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Objective: To evaluate the safety and tolerability of ubrogepant for the acute treatment of migraine in participants taking atogepant for the preventive treatment of episodic migraine (EM)., Background: Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for the preventive treatment of migraine in adults and ubrogepant is an oral CGRP receptor antagonist approved for the acute treatment of migraine in adults, with or without aura. The safety and tolerability of the concomitant use of ubrogepant and atogepant have not been previously evaluated in a clinical setting., Methods: The TANDEM study, a phase 4, two-period, multicenter, open-label study conducted in the United States, enrolled adults with migraine, with or without aura, and <15 headache days/month. In Treatment Period 1, participants took atogepant 60 mg once daily (QD) for 12 weeks and their own non-gepant acute headache medication for breakthrough migraine attacks. In Treatment Period 2, participants continued taking atogepant 60 mg QD and ubrogepant 100 mg was taken as needed (PRN) for the treatment of breakthrough migraine attacks (up to eight per 4-week interval) for 12 weeks. In Treatment Period 2, an optional second ubrogepant dose or the participant's own acute medication could be used to rescue headaches that did not resolve within 2-24 h post initial ubrogepant dose. The primary objective evaluated the safety and tolerability of the concomitant use of ubrogepant and atogepant., Results: Of 263 participants enrolled, 262 were treated in Treatment Period 1 (Safety Population 1) and 218 continued and were treated in Treatment Period 2 (Safety Population 2). The mean (standard deviation) number of ubrogepant use days in Treatment Period 2 was 6.6 (5.03) over the 12 weeks. In Treatment Periods 1 and 2, 49.6% and 43.1% of participants experienced a treatment-emergent adverse event (TEAE), respectively. The most common TEAEs (≥5%) in Treatment Period 1 and Treatment Period 2 were COVID-19 (8.4%, 3.2%), fatigue (6.5%, 1.4%), nausea (6.1%, 0.9%), decreased appetite (5.7%, 0.9%), and constipation (5.3%, 0.9%). In Treatment Period 2, no increase in the incidence and types of TEAEs in relation to the number of ubrogepant use days or doses taken were identified. During the whole treatment period, 9.9% of participants discontinued atogepant or ubrogepant treatment due to TEAEs. There was one serious TEAE in Treatment Period 1 (ureterolithiasis) and one in Treatment Period 2 (cervical myelopathy), and both were considered not related to study treatment by the study investigators., Conclusion: The use of atogepant 60 mg QD for the preventive treatment of EM and ubrogepant 100 mg PRN for the acute treatment of migraine over the 12-week open-label concomitant use treatment period was safe and well tolerated. The overall safety results were consistent with the known safety profiles of atogepant and ubrogepant when used alone and no new safety signals were identified., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

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 (C max ) by 22%. The 90% confidence intervals for the geometric mean ratios of C max 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., (© 2024 Abbvie. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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., Trial Registration Information: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020., Classification of Evidence: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.

Background and Objectives: Atogepant is an oral, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine. We evaluated the efficacy of atogepant for the preventive treatment of chronic migraine (CM) in participants with and without acute medication overuse., Methods: This subgroup analysis of the phase 3, 12-week, randomized, double-blind, placebo-controlled PROGRESS trial evaluated adults with a ≥1-year history of CM, ≥15 monthly headache days (MHDs), and ≥8 monthly migraine days (MMDs) during the 4-week baseline period. Participants were randomized (1:1:1) to placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for 12 weeks and were analyzed by acute medication overuse status (triptans/ergots for ≥10 days per month, simple analgesics for ≥15 days per month, or combinations of triptans/ergots/simple analgesics for ≥10 days per month). Outcomes included change from baseline in mean MMDs, MHDs, and monthly acute medication use days; ≥50% reduction in mean MMDs across 12 weeks; and patient-reported outcome (PRO) measures., Results: Of 755 participants in the modified intent-to-treat population, 500 (66.2%) met baseline acute medication overuse criteria (placebo, n = 169 [68.7%]; atogepant 30 mg BID, n = 161 [63.6%]; atogepant 60 mg QD, n = 170 [66.4%]). The least squares mean difference (LSMD) (95% CI) from placebo in MMDs was -2.7 (-4.0 to -1.4) with atogepant 30 mg BID and -1.9 (-3.2 to -0.6) with atogepant 60 mg QD. Mean MHDs (LSMD [95% CI] -2.8 [-4.0 to -1.5] and -2.1 [-3.3 to -0.8]) and mean acute medication use days (LSMD [95% CI] -2.8 [-4.1 to -1.6] and -2.6 [-3.9 to -1.3]) were reduced and a higher proportion of participants achieved ≥50% reduction in MMDs (odds ratio [95% CI] 2.5 [1.5-4.0] and 2.3 [1.4-3.7]) with atogepant 30 mg BID and atogepant 60 mg QD. There was a 52.1%-61.9% reduction in the proportion of atogepant-treated participants meeting acute medication overuse criteria over 12 weeks. Atogepant improved PRO measures. Similar results were observed in the subgroup without acute medication overuse., Discussion: Atogepant was effective in participants with CM, with and without acute medication overuse, as evidenced by reductions in mean MMDs, MHDs, and acute medication use days; reductions in the proportion of participants meeting acute medication overuse criteria; and improvements in PROs., Trial Registration Information: ClinicalTrials.gov NCT03855137. Submitted: February 25, 2019; first patient enrolled: March 11, 2019. clinicaltrials.gov/ct2/show/NCT03855137., Classification of Evidence: This study provides Class II evidence that atogepant reduces mean MMDs, MHDs, and monthly acute medication use days in adult patients with or without medication overuse.

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)., Competing Interests: Declaration of interests JMT, KN, HG, RDAF, and GF are employees of AbbVie and may hold AbbVie stock. CT reports support from Abbvie and Novartis for investigator-initiated trials; consulting fees from Abbvie, Eli Lilly, Dompé, Teva, Lundbeck, Pfizer, and Medscape for participating in advisory boards; support from Abbvie, Eli Lilly, Dompé, Teva, Lundbeck, and Pfizer for attending meetings; and personal fees from Abbvie, Eli Lilly, Teva, Lundbeck, and Pfizer for lecturing at symposia. She is principal investigator of clinical trials sponsored by Abbvie, Eli Lilly, Lundbeck, Pfizer, and Teva. She has received research grants from the European Commission, the Italian Ministry of Health, and the Migraine Research Foundation. PP-R reports support for the present study from AbbVie and personal fees for consulting from AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, and Teva. She has received personal fees for speaking from AbbVie, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, and Teva, and has had grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigación Carlos III, International Headache Society, Novartis, and Teva. She has participated in an advisory board for Lilly Foundation Spain. ML-M reports support for the present study from AbbVie and reports personal fees for speaker panels from Amicus, Eli Lilly, Lundbeck, Teva, UPSA, and Zambon. He has received consulting fees from AbbVie, Eli Lilly, Grunenthal, Lundbeck, Medtronic, Novartis, Orion, Pfizer, Reckitt Benkiser, Sun Pharmaceutical, Teva, UPSA, and Zambon. He has received grants for institutional support from Eli Lilly, Lundbeck, Medtronic, Novartis, Pfizer, and Teva. SS has received consulting fees from Impel Neuropharma, and personal payment as a speaker for AbbVie, Amgen, BDSI, Biohaven, Eli Lilly, Impel Neuropharma, and Teva. She has participated in advisory boards for AbbVie, Amgen, BDSI, Biohaven, Eli Lilly, Impel Neuropharma, and Teva and serves as Board of Directors for the Southern Headache Society and Carolina Headache Foundation. TN reports support for the present study from AbbVie and has received personal payments for consulting fees and speaking fees from Eli Lilly, Glenmark, Lundbeck, Novartis, Pfizer, St Jude Medical, Teva Pharmaceuticals, and UCB. He has received grants for institutional support from Eli Lilly, Glenmark, Lundbeck, Novartis, Pfizer, St Jude Medical, Teva Pharmaceuticals, and UCB. He also has served on advisory boards or as a principal investigator in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Neurocrine, Novartis, Teva Pharmaceuticals, and UCB., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant., (© 2024 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome., Methods: This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18-75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020)., Findings: Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63-2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo., Interpretation: Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome., Funding: AbbVie., Competing Interests: Declaration of interests DWD is a consultant for Amgen, Atria, CapiThera, Cerecin, Ceruvia Lifesciences, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer; receives honoraria from the American Academy of Neurology, Headache Cooperative of the Pacific, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group, Clinical Education Alliance, Teva, Amgen, Eli Lilly, Lundbeck, Pfizer, Vector Psychometric, Clinical Care Solutions, CME Outfitters, Curry Rockefeller, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin, Medlogix Communications, Medica Communications, MJH Life Sciences, Miller Medical Communications, WebMD Health, Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press; receives speaker fees from Teva, Amgen, Eli Lilly, Lundbeck, and Pfizer; is a board member for the American Brain Foundation, American Migraine Foundation, OneNeurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, Domestic Violence HOPE Foundation, Panfila, Epien, Matterhorn, Ontologics, King-Devick Technologies, Precon Health, Axon Therapeutics, and Cephalgia; receives research support from the US Department of Defense, US National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, and US Patient-Centered Outcomes Research Institute; holds stock options in Ctrl M, Aural Analytics, ExSano, Palion, Man and Science, Healint, Theranica, Second Opinion, Mobile Health, Epien, Nocira, King-Devick Technologies, Precon Health, AYYA Biosciences, Axon Therapeutics, Cephalgia, and Atria Health; is a shareholder in Matterhorn and Ontologics; is an employee of Atria Health; holds patent 17189376.1-1466 (Onabotulinum toxin dosage regimen for chronic migraine prophylaxis); and has submitted a patent application for SynaQuell via Precon Health. PJG receives financial support for this study and personal fees from AbbVie; receives a grant from Celgene; receives personal fees from Aeon Biopharma, Amgen, BioDelivery Sciences International, CoolTech, Dr Reddy's, Eli Lilly, Epalex, Impel NeuroPharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, ShiraTronics, Teva Pharmaceuticals, Tremeau, Gerson Lehrman, Guidepoint, SAI Med Partners, and Vector Metric; receives fees for educational materials from CME Outfitters, Omnia Education, and WebMD; receives fees for publishing and for medicolegal advice for headache from Massachusetts Medical Society and Oxford University Press; and holds a patent for Magnetic stimulation for headache, licensed to eNeura. TJS is on the board of directors for the American Headache Society and the American Migraine Foundation; receives research support from Amgen, Henry Jackson Foundation, Mayo Clinic, US National Institutes of Health, US Patient-Centered Outcomes Research Institute, SPARK Neuro, and US Department of Defense; is a consultant or advisory board member for AbbVie, Allergan, Axsome, Collegium, Eli Lilly, Linpharma, Lundbeck, Satsuma, and Theranica; holds stock options in Aural Analytics and Nocira; and receives royalties from UpToDate. RBL receives financial support for this study from AbbVie; receives research support, paid to his institution, from the US National Institutes of Health, the S&L Marx Foundation, the Czap Foundation, the National Headache Foundation, and the US Food and Drug Administration; is a consultant or advisory board member for and receives honoraria or research support from AbbVie, Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr Reddy's, Promius, electroCore, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Alder, Merck Sharp & Dohme, Pernix, Pfizer, Teva, Vector, and Vedanta Research; and holds stock options in Biohaven and Manistee. CL and JMT are employees of AbbVie and hold AbbVie stock. KL, SYY, LS, and MF are former employees of AbbVie and hold AbbVie stock., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate an alternative method of defining acute treatment success in migraine by combining multiple indicators into a single dichotomous measure of success., Background: Migraine is characterized by a symptom complex; combining these features as a single endpoint may improve the measurement of treatment effects and better predict patient satisfaction with treatment., Methods: We used a confirmatory latent class model (LCM) with two latent classes interpreted as treatment success and treatment failure. Pooled data for placebo and ubrogepant 50 mg from the ACHIEVE I and ACHIEVE II trials and data for ubrogepant 100 mg from ACHIEVE I were used. LCM inputs included pre-dose and 2-h post-dose measures of pain severity (0-3), the presence/absence of associated symptoms (nausea, photophobia, and phonophobia [0 or 1]), and functional disability (0-3). All definitions were validated against satisfaction with study medication (SWSM) at 24 h post-dose; results were compared with 2-hour pain freedom (2hPF)., Results: This pooled analysis included 2247 participants. At 2 h post-dose in the ubrogepant 50 and 100 mg dose groups, 53.2% (472/887) and 54.9% (246/448) of participants, respectively, were classified as achieving treatment success using the LCM-based approach, compared to 39.0% (356/912) of participants in the placebo group. The results for treatment success using the 2hPF endpoint were 20.7% (184/887) and 21.5% (96/447) in the ubrogepant 50 and 100 mg dose groups, respectively, compared to 12.7% (116/912) for placebo. Using 24-h SWSM as an external validator, the LCM approach sensitivity and correct classification rates were higher than for 2hPF., Conclusion: The LCM approach led to higher rates of treatment success and greater separation between ubrogepant and placebo and was a more sensitive predictor of treatment satisfaction than the regulatory endpoint of 2hPF., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine., Methods: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18-80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1-4, 5-8, and 9-12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137)., Findings: Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18-74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was -7·5 (SE 0·4) with atogepant 30 mg twice a day, -6·9 (0·4) with atogepant 60 mg once a day, and -5·1 (0·4) with placebo. Least squares mean difference from placebo was -2·4 with atogepant 30 mg twice a day (95% CI -3·5 to -1·3; adjusted p<0·0001) and -1·8 with atogepant 60 mg once a day (-2·9 to -0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%])., Interpretation: Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant., Funding: Allergan (now AbbVie)., Competing Interests: Declaration of interests PPR reports support for the present study from AbbVie, personal fees from AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, and Teva, and grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigación Carlos III, International Headache Society, Novartis, and Teva. JA reports support for the present study from AbbVie, personal fees from AbbVie, Aeon, Amgen, Axsome, Biohaven, BioDelivery Sciences International, Eli Lilly, GlaxoSmithKline, Impel, Linpharma, Lundbeck, Miravio, Neso, Neurolief, Satsuma, Teva, and Theranica, clinical trial support from AbbVie, Biohaven, Eli Lilly, Satsuma, and Zosano, and stock options from CtrlM. She has provided editorial services to Current Pain and Headache Reports, Medscape, NeurologyLive, and SELF magazine. MA reports support for the present study from AbbVie, personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals, and grants paid to his institution from the Lundbeck Foundation, Novartis, and Novo Nordisk Foundation. PJG reports support for the present study and personal fees during the conduct of the study from AbbVie, a grant from Celgene, and personal fees from Aeon Biopharma, Amgen, BioDelivery Sciences International, CoolTech LLC, Dr Reddy's Laboratories, Eli Lilly and Company, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, Shiratronics, Teva Pharmaceuticals, and Tremeau, personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric, fees for educational materials from CME Outfitters and WebMD, and fees for publishing from Massachusetts Medical Society and Oxford University Press and for medicolegal advice in headache. He has a patent for magnetic stimulation for headache, which is licensed to eNeura without fee. RBL reports support for the present study from AbbVie, research support paid to his institution for the present study from the National Institutes of Health/National Institute on Aging (2PO1 AG003949, Einstein Aging Study), the S&L Marx Foundation, the Czap Foundation, the National Headache Foundation, the Migraine Research Foundation, and the US Food and Drug Administration, and personal fees from AbbVie/Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr. Reddy's Laboratories (Promius), electroCore, Eli Lilly, eNeura, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Teva, Vector, and Vedanta Research. He holds stock or options in Biohaven and Manistee. UR reports support for the present study paid to his institution from AbbVie, grants from BMBF (German Ministry for Research) and Novartis, and personal and institutional fees from AbbVie, Allergan, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, StreaMedUp, and Teva. HG, BS, RB, RDAF, EM, and JMT are employees of AbbVie and may hold AbbVie stock. KL, RM, SYY, LS, and MF are former employees of AbbVie and may hold AbbVie stock., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the efficacy and safety of ubrogepant for the acute treatment of perimenstrual migraine (pmM) attacks., Background: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults., Methods: After completing one of two phase 3 trials, participants could enroll in a phase 3, 52-week, open-label, long-term safety extension trial and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. This post hoc analysis evaluated the efficacy of ubrogepant in a subset of women who treated ≥1 pmM or non-pmM attack with ubrogepant. A pmM attack started on or between 2 days before and the first 3 days of menstrual bleeding. Mean (standard deviation [SD]) percentages of ubrogepant-treated attacks achieving 2-h pain freedom and pain relief were reported, with outcomes weighted equally by participant., Results: Of 734 women in the modified intent-to-treat population, 354 reported ≥1 menstrual cycle start date and a ubrogepant-treated headache day in the same month. A qualifying pmM and non-pmM attack was reported by 278 and 716 women, respectively. Pain freedom at 2 h was achieved in a mean (SD) of 28.7% (37.4) of pmM attacks and 22.1% (26.9) of non-pmM attacks treated with ubrogepant 50 mg (p = 0.054) and 29.7% (35.2) versus 25.3% (26.3) of attacks treated with ubrogepant 100 mg (p = 0.757). No difference was found in the mean percentage of ubrogepant-treated pmM and non-pmM attacks that achieved 2-h pain relief with ubrogepant 50 mg (64.8% [39.9] vs. 65.2% [32.4]; p = 0.683) and with 100 mg (67.1% [37.4] vs. 68.4% [30.2]; p = 0.273). Treatment-related treatment-emergent adverse events were reported by 8.8% (12/137) and 12.8% (18/141) in the ubrogepant 50 and 100 mg pmM subgroups, respectively., Conclusions: Ubrogepant demonstrated similar efficacy for the treatment of pmM and non-pmM attacks. No new safety signals were identified., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on single-dose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: C max and AUC of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multiple-dose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inhibitor and decreased significantly when co-administered with a strong CYP3A4 inducer.

Objective: To evaluate potential drug-drug interactions of ubrogepant and atogepant., Background: Ubrogepant and atogepant, calcitonin gene-related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks., Methods: A phase Ib, multi-center, open-label, fixed-sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration-approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed-dose schedule every 3 days, regardless of whether a participant was experiencing a migraine attack. Secondary endpoints included safety and tolerability. Clinical safety measurements were monitored throughout the study., Results: Of the 31 participants enrolled, 26 completed the study. A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Co-administration of ubrogepant with atogepant resulted in a 19% increase (geometric mean ratio 118.80, 90% confidence interval [CI] 108.69-129.84) in the ubrogepant area under the plasma concentration-time curve and a 26% increase (geometric mean ratio 125.63, 90% CI 105.58-149.48) in the ubrogepant maximum plasma concentration. These statistically significant changes in ubrogepant exposure were not clinically meaningful, and no new safety concerns were identified for the combination., Conclusion: The combination use of atogepant and ubrogepant was safe and well tolerated in adult participants with a history of migraine enrolled in the study. Pharmacokinetic changes during co-administration were not clinically meaningful., (© 2023 AbbVie Inc and The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: Atogepant is a United States Food and Drug Administration-approved oral calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. The study objective was to evaluate the long-term safety and tolerability of atogepant in participants who completed the phase 3 ADVANCE trial (NCT03777059)., Methods: This 40-week, open-label extension trial (NCT03939312) monitored safety in participants receiving oral atogepant 60 mg once daily, followed by a four-week safety follow-up period., Results: Of the 685 participants taking at least one dose of atogepant, the treatment period was completed by 74.6% of participants with a mean (standard deviation) treatment duration of 233.6 (89.3) days. Treatment-emergent adverse events occurred in 62.5% of participants, with upper respiratory tract infection (5.5%), urinary tract infection (5.3%), nasopharyngitis (4.8%), sinusitis (3.6%), constipation (3.4%), and nausea (3.4%) occurring at ≥3%. Serious adverse events were observed in 3.4% of participants (none were treatment-related), and there were no deaths. Adverse events leading to discontinuation occurring at >0.1% were nausea (0.4%) and abdominal pain, vomiting, weight decrease, dizziness, and migraine (0.3% each)., Conclusion: These results are consistent with atogepant's known safety profile and support long-term use of atogepant 60 mg once daily dosing as safe and well tolerated.ClinicalTrials.gov Registration Number: NCT03939312.

Objective: To assess long-term safety, tolerability, and efficacy of once-daily oral atogepant 60 mg in adults with migraine., Background: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of episodic migraine., Methods: A 52-week, multicenter, randomized, open-label trial of adults (18-80 years) with migraine. Lead-in trial completers or newly enrolled participants with 4-14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia-Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs., Results: The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was -3.8 (0.1) for weeks 1-4 and -5.2 (0.2) at weeks 49-52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1-4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49-52., Conclusion: Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1-year, open-label trial was safe, well tolerated, and efficacious., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background and Objectives: To examine the efficacy of ubrogepant in the treatment of migraine with mild vs moderate or severe pain., Methods: This was a phase 3, open-label, dose-blinded, 52-week extension trial. Adults with migraine were randomized 1:1:1 (usual care, ubrogepant 50 mg, or ubrogepant 100 mg). Participants treated up to 8 migraine attacks of any pain intensity every 4 weeks. Efficacy outcomes (only collected for ubrogepant) included 2-hour pain freedom (2hPF), freedom from associated symptoms, and from disability. A generalized linear mixed model with binomial distribution and logit link function was used to assess the influence of baseline pain intensity on treatment outcomes in this post hoc analysis., Results: Data for 19,291 attacks from 808 participants were included. 2hPF rates were higher for attacks treated when pain was mild vs moderate or severe: ubrogepant 50 mg (47.1% vs 23.6%; odds ratio [95% CI] 2.89 [2.57-3.24]) and ubrogepant 100 mg (55.2% vs 26.1%; 3.50 [3.12-3.92]; p < 0.0001 both doses). Rates of freedom from photophobia, phonophobia, and nausea 2 hours after treatment were also significantly higher following the treatment of mild vs moderate or severe pain ( p < 0.001 all symptoms, both doses). At 2 hours, the proportion of attacks with normal function was more than double for both doses of ubrogepant ( p < 0.001). The most common adverse event was upper respiratory tract infection (∼11% both doses). Serious adverse events were reported by 2% in ubrogepant 50 mg and 3% in ubrogepant 100 mg., Discussion: Relative to treatment of attacks with moderate or severe pain, treatment with ubrogepant during mild pain resulted in significantly higher rates of freedom from pain, freedom from associated symptoms, and achieving normal function 2 hours after administration., Trial Registration Information: ClinicalTrials.gov, NCT02873221., Classification of Evidence: This trial provides Class III evidence that treatment of migraine with ubrogepant when pain is mild vs moderate or severe increases the likelihood of achieving pain freedom, absence of symptoms, and normal function within 2 hours postdose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Importance: Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments., Objective: To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates., Design, Setting, and Participants: This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US., Interventions: Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks., Main Outcomes and Measures: These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period., Results: Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo., Conclusions and Relevance: At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses., Trial Registration: ClinicalTrials.gov Identifier: NCT03777059.

Background: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of migraine., Methods: In the double-blind, phase 3 ADVANCE trial, participants with 4-14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1-4, and proportion of participants with a migraine on each day during the first week., Results: We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1-4, mean change from baseline in mean monthly migraine days ranged from -3.1 to -3.9 across atogepant doses vs -1.6 for placebo ( p  < 0.0001). For weeks 5-8 and 9-12, reductions in mean monthly migraine days ranged from -3.7 to -4.2 for atogepant vs -2.9 for placebo ( p  ≤ 0.012) and -4.2 to -4.4 for atogepant vs -3.0 for placebo ( p  < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from -0.77 to -1.03 for atogepant vs -0.29 with placebo ( p  < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo ( p  ≤ 0.0071)., Conclusion: Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period. Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059.