic migraine (CM) and/or medication overuse, available treatment options are limited. Recently, four calcitonin gene-related peptide receptor antagonists, known as gepants, have been approved for the treatment of migraine. This review focuses on the preventive treatment of CM with gepants and highlights recent findings. Recent Findings: Two randomized controlled trials (RCTs) have shown promising results for rimegepant and atogepant as preventive treatments for CM. In an RCT targeting patients with CM, atogepant demonstrated a significant reduction in the mean monthly migraine days, irrespective of acute medication overuse. Moreover, the patients reported no significant safety concerns and exhibited good tolerance to treatment. Summary: These findings highlight the potential of gepants as a new and effective therapeutic option for patients with CM and/or medication overuse. Gepant use will help improve the management and quality of life of individuals with this debilitating condition. [ABSTRACT FROM AUTHOR]

Purpose of Review: Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating headaches acutely and preventively, gepants are preferred over triptans. We will cover the indications for the four FDA-approved gepants in adults: rimegepant, atogepant, ubrogepant, and zavegepant. This review will illustrate how gepants will continue to revolutionize the acute and preventive treatment of headaches. Recent Findings: Gepants are now available in oral tablet, dissolving tablet, and intra-nasal spray formulations. Recent studies have shown promising utility in treating the pre-headache or prodromal phase. They have favorable tolerability, no evidence for association with medication overuse, and remain a safer alternative in those who have cerebrovascular risk factors. Additional research is needed to explore occurrence of Raynaud's phenomenon in participants treated with gepants, as it has been associated with CGRP monoclonal antibodies, but are not extensively studied in gepants. Summary: Gepants are expected to play a significant role in the next generation of migraine treatments. [ABSTRACT FROM AUTHOR]

Introduction: The objectives of this study were to (1) report long-term health-related quality of life (HRQoL) outcomes among patients using rimegepant preventatively in BHV3000-305 (NCT03732638) open-label extension (OLE) and (2) map Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2) to EQ-5D-3L utility values over the double-blind treatment (DBT; 0–12 weeks) and the OLE (13–64 weeks) to assess the influence of treatment on these values. Methods: This was a post hoc analysis using data from a rimegepant study for the prevention of migraine (BHV3000-305). Adult patients with migraine took either rimegepant 75 mg or placebo every other day (EOD) during the DBT phase. All patients received rimegepant during the OLE. MSQv2 was measured at baseline, weeks 12, 24, and 64. A validated algorithm was used to map MSQv2 scores to EQ-5D utilities. Results: Baseline data were available for 347 patients treated with placebo and 348 treated with rimegepant in the DBT period, who continued to the OLE. Baseline EQ-5D utilities were similar between trial arms: 0.598 for placebo and 0.614 for rimegepant. EQ-5D improved from baseline to week 12 and utilities increased by + 0.09 for placebo and + 0.10 for rimegepant (p value = 0.011). By 24 weeks, at which point patients who were originally randomized to placebo had received rimegepant 75 mg EOD for 12 weeks, HRQoL measures (MSQv2 and EQ-5D) were similar across groups, demonstrating rapid onset of treatment effect. This HRQoL improvement was durable out to 64 weeks. Conclusion: Compared to placebo, treatment with rimegepant 75 mg was associated with greater improvement in EQ-5D utilities during the 12-week DBT phase. Patients originally randomized to placebo experienced a similar improvement in EQ-5D utilities after switching to rimegepant during the OLE, demonstrating that benefits are realized within 12 weeks of active treatment. This preventive effect was durable out to 64 weeks and was associated with an additional increase in HRQoL over time. Trial Registration: NCT03732638. [ABSTRACT FROM AUTHOR]

Introduction: Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants.Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg as needed up to once daily for up to 52 weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no).Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52.Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use.Clinicaltrials.gov: NCT03266588.Methods: Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants.Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg as needed up to once daily for up to 52 weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no).Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52.Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use.Clinicaltrials.gov: NCT03266588.Results: Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants.Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg as needed up to once daily for up to 52 weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no).Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52.Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use.Clinicaltrials.gov: NCT03266588.Conclusions: Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants.Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg as needed up to once daily for up to 52 weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no).Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52.Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use.Clinicaltrials.gov: NCT03266588.Trial Registration: Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants.Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2–14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75 mg as needed up to once daily for up to 52 weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no).Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52.Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use.Clinicaltrials.gov: NCT03266588. [ABSTRACT FROM AUTHOR]

Background: In the absence of head-to-head trials, comprehensive evidence comparing onset of efficacy of novel agents for acute treatment of migraine is lacking. This study aimed to explore the relative efficacy of lasmiditan (serotonin [5-hydroxytryptamine] 1F receptor agonist) versus rimegepant and ubrogepant (calcitonin gene-related peptide antagonists) for the acute oral treatment of migraine through network meta-analysis (NMA). Methods: Data included in the NMA were identified through a systematic literature search (conducted April 2018, updated May/December 2020) of phase II–IV, randomised controlled trials (RCTs) in adults with chronic/episodic migraine with/without aura. Treatments included: lasmiditan 50, 100, 200 mg; rimegepant 75 mg; ubrogepant 25, 50, 100 mg. Pairwise treatment comparisons from Bayesian fixed-effect/random-effects NMA, adjusted by baseline risk where appropriate, were conducted. Comparisons were reported as odds ratios with 95% credible intervals. Early-onset efficacy endpoints included: pain freedom at 2 hours and pain relief at 1 and 2 hours. Adverse drug reaction (ADR) profiles were summarised. Heterogeneity and inconsistency in the network were explored; sensitivity analyses investigated robustness of findings. Results: Across 12 RCTs included in the base case, females represented >80% of included patients (mean age 37.9–45.7 years). Odds of achieving both pain freedom and pain relief at 2 hours were higher with lasmiditan 100 and 200 mg versus rimegepant 75 mg and ubrogepant 25 and 50 mg. Results for pain relief at 1 hour were consistent with those at 2 hours, but fewer comparisons were available. There were no statistically significant differences between lasmiditan 50 mg and ubrogepant or rimegepant for any outcome. Sensitivity analyses were in the same direction as base case analyses. Most commonly reported ADRs (incidence ≥2%) were: dizziness, fatigue, paraesthesia, sedation, nausea/vomiting and muscle weakness with lasmiditan; nausea with rimegepant; and nausea, somnolence and dry mouth with ubrogepant. Conclusions: The efficacy findings of this indirect comparison indicate that lasmiditan 100 mg or 200 mg might be an appropriate acute treatment option for patients with migraine seeking a fast onset of action. Differently from rimegepant and ubrogepant, lasmiditan use is associated with mainly neurological events, which are mostly mild or moderate in severity and self-limiting. 350/350 words [ABSTRACT FROM AUTHOR]

Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores − 9.2988, − 8.3629, and − 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π–π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is associated with considerable disability for patients not adequately managed with current standards of care. New acute therapies may offer relief for this population of patients; however, population size and associated potential costs of new therapies are unclear. In this study, a conceptual framework was developed to estimate anticipated use of new acute therapies. Methods: Targeted literature review (TLR) was conducted to identify factors affecting access to migraine-specific acute therapies, and characteristics of individuals who would be eligible for new acute therapies. Findings from the TLR were combined to create a framework for estimating the size of the eligible patient population. This framework was used to calculate two estimates of the eligible patient population by applying parameters (i) identified in the TLR and (ii) from a recent budget-impact analysis (BIA). Results: The primary factors affecting access to migraine-specific acute therapies identified in the TLR were consulting a healthcare professional for headache, receiving a migraine diagnosis, and receiving a prescription for migraine-specific treatment. Characteristics of individuals likely to use new acute therapies reflected in the TLR were contraindication to triptans, or failure to respond to/tolerate at least two oral triptans. Application of the framework suggested that 15–25% of individuals with migraine would be eligible for new acute therapies. Conclusion: A limited number of patients currently use migraine-specific acute therapies. Among such patients, a significant proportion do not have adequate symptom control. Accordingly, a minority of individuals with migraine may be expected to use new acute therapies. The framework developed in this study is intended to facilitate estimating the eligible patient population in assessments of costs of new acute therapies. Such assessments should also consider recommendations that patients have access to multiple types of acute therapies, which may yield savings from reduced medication-overuse headache (MOH), progression to chronic migraine, and urgent-care costs. [ABSTRACT FROM AUTHOR]