Introduction:Upadacitinib has demonstrated high andrapid rates of efficacy in adolescent and adult patients withmoderate-to-severe atopic dermatitis (AD) as assessed bythe Eczema Area and Severity Index (EASI). This post hocanalysis assessed the EASI response in four anatomical re-gions for patients with moderate-to-severe AD treated withupadacitinib compared to dupilumab over 24 weeks.Methods:Data from patients randomized 1:1 to receiveupadacitinib 30 mg extended-release tablet orally once dailyor dupilumab 300 mg by subcutaneous injection every2 weeks after a loading dose of 600 mg in the Heads Upstudy were analyzed for achievement of >= 75%,>= 90%, or100% reduction of EASI in four body regions: (1) head andneck, (2) trunk (including genitals), (3) upper limbs, and (4)lower limbs (including buttocks) at each study visit throughweek 24. Patient response data from the Head and NeckPatient Global Impression of Severity (HN-PGIS) were alsoanalyzed at each study visit for comparison of upadacitinibto dupilumab.Results:Greater proportions of patientstreated with upadacitinib versus dupilumab achieved skinclearance rates of >= 75% (EASI 75) at week 1 and higherclearance rates of >= 90% (EASI 90) or 100% (EASI 100) byweek 4 or earlier in all four body regions. This difference was maintained at each visit through week 24 for both EASI 90and EASI 100. Patient responses on the HN-PGIS indicatedthat a greater proportion of patients (nominalpvalue<0.05)treated with upadacitinib compared to dupilumab reportedthat AD symptoms in the head and neck region were absentor minimal as early as week 1.Conclusion:Compared todupilumab, upadacitinib treatment provided higher rates ofrapid, sustained efficacy for the head and neck, trunk, upperlimbs, and lower limbs for the treatment of moderate-to-severe AD as measured by the EASI and supported by pa-tient responses.(c) 2024 The Author(s).Published by S. Karger AG, Basel

Introduction Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. Methods This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). Results Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (>= 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. Conclusions Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD.

Purpose: Atopic dermatitis (AD) adversely impacts quality of life (QoL). We evaluated the effect of upadacitinib, an oral selective Janus kinase inhibitor approved for moderate-to-severe AD, plus topical corticosteroids (+TCS) on patient-reported outcomes (PROs) over 52 weeks. Materials and methods: In the phase 3 AD Up study (NCT03568318), adults and adolescents with moderate-to-severe AD were randomized 1:1:1 to once-daily upadacitinib 15 mg, 30 mg, or placebo + TCS. Itch, skin pain/symptoms, sleep, QoL, daily activities, emotional state, mental health, and patient impressions of disease severity/improvement/treatment satisfaction were assessed. Results: This analysis included 901 patients. Within 1-2 weeks, PRO improvements were greater with both upadacitinib doses than with placebo (p <.05). Improvements increased through weeks 4-8; rates were generally maintained through week 52. At week 52, the proportion of patients with clinically meaningful improvements in itch (Worst Pruritus Numerical Rating Scale improvement >= 4), skin pain (AD Symptom Scale Skin Pain improvement >= 4), sleep (AD Impact Scale [ADerm-IS] Sleep improvement >= 12), daily activities (ADerm-IS Daily Activities improvement >= 14), and emotional state (ADerm-IS Emotional State improvement >= 11) ranged from 62.1%-77.7% with upadacitinib 15 mg + TCS and 71.3%-83.6% with upadacitinib 30 mg + TCS. Conclusions: Upadacitinib + TCS results in rapid, sustained improvements in burdensome AD symptoms and QoL.

Abstract Background Atogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. Methods These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. Results In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8–81.1% following an initial ≥50% response, 47.3–61.9% following an initial ≥75% response, and 34.8–41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. Conclusion Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. Trial registration ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

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).

Abstract Introduction/Background Atopic dermatitis (AD) is a debilitating chronic inflammatory skin disease with fluctuating disease severity that requires long-term control. Patients report that complete or almost complete skin clearance is highly important as a treatment goal. Upadacitinib is a selective oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 vs JAK2, JAK3, and tyrosine kinase 2. Objectives In this post-hoc analysis of the upadacitinib phase 3/3b studies, we analyzed the time patients spent in skin clearance response states over 16 weeks with upadacitinib 15 mg (UPA 15) and 30 mg (UPA 30) compared to placebo and dupilumab. Methods Data were from phase 3/3b multicenter, randomized, double-blinded studies comparing the safety and efficacy of upadacitinib to either placebo (Measure Up 1 and Measure Up 2) or dupilumab (Heads Up) in patients with moderate-to-­severe AD. In the Measure Up 1 and Measure Up 2 studies, adults and adolescents were randomized to receive UPA 15, UPA 30, or placebo once daily for 16 weeks. In the Heads Up study, adults were randomized to receive UPA 30 once daily or dupilumab 300 mg every 2 weeks beginning at week 2 following an initial loading dose of 600 mg. The days patients spent in skin clearance response states based on Eczema Area Severity Index (EASI) improvements ≥75%/90%/100% (EASI 75/90/100) from baseline were assessed. Missing data at study visits were imputed using non-responder imputation. Response states between study visits were interpolated using last observation carried forward. Results Integrated data from Measure Up 1 and Measure Up 2 included 1683 adults and adolescents randomized to UPA 15 (N=557), UPA 30 (N=567), or placebo (N=559); 44.0% were female, and 48.8% had previously received systemic therapy. In the Heads Up study, 673 adults were randomized to UPA 30 (N=342) or dupilumab (N=331); 44.3% were female, and 52.7% had previously received systemic therapy. Patients in Measure Up 1 and 2 taking UPA 15 or UPA 30 cumulatively spent a greater proportion of days in EASI 75 (UPA 15: 54.2%, UPA 30: 64.6%, Placebo: 10.2%), EASI 90 (UPA 15: 32.0%, UPA 30: 44.0%, Placebo: 3.2%), and EASI 100 (UPA 15: 7.5%, UPA 30: 13.5%, Placebo: 0.6%) response states compared to placebo over 16 weeks. In the Heads Up study, patients taking UPA 30 vs dupilumab cumulatively spent a greater proportion of days in EASI 75 (67.1% vs 44.9%), EASI 90 (47.0% vs 23.2%), and EASI 100 (12.6% vs 3.6%) response states over 16 weeks. Conclusions Treatment of moderate-to-severe AD with UPA 15 or UPA 30 resulted in a greater proportion of days spent with higher levels of skin clearance (EASI 75/90/100) compared to placebo over 16 weeks, mirroring findings from the Heads Up study comparing UPA 30 to dupilumab. Increases in time spent with high levels of skin clearance with upadacitinib treatment may reflect improved long-term disease control and translate into more time spent experiencing a better quality of life that is less burdened by AD.

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).

Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients’ quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8–13.4 times as many days with an EASI 90 response and 7.0–10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

Abstract Introduction/Background Atopic dermatitis is a chronic inflammatory skin disease characterized by intense and debilitating pruritus – its most burdensome symptom – and requires long-term control. Results from the Heads Up trial (NCT03738397) found that upadacitinib (UPA) 30 mg was superior to dupilumab (DUPI) 300 mg for improving itch as indicated by increases in the percent of improvement from baseline for Worst Pruritus NRS scores (WP-NRS). Objective This analysis compared the proportion of days patients treated with UPA or DUPI spent in itch response states indicated by WP-NRS. Methods Heads Up was a 24-week head-to-head phase 3b multicenter, randomized, double-blind study comparing UPA 30 mg to DUPI 300 mg in adults with moderate-to-severe AD. We compared the proportion of days patients treated with UPA or DUPI spent in an improved-itch state (WP-NRS improvement ≥4 relative to baseline; among patients with baseline WP-NRS ≥4) or a state of no/minimal itch (WP-NRS 0/1; among patients with baseline WP-NRS >1). Results Participants included 673 patients randomized into two groups: those taking UPA (N=342) or DUPI (N=331). At 4 and 16 weeks, patients treated with UPA vs DUPI spent a greater proportion of days in an improved-itch state (week 4: 50.0% vs 19.3%; week 16: 60.4% vs 35.7%), and in a state of no/minimal itch (week 4: 22.1% vs 4.3%; week 16: 34.4% vs 11.4%). Conclusions Treatment of moderate-to-severe AD with UPA 30 mg daily resulted in a greater proportion of days spent with meaningful itch improvement (WP-NRS improvement ≥4) and more time with no/minimal itch (WP-NRS 0/1) compared to treatment with DUPI over 4 and 16 weeks.

A treat-to-target approach was recently developed to guide systemic treatment for adults with atopic dermatitis (AD). Recommendations outlined criteria for a 3-month initial acceptable treatment target and a 6-month optimal target, evaluated using global assessment of patient-reported disease severity, as well as Eczema Area and Severity Index, itch assessed on an 11-point numerical rating scale, Dermatology Life Quality Index, or Patient-Oriented Eczema Measure. Achievement of these targets with once-daily upadacitinib (15 mg and 30 mg) monotherapy was evaluated using integrated adult data from the Measure Up 1 and 2 phase 3 studies. Among the 852 patients treated with upadacitinib 15 mg or 30 mg, the 3-month initial acceptable target was achieved by >80%, >78%, and ≥87% of patients, and the 6-month optimal target was achieved by ≥53%, >61%, and >73% of patients at weeks 2, 16, and 52, respectively. Achievement of all 6 individual criteria for each of the target goals also increased over time. These findings suggest that upadacitinib 15 mg and 30 mg may help improve standards of care in patients with moderate-to-severe AD by achieving 6-month target goals at 16 weeks and as early as 2 weeks for most patients.

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 AND OBJECTIVES:Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine. METHODS:ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18-80 years with >1 year history of EM and 4-14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2-4 classes of oral preventives. PROGRESS included participants aged 18-80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1-4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1-4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1-2 and 4. RESULTS:The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23-0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29-0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43-0.93, p = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1-4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1-4 compared with placebo. DISCUSSIONS:Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM. TRIAL REGISTRATION:ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.

Objective: To determine the number needed to treat (NNT) and number needed to harm (NNH) for atogepant for the preventive treatment of episodic migraine (EM). Background: Atogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the preventive treatment of EM in adults. NNT and NNH are clinically relevant assessments of effect size that can inform management. The Migraine-Specific Quality of Life Questionnaire (MSQ v2.1) Role Function-Restrictive (RFR) domain assesses impacts of migraine on daily functioning that are important to people with migraine. Design/Methods: The ADVANCE trial (NCT02848326) was a 12-week, randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of atogepant for the preventive treatment of EM. The NNT was calculated based on achievement of a ≥50% decrease in mean monthly migraine days (MMDs) (NNT≥50%) across 12 weeks. A second NNT was calculated based on achievement of a ≥10.9-point clinically relevant improvement from baseline in MSQ-RFR score (NNTMSQ-RFR) at week 12. NNH was calculated using the proportion of participants reporting a treatment-emergent adverse event (TEAE) leading to discontinuation. Results: A 50% reduction of MMDs from baseline was achieved by 56%–61% of atogepant participants versus 29% of placebo participants. The calculated NNTs≥50% for atogepant 10 mg, 30 mg, and 60 mg were 3.8, 3.4, and 3.1, respectively. The NNTsMSQ-RFR for the atogepant dose groups were 5.9, 5.7, and 6.3, respectively. TEAEs leading to discontinuation in participants treated with atogepant 10 mg, 30 mg, and 60 mg were reported by 4.1%, 1.8%, and 2.6% of participants, respectively, versus 2.7% of placebo-treated participants. The NNH was 73.0 for atogepant 10 mg. In the atogepant 30 mg and 60 mg dose groups, a lower percentage of participants discontinued versus placebo, resulting in negative NNT calculations (−105.5 and −949.7, respectively). Conclusions: These findings show a positive benefit-risk profile with atogepant for the preventive treatment of EM. Disclosure: Dr. Nahas has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for AbbVie. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. Dr. Nahas has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eli Lilly. Dr. Nahas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Nahas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Theranica. Dr. Nahas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BioDelivery Sciences. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Axsome. Dr. Nahas has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for AbbVie. Dr. Nahas has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Teva. Dr. Nahas has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Eli Lilly. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. Dr. Nahas has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Learning Network. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Jackson & Campbell. Dr. Nahas has received publishing royalties from a publication relating to health care. Dr. Nahas has received publishing royalties from a publication relating to health care. Dr. Nahas has received personal compensation in the range of $500-$4,999 for serving as a expert/talent for CME event with Medscape/WebMD. Dr. Ailani has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Allergan/Abbvie. Dr. Ailani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amgen. Dr. Ailani has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Ailani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck/Alder. Dr. Ailani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Dr. Ailani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Impel. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nesos. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GlaxoSmithKline. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BiodeliveryScienceIndustry. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Miravo. Dr. Ailani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Pfizer. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Impel. Dr. Ailani has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan/Abbvie. Dr. Ailani has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Theranica. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Satsuma. Dr. Ailani has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aeon. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Axsome. Dr. Ailani has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lindpharma. Dr. Ailani has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Current Pain and Headache Report. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Live. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Medscape. Dr. Ailani has stock in Ctrl M. The institution of Dr. Ailani has received research support from Allergan/Abbvie. The institution of Dr. Ailani has received research support from Eli Lilly. The institution of Dr. Ailani has received research support from Zosano. Dr. Ailani has received research support from Satsuma. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Advisory Panel with Medscape. Dr. Ailani has received personal compensation in the range of $500-$4,999 for serving as a Medical Advisor with SELF. Dr. McAllister has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aeon. Dr. McAllister has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for lilly. Dr. McAllister has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for teva. Dr. McAllister has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for abbvie. Dr. McAllister has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for biohaven. Dr. McAllister has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for lundbeck. Dr. McAllister has stock in Percept. Dr. Halker Singh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Impel. Dr. Halker Singh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Supernus. Dr. Halker Singh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Halker Singh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Dr. Halker Singh has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Current Neurology & Neuroscience Reports. Dr. Halker Singh has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Headache Journal. Dr. Halker Singh has received publishing royalties from a publication relating to health care. Dr. Halker Singh has received publishing royalties from a publication relating to health care. Dr. Halker Singh has received personal compensation in the range of $5,000-$9,999 for serving as a CME speaker with Pri-med. Dr. Halker Singh has received personal compensation in the range of $5,000-$9,999 for serving as a CME speaker with Medscape. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Allergan/Abbvie. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amgen. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Lipton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lundbeck. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for GlaxoSmithKline. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vedanta. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Lipton has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Lipton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Grifols. Dr. Lipton has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergan/Abbvie. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. Dr. Lipton has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Lipton has stock in Biohaven. Dr. Lipton has stock in Manistee. The institution of Dr. Lipton has received research support from Teva. The institution of Dr. Lipton has received research support from Amgen. The institution of Dr. Lipton has received research support from Allergan/Abbvie. The institution of Dr. Lipton has received research support from Gammacore. The institution of Dr. Lipton has received research support from Axsome. The institution of Dr. Lipton has received research support from Charleston Labs. The institution of Dr. Lipton has received research support from Eli Lilly. The institution of Dr. Lipton has received research support from Satsuma. The institution of Dr. Lipton has received research support from NIH . The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from NINDS. The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from NIA. The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from NIA. The institution of Dr. Lipton has received research support from NIH. The institution of Dr. Lipton has received research support from Veterans Administration. The institution of Dr. Lipton has received research support from NIH. Dr. Lipton has received publishing royalties from a publication relating to health care. Dr. Ma has received personal compensation for serving as an employee of AbbVie. Dr. Ma has received stock or an ownership interest from AbbVie. Pranav Gandhi has received personal compensation for serving as an employee of AbbVie. Pranav Gandhi has stock in AbbVie Inc. Dr. Smith has received personal compensation for serving as an employee of AbbVie. Dr. Smith has stock in AbbVie. Dr. Smith has received publishing royalties from a publication relating to health care. Dr. Liu has nothing to disclose. Dr. Chalermpalanupap has received personal compensation for serving as an employee of AbbVie. Dr. Chalermpalanupap has stock in AbbVie. Dr. Dabruzzo has received personal compensation for serving as an employee of AbbVie. Dr. Dabruzzo has stock in AbbVie.