ABSTRACT Ubrogepant (Ubrelvy), a CGRP receptor antagonist, is approved for acute treatment of migraine with or without aura in adults. Because ubrogepant treats a neurological condition, it is of interest to know central nervous system exposure. Ubrogepant concentrations in plasma and cerebrospinal fluid (CSF) were measured in participants with a history of migraine. This analysis included a subset of participants with a ≥ 1 year history of migraine who were enrolled in a Phase 1b multi‐center, open‐label trial and who underwent a single CSF collection via lumbar puncture. All participants received a single oral dose of 100 mg ubrogepant. Plasma and CSF ubrogepant concentrations were measured using LC–MS/MS at pre‐defined post‐dose timepoints (plasma: 0–24 h; CSF: 2 or 4 h). Ubrogepant CSF/plasma concentration ratios at 2 and 4 h were determined. Ubrogepant safety and tolerability were evaluated through reporting of treatment‐emergent adverse events (TEAEs; ≤ 30‐days after dosing), physical examination, ECG, laboratory testing, and vital sign monitoring. A total of 8 participants were included. Mean (±SD) age was 34.5 ± 9.58 years and 4 participants (50%) were male. At 2 h, mean (±SD) CSF and plasma ubrogepant concentrations were 1.1 ± 0.8 and 354 ± 163 ng/mL, respectively (CSF/plasma ratio: 0.36% ± 0.29%); at 4 h, 2.3 ± 1.9 and 218 ± 84 ng/mL, respectively (CSF/plasma ratio: 0.94% ± 0.64%). No serious TEAEs, deaths, or significant changes in laboratory values, vital signs, or ECGs occurred. Because ubrogepant half maximal effective concentration (EC50) has been estimated at ~1.4 ng/mL, ubrogepant could act both centrally and peripherally to relieve migraine symptoms. ClinicalTrials.gov, NCT04179474 (registration date: 27 November 2019).

OBJECTIVE:To assess weight loss with atogepant 60 mg once daily during long-term treatment of chronic migraine (CM) and episodic migraine (EM) among participants previously failed by two to four classes of conventional oral preventive medications. BACKGROUND:The risk of migraine, including CM, in individuals with obesity is higher than in those without obesity. Calcitonin gene-related peptide has been linked to the pathophysiology of both obesity and migraine. Weight loss with atogepant, a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of migraine, has been observed during the 12-week EM and CM trials, as well as in long-term (40- or 52-week) EM trials. Long-term effects of atogepant on body weight in participants with increased migraine burden (i.e., EM or CM) have not been reported. METHODS:In this interim analysis of a safety endpoint from study 312, a phase 3, open-label, extension study, weight loss was assessed in the overall population and by prior participation in each lead-in study (12-week double-blind treatment period): PROGRESS (phase 3, multicenter, randomized, controlled study in CM) or ELEVATE (phase 3, multicenter, randomized, controlled study in EM treatment failure). Change from baseline in body weight at each study visit through end of treatment (PROGRESS and ELEVATE) or up to week 52 (study 312) was assessed (safety endpoint). Proportions of participants with ≥5% weight loss at any time, at the end of the lead-in study, or at week 52 in study 312 were evaluated. RESULTS:Participants from PROGRESS (n = 325) and ELEVATE (n = 270) rolled over to study 312 (n = 595) and were treated with atogepant 60 mg once daily. In study 312, mean (standard deviation) body weight decreased over time (-2.16 kg [5.89 kg; -4.76 lb] at week 52), with 44.8% (265/592) of participants experiencing a ≥5% weight loss at any time during the study and 29.5% (140/474) experiencing a ≥5% weight loss at week 52. In study 312, weight loss from lead-in study baseline was evident as early as week 4 and appeared to plateau around weeks 28 to 36, reaching a maximum numerical weight loss at week 44. Higher baseline body mass index was associated with greater odds of achieving ≥5% weight loss both at any time and at week 52. No significant effect of sex, race, adverse drug reactions, or therapeutic response to treatment was observed. CONCLUSIONS:Participants receiving atogepant 60 mg once daily for long-term preventive treatment of migraine were observed to have a decrease in mean body weight after 1 year of open-label treatment. Approximately 30% of participants experienced a clinically meaningful (≥5%) weight loss threshold after 1 year of open-label treatment. Future studies are needed to further characterize the mechanisms of weight loss associated with atogepant treatment.

The aim of this study was to determine the cerebrospinal fluid (CSF) to plasma concentration ratio of atogepant. Healthy adult participants (N = 28) were enrolled into this phase 1, open-label study and received atogepant 60 mg once daily for 8 days. Steady-state atogepant concentrations were determined from CSF samples collected on Day 6 at 2 (n = 12) or 6 (n = 12) h postdose, and plasma samples were collected over 24 h after the Day 7 dose. Descriptive statistics for the atogepant CSF-to-plasma (CSF/plasma) ratio were calculated for each time point. The safety and tolerability profiles of atogepant were evaluated by clinical assessment of adverse events, physical examinations, 12-lead ECGs, laboratory tests, and vital sign measurements. The majority of adverse events were nonserious and mild in severity. Two participants discontinued the study. One due to asymptomatic moderately elevated liver enzymes and another due to mild confusional state/insomnia. Steady-state mean ± SD plasmatotal (bound + unbound) and CSF atogepant concentrations at 2 h were 652.54 ± 385.40 and 0.49 ± 0.78 ng/mL, and at 6 h were 163.14 ± 85.87 and 1.21 ± 1.14 ng/mL, respectively. The mean atogepant CSF/plasmatotal concentration ratio was 0.1% at 2 h and 0.7% at 6 h postdose. CSF/plasmaunbound concentration ratios at 2 and 6 h were 1.4% and 14.3%, respectively. Although the CNS penetration was low, considering atogepant's high affinity to CGRP receptors (Ki = 0.016 ng/mL) and a CIDV (capsaicin-induced dermal vasodilation) EC50 (half maximal effective concentration) value of 0.91 ng/mL, more research is needed to determine if atogepant acts both centrally and peripherally to prevent/treat a migraine attack.

Background and ObjectiveLimited data are available describing the frequency, severity, and consistency of prodromal symptoms followed by headache. This analysis of the PRODROME trial screening period characterized prodromal symptoms in people with migraine, including the most common symptoms and their severity, and the frequency and consistency with which prodromal symptoms were followed by headache.MethodsPRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial conducted in the United States that enrolled adults with 2-8 migraine attacks per month who stated they could identify prodromal symptoms that were reliably followed by a headache. The trial included a 60-day screening period designed to test the predictive validity of "qualifying prodrome events" before the onset of headache. Participants used an eDiary to report qualifying prodrome events, defined as prodromal symptoms whereby the participant was confident a headache would follow within 1-6 hours. This analysis evaluated common prodromal symptoms and their severity, time from prodrome onset to headache onset, and the percentage of participants who identified prodromal symptoms that were followed by a headache >= 75% of the time over the 60-day screening period.ResultsA total of 920 participants entered eDiary data, with a mean of 5.2 qualifying prodrome events during the 60-day screening period. A total of 4,802 qualifying prodrome events were recorded. The most common prodromal symptoms identified were sensitivity to light (57.2%; 2,748/4,802), fatigue (50.1%; 2,408/4,802), neck pain (41.9%; 2,013/4,802), sensitivity to sound (33.9%; 1,630/4,802), either difficulty thinking or concentrating (30.0%; 1,442/4,802), and dizziness (27.8%; 1,333/4,802). Of all qualifying prodrome events reported, 81.5% (3,913/4,802) were followed by headache of any intensity within 1-6 hours. For each participant, a mean of 84.4% of their qualifying prodrome events were followed by a headache within 1-6 hours, with 76.9% of participants identifying qualifying prodrome events that were followed by headache within 1-6 hours >= 75% of the time.DiscussionParticipants were able to identify migraine attacks in which prodromal symptoms were reliably followed by a headache within 1-6 hours. These findings suggest the potential for initiating treatment during the prodrome to prevent headache.Trial Registration InformationClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; First patient enrolled: August 21, 2020. clinicaltrials.gov/study/NCT04492020.

Atogepant is approved for the preventive treatment of migraine and is taken orally once daily. This work aimed to characterize the plasma and milk pharmacokinetics of atogepant in lactating females. An open-label, phase 1 study (NCT05892757) was conducted in 12 healthy, lactating adult women 1–6 months postpartum from July 11, 2023, to February 22, 2024. A single 60-mg dose of atogepant was administered to participants to determine atogepant’s plasma and milk pharmacokinetics, the excretion of atogepant in breast milk, and the relative infant dose (RID). Atogepant was analyzed using validated LC–MS/MS assays in plasma and breast milk samples collected up to 24 h after dosing and during specified intervals through 24 h, respectively. Plasma and milk pharmacokinetic parameters were estimated using non-compartmental methods and compared using linear mixed-effects models. Safety was assessed via adverse event reporting, clinical labs, vital signs, and ECGs throughout the study. The mean (range) milk-to-plasma ratio for atogepant was 0.076 (0.023–0.104). With nearly undetectable levels of atogepant in breast milk 16–24 h after dosing, the cumulative mean (range) amount of atogepant excreted in breast milk over 24 h was 0.009 mg (0.005–0.016 mg; 0.015 https://clinicaltrials.gov/study/NCT05892757 .

AimLong-term data for oral calcitonin gene-related peptide receptor antagonist, atogepant, in episodic migraine (EM) has been reported. This is the first report on one-year outcomes in participants with chronic migraine (CM) and in the EM population with prior preventive treatment failures. Here, we report the long-term safety, tolerability, efficacy and functional outcomes of one-year preventive treatment of EM or CM with atogepant.MethodsThis is an interim analysis of an ongoing, open-label, multicenter, 156-week, safety extension study that enrolled completers from phase 3 PROGRESS and ELEVATE trials. The participants completing week 52 or early termination were evaluated. Eligible adults with at least a one-year history of migraine, with either CM (PROGRESS) or EM who previously had inadequate response to two to four classes of conventional oral preventive treatments (ELEVATE). All participants received atogepant 60 mg once daily. The primary outcome was safety and tolerability of atogepant. Efficacy and functional outcomes were prespecified exploratory analyses.ResultsOf 596 participants, 595 (PROGRESS, n = 325; ELEVATE, n = 270) were treated and included in the safety population and 524 (PROGRESS, n = 284; ELEVATE, n = 240) were included in the modified intent-to-treat population. In this interim analysis, mean duration of atogepant exposure was 496.5 days. Treatment-emergent adverse events (TEAEs) occurred in 79.0% of participants; most were mild/moderate and not related to atogepant. Common TEAEs (≥5%) included COVID-19 (28.7%), nasopharyngitis (10.9%) and constipation (8.2%). TEAEs leading to discontinuation occurred in 5.9% of participants. One death attributed to asphyxia by housefire was observed. Other serious TEAEs occurred in 5.5% of participants and none were related to atogepant. Alanine aminotransferase and/or aspartate aminotransferase ≥3× upper limit of normal occurred in two participants; neither met Hy's law criteria. Improvements in efficacy and functional outcomes from lead-in study baseline were observed at weeks 13-16 in this open-label study and were consistent through 48 and 52 weeks, respectively.ConclusionsOverall safety results were consistent with the known safety profile of atogepant and the drug was well-tolerated over the course of the study. No new safety signals were identified. Improvements in efficacy and functional outcomes were consistent during the study.Trial RegistrationClinicalTrials.gov identifier: NCT04686136.

OBJECTIVE:The objectives of this study were to evaluate the safety, plasma and milk pharmacokinetics, excretion in breast milk, and the relative infant dose of ubrogepant following a single oral dose. BACKGROUND:Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. Preclinical findings in rats demonstrated comparable concentrations of ubrogepant in milk versus plasma; however, the quantification of ubrogepant excretion in human breast milk and breastfed infant exposure have not been previously evaluated. METHODS:This open-label, phase 1 study (NCT05892757) enrolled healthy, lactating adult women from July 11, 2023, to February 22, 2024. Participants were 1-6 months postpartum and received a single dose of ubrogepant 100 mg (2 × 50 mg tablets) orally. Plasma and breast milk samples were collected for up to 24 h after dosing to evaluate pharmacokinetics and ubrogepant concentrations were determined using validated liquid chromatography tandem mass spectrometry assays. Standard pharmacokinetic parameters were calculated from the plasma concentration and breast milk data using non-compartmental analyses. The milk-to-plasma concentration ratio was calculated based on the ratio of the area under the plasma concentration-time curve from time 0 to infinity (AUC∞) of human milk to the AUC∞ of plasma. The relative infant dose was calculated as 100 times the quotient of the body weight-normalized infant dose and the body weight-normalized maternal dose. Safety and tolerability were assessed via adverse events, vital signs, electrocardiograms, and clinical laboratory measurements. RESULTS:A total of 12 women were enrolled who each received a single dose of oral ubrogepant 100 mg. The mean milk-to-plasma ratio was 0.23, the cumulative amount of ubrogepant excreted in breast milk was <0.02% and the calculated relative infant dose was 0.15%. The maximum observed breast milk concentration and AUC of ubrogepant in breast milk were significantly lower (75% and 78%, respectively) compared to plasma. Only two mild adverse events were reported. CONCLUSION:Less than 0.02 mg of a 100 mg dose of ubrogepant was excreted in breast milk over a 24-h period. The minimal transfer of ubrogepant into breast milk is not considered clinically relevant.

This Phase 1 study of ubrogepant was conducted to establish the bioequivalence (BE) of the 50- and 100-mg to-be-marketed (TBM) tablet formulations with the clinical trial (CT) 100-mg tablet formulation and evaluate the food effect on the bioavailability of the 100-mg TBM tablet. This 2-part study enrolled healthy participants aged 18-45 years. Part A assessed BE following a single dose of TBM versus CT tablets. Part B evaluated the impact of a high-fat meal on ubrogepant pharmacokinetics. Safety and tolerability were assessed along with standard pharmacokinetic parameters. In Part A (n  =   47), the geometric mean ratio and 90% confidence intervals for maximum plasma drug concentration, area under the plasma concentration–time curve (AUC) from time zero to time t, and AUC from time zero to infinity for the TBM and CT formulations demonstrated BE. The time to peak exposure was the same for both formulations. In Part B ( n   =  18), a high-fat meal delayed time to peak exposure and reduced maximum plasma drug concentration by 22%, with no effect on AUC. The occurrence of treatment-emergent adverse events was low, and the majority were mild. Ubrogepant TBM and CT tablets (1 × 100 mg or 2 × 50 mg) were bioequivalent under fasted conditions, and a high-fat meal had no clinically relevant effect on the bioavailability of the TBM tablet formulation.

PRODROME was a phase 3, placebo-controlled, double-blind crossover trial evaluating whether ubrogepant 100 mg, a calcitonin gene-related peptide receptor antagonist, dosed during the premonitory (prodromal) phase of migraine, prevented development of headache and resolved prodromal symptoms. Qualifying prodromal events were defined as attacks with symptoms in which the participant was confident headache would follow within 1–6 h. Of 1,087 screened participants, 477 formed the efficacy analysis population. Outcomes were collected across 48 h showing, for example, at 2 h post-dose, absence of photophobia in 19.5% and 12.5% of ubrogepant- and placebo-treated events, respectively (odds ratio (OR) = 1.72 (95% confidence interval (CI) = 1.13–2.61)); at 3 h post-dose, absence of fatigue occurred in 27.3% and 16.8% (OR = 1.85 (95% CI = 1.17–2.92)) and absence of neck pain in 28.9% and 15.9% (OR = 2.04 (95% CI = 1.25–3.32)) of events; at 4 h post-dose, absence of phonophobia in 50.7% and 35.8% (OR = 1.97 (95% CI = 1.38–2.80)) of events; and at 24 h post-dose, absence of dizziness in 88.5% and 82.3% (OR = 1.82 (95% CI = 1.00–3.30)) of events. At 1 h and 6 h post-dose, respectively, absence of difficulty concentrating occurred in 8.7% and 2.1% (OR = 4.26 (95% CI = 1.17–15.54)) and absence of difficulty thinking occurred in 56.9% and 41.8% (OR = 2.05 (95% CI = 1.14–3.71)) of events. Treatment with ubrogepant during the prodromal phase may ameliorate common prodromal symptoms, with improvements possibly as early as 1 h post-dose.

This Phase 1 study of ubrogepant was conducted to establish the bioequivalence (BE) of the 50‐ and 100‐mg to‐be‐marketed (TBM) tablet formulations with the clinical trial (CT) 100‐mg tablet formulation and evaluate the food effect on the bioavailability of the 100‐mg TBM tablet. This 2‐part study enrolled healthy participants aged 18‐45 years. Part A assessed BE following a single dose of TBM versus CT tablets. Part B evaluated the impact of a high‐fat meal on ubrogepant pharmacokinetics. Safety and tolerability were assessed along with standard pharmacokinetic parameters. In Part A (n = 47), the geometric mean ratio and 90% confidence intervals for maximum plasma drug concentration, area under the plasma concentration–time curve (AUC) from time zero to time t, and AUC from time zero to infinity for the TBM and CT formulations demonstrated BE. The time to peak exposure was the same for both formulations. In Part B ( n = 18), a high‐fat meal delayed time to peak exposure and reduced maximum plasma drug concentration by 22%, with no effect on AUC. The occurrence of treatment‐emergent adverse events was low, and the majority were mild. Ubrogepant TBM and CT tablets (1 × 100 mg or 2 × 50 mg) were bioequivalent under fasted conditions, and a high‐fat meal had no clinically relevant effect on the bioavailability of the TBM tablet formulation.

Background Published evidence supporting efficacy of calcitonin gene-related peptide receptor antagonists as acute migraine treatments in males is limited. Methods To fill the gap, we present male and female data from four ubrogepant and four atogepant randomized, double-blind, placebo-controlled trials for acute and preventive treatment of migraine, respectively. Acute outcomes included 2-h pain freedom and absence of most bothersome symptom (co-primary; headache-phase randomized, double-blind, placebo-controlled trials); absence of moderate-to-severe headache within 24 h (primary; prodrome randomized, double-blind, placebo-controlled trial). Preventive outcome included change from baseline in mean monthly migraine days across 12 weeks (primary). Results Pooled data from phase 3 headache-phase ubrogepant randomized, double-blind, placebo-controlled trials showed similar rates of pain freedom (19.4% vs 21.1%) and absence of most bothersome symptom (35.1% vs 39.0%) 2 h post-dose between males and females, respectively. Time course of pain freedom and absence of most bothersome symptom over 48 h was similar between male and female subgroups. Comparable reductions in mean monthly migraine days across 12-week treatment periods were found between males and females treated with atogepant 60 mg once-daily in pooled episodic migraine and chronic migraine randomized, double-blind, placebo-controlled trials. Conclusion/Interpretation In ubrogepant and atogepant randomized, double-blind, placebo-controlled trials, although analysis power for males is limited due to small sample sizes, evidence supports similar treatment effects in males and females with migraine. Trial registration ClinicalTrials.gov: NCT02828020; NCT02867709; NCT04492020; NCT01613248; NCT02848326; NCT03777059; NCT04740827; NCT03855137

BACKGROUND:Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. METHODS:ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. FINDINGS:Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. INTERPRETATION:Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. FUNDING:Allergan (now AbbVie).

BACKGROUND:We aimed to assess the effects of preventive migraine treatment with atogepant vs. placebo on patient-reported quality of life and functioning. METHODS:Analyses of patient-reported outcomes from three 12-week, randomized, placebo-controlled trials evaluating preventive migraine treatment with atogepant 60 mg once-daily: ADVANCE (low-frequency episodic migraine [LFEM], 4-8 monthly migraine days [MMDs] and high-frequency episodic migraine [HFEM], 8-14 MMDs), PROGRESS (chronic migraine, CM) and ELEVATE (episodic migraine in those previously failed by two to four classes of oral preventive treatments). RESULTS:Least squares mean differences (95% confidence interval (CI)) in change from baseline were greater (p < 0.05) for atogepant vs. placebo for Migraine-Specific Quality of Life questionnaire Role Function-Restrictive domain scores at week 12 (ADVANCE: LFEM 12.0 (95% CI = 6.0-18.0), HFEM 9.9 (95% CI = 3.4-16.4); PROGRESS: 6.2 (95% CI = 2.5-9.8); ELEVATE: 17.7 (95% CI = 13.1-22.3)), for Headache Impact Test-6 total scores at week 12 (ADVANCE: LFEM -4.7 (95% CI = -6.7 to -2.7); HFEM -3.4 (95% CI = -5.5 to -1.2); PROGRESS: -2.8 (95% CI = -4.1 to -1.4); ELEVATE: -6.5 (95% CI = -8.3 to -4.7)) and for Activity Impairment in Migraine-Diary-Performance of Daily Activities scores across 12 weeks (ADVANCE: LFEM -2.3 (95% CI = -3.9 to -0.7), HFEM -4.5 (95% CI = -6.9 to -2.2); PROGRESS: -3.4 (95% CI = -5.3 to -1.5); ELEVATE: -4.7 (95% CI = -6.4 to -3.1)). CONCLUSIONS:Preventive migraine treatment with atogepant 60 mg once-daily vs. placebo improved measures of migraine-related quality of life and functioning among participants with different headache frequencies and histories of previous treatment failure.Trial Registration: ClinicalTrials.gov: NCT03777059 (ADVANCE); NCT03855137 (PROGRESS); NCT04740827 (ELEVATE).

Background and Objectives Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated. Methods PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours. Results Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001). Discussion Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo.

To determine the cerebrospinal fluid (CSF) to plasma concentration ratio of ubrogepant in participants with a history of migraine.

BACKGROUND:Migraine is associated with obesity. These analyses evaluated weight change with atogepant used as a preventive migraine treatment. METHODS:Five atogepant clinical trials in adults with migraine (one phase 2b/3; four phase 3) were included: Three 12-week, randomized, placebo-controlled trials (episodic migraine: two; chronic migraine: one); one 40-week, open-label extension trial and one 52-week, standard care, randomized, long-term safety trial in episodic migraine. Change from baseline in body weight was measured. RESULTS:Mean baseline body mass indexes were 30.0-30.7 kg/m2 (pooled episodic migraine [United States only]) and 25.0-25.5 kg/m2 (chronic migraine [East Asia, Europe, and North America]). More participants treated with atogepant 60 mg once-daily compared to placebo experienced ≥7% weight loss at any time in the pooled episodic migraine placebo-controlled trials (4.9% vs. 2.8%), chronic migraine placebo-controlled trial (5.8% vs. 2.0%), and pooled open-label extension and long-term safety trials (24.0% vs.14.7% in standard care [long-term safety only]). In the placebo-controlled trials, weight loss with atogepant 60 mg once-daily was observed at week 2 (pooled episodic migraine: -0.32%; chronic migraine: -0.39%), increasing at week 12 (pooled episodic migraine: -1.02%; chronic migraine: -1.50%); compared to weight gain with placebo at week 12 (pooled episodic migraine: +0.49%; chronic migraine: +0.10%). In the long-term episodic migraine studies, weight loss with atogepant 60 mg once-daily was observed at week 4 (long-term safety: -0.42%; open-label extension: -0.76%), increasing at week 40 (long-term safety: -2.38%; open-label extension: -2.09%). CONCLUSION:Atogepant was associated with modest dose- and duration-dependent weight loss. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT02848326 (CGP-MD-01); NCT03777059 (3101-301-002); NCT03700320 (long-term safety trial); NCT03939312 (open-label extension trial); NCT03855137 (3101-303-002).

Atogepant, an oral calcitonin gene‐related peptide receptor antagonist, is approved for the preventive treatment of migraine. A phase 1, open‐label, single‐dose, 2‐period crossover study evaluated the effect of a high‐fat meal on the pharmacokinetics and safety of atogepant in 20 healthy adults. Administration of atogepant 60 mg immediate‐release (IR) tablets under fed conditions reduced the area under the plasma concentration‐time curve (AUC) from 0 to time t and from 0 to time infinity by approximately 18% and reduced the maximum plasma concentration (Cmax) by 22%. The 90% confidence intervals for the geometric mean ratios of Cmax and AUC were not contained within the bioequivalence limits of 80%‐125%. There was no change in the median time to maximum plasma concentration in the fed versus fasted state. The incidence of treatment‐emergent adverse events (TEAEs) was similar between fed and fasted conditions. Four TEAEs were considered related to study intervention and were reported after participants received atogepant under fasted conditions (3 participants). A single‐dose atogepant 60 mg IR tablet was safe and tolerated under both fed and fasted states. Due to the wide effective dose range of 10‐60 mg/day for atogepant for the preventive treatment of migraine, the food effect on its pharmacokinetics is not considered clinically relevant.