Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: 52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and Measure Up 2).

BACKGROUND: Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis. OBJECTIVE: We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis. METHODS: Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week 16. RESULTS: This analysis included 1609 patients (upadacitinib 15 mg, N = 557; upadacitinib 30 mg, N = 567; placebo, N = 485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib 30 mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes. CONCLUSIONS: Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week 52. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018).

Atopic dermatitis, or eczema, is a condition that causes painful itchy dry skin, which is burdensome for patients and has a negative impact on quality of life. These symptoms frequently lead to disruption of daily activities such as school and work, decreased self-confidence, social isolation, anxiety, depression, and sleep disturbance. Symptoms of atopic dermatitis, such as itch and sleep disturbance, can only be assessed by patients. Therefore, it is important to consider patients' perceptions of their symptoms and the related impact on their quality of life, especially when evaluating treatment benefits. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. In two clinical trials (Measure Up 1 and Measure Up 2), we investigated how treatment with upadacitinib (15-mg or 30-mg dose) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis would impact their symptoms and quality of life over a 1-year period. We measured changes over time in patients' assessments of itch, pain, other skin-related symptoms, sleep, daily activities, emotional state, mental health, and overall quality of life. Patients treated with upadacitinib experienced improvements in symptoms of atopic dermatitis and quality of life within the first 1­2 weeks of treatment. These improvements continued to steadily increase in the following weeks and lasted through 1 year of treatment. In conclusion, once-daily treatment with upadacitinib 15 or 30 mg led to early and lasting improvements in the well-being of patients with atopic dermatitis.

Real-world clinical, psychosocial and economic burden of atopic dermatitis: Results from a multicountry study.

BACKGROUND: Atopic dermatitis (AD), a relapsing, inflammatory skin disease, is associated with pruritus that can negatively affect patients' quality of life. Understanding the burden of AD is critical for informing and tailoring treatment and disease management to improve patient outcomes. This study characterized global treatment patterns and the clinical, psychosocial and economic burden of moderate-to-severe AD. METHODS: MEASURE-AD was a cross-sectional 28-country study in patients with physician-confirmed moderate-to-severe AD who were either receiving or eligible for systemic therapy for AD. Patients ≥12 years were enrolled between December 2019 and December 2020 while attending routine office or clinic visit. Primary outcomes included Worst Pruritus Numeric Rating Scale (WP-NRS; range: 0-10) and Dermatology Life Quality Index (DLQI; range: 0-30) and Children's DLQI (CDLQI; range: 0-30). Secondary outcomes included physician- and patient-reported clinical, psychosocial and economic burden. RESULTS: Of the 1591 patients enrolled, 1558 (1434 adults and 124 adolescents) fulfilled all patient selection criteria and were included in this analysis. Almost all patients (98.4%) in the total population were using AD medications and more than half (56%) were receiving systemic medication (15% systemic monotherapy). The most used systemic therapies were dupilumab (56.3%), systemic glucocorticoids (18.1%) and methotrexate (16.2%). Mean WP-NRS was 5.3 in the total population, and most patients (≥55%) reported moderate-to-severe pruritus (WP-NRS ≥4). Mean DLQI was 10.8 and mean CDLQI was 9.6. Secondary endpoints demonstrated substantial clinical, psychosocial, and economic burden of disease. Subgroup analysis demonstrated that patients receiving systemic therapy had lower disease burden than those not taking systemic medications. CONCLUSIONS: While systemic therapy lowers overall disease burden, patients with moderate-to-severe AD continue to have substantial multidimensional disease burden and uncontrolled disease. Overall, there is a need for effective disease management, including effective treatments that improve patients' psychosocial outcomes and reduce the economic burden of AD.

Aggregate Response Benefit in Skin Clearance and Itch Reduction With Upadacitinib or Dupilumab in Patients With Moderate-to-Severe Atopic Dermatitis®.

Background: In patients with moderate-to-severe atopic Dermatitis® (AD), greater skin clearance and itch reduction are associated with more pronounced improvements in quality of life (QoL). Objective: To characterize the aggregate response benefit with upadacitinib versus dupilumab or placebo in patients with moderate-to-severe AD. Methods: Degree of skin clearance and itch response in 3 phase 3 studies (Heads Up [NCT03738397] and Measure Up 1/2 [integrated; NCT03569293/NCT03607422]) were assessed by the Eczema Area and Severity Index (EASI) and Worst Pruritus Numerical Rating Scale (WP-NRS), respectively, using mutually exclusive categories. The aggregate response benefit with upadacitinib over dupilumab or placebo was determined by summing incremental differences for each EASI or WP-NRS category across the full distribution of patient responses. Results: Comparisons across EASI improvement threshold distributions, EASI severity levels, and WP-NRS categories demonstrated an aggregate response benefit favoring upadacitinib over dupilumab as early as week 4 and continuing at weeks 16 and 24. Similar trends were observed for upadacitinib 15 and 30 mg versus placebo. Conclusions: The aggregate response benefit in skin clearance and itch reduction favored upadacitinib 30 mg over dupilumab and upadacitinib 15 or 30 mg over placebo. These benefits may translate to overall greater improvements in patient QoL.

Comparative Efficacy of Targeted Systemic Therapies for Moderate-to-Severe Atopic Dermatitis without Topical Corticosteroids: An Updated Network Meta-analysis.

INTRODUCTION: The treatment landscape for moderate-to-severe atopic dermatitis (AD) continues to expand. This network meta-analysis (NMA) updates a previously conducted NMA to include data from the most recent phase 3 trials to assess the comparative efficacy of targeted systemic therapies without the addition of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) in adults with moderate-to-severe AD. METHODS: Data from recent phase 3 monotherapy trials of lebrikizumab, ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), were included in the analyses, along with other eligible phase 3/4 randomized placebo-controlled trials for abrocitinib, baricitinib, dupilumab, tralokinumab, and upadacitinib identified through a systemic literature review in Silverberg et al. (Dermatol Ther (Heidelb) 12(5):1181-1196, 2022). The proportion of patients achieving Eczema Area and Severity Index (EASI) improvement ≥ 90% from baseline (EASI-90), EASI improvement ≥ 75% from baseline (EASI-75), ≥ 4-point improvement on Pruritus Numerical Rating Scale from baseline (ΔNRS ≥ 4), and Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and reduction of ≥ 2 points from baseline (IGA 0/1) were evaluated using a Bayesian network meta-analysis. RESULTS: The updated NMA analyzed 13 unique placebo-controlled trials involving 7105 patients in 32 arms across 6 targeted therapies. Upadacitinib 30 mg was the most efficacious therapy across all endpoints at the primary timepoint (week 12 or 16) and at earlier timepoints, generally followed by abrocitinib 200 mg, upadacitinib 15 mg, dupilumab 300 mg, and lebrikizumab 250 mg or abrocitinib 100 mg. Baricitinib 2 mg and tralokinumab were generally ranked lower across outcomes. CONCLUSIONS: Many factors need to be considered for treatment selection for AD, especially as new treatments continue to emerge. After incorporating recent placebo-controlled phase 3 data of lebrikizumab, upadacitinib 30 mg, upadacitinib 15 mg, and abrocitinib 200 mg remain the most efficacious targeted systemic therapies over 12-16 weeks of therapy in AD. These updated findings can help healthcare providers when creating a patient's personalized treatment plan.

Upadacitinib treatment withdrawal and retreatment in patients with moderate-to-severe atopic dermatitis: Results from a phase 2b, randomized, controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic eczematous lesions. The effect of treatment withdrawal after response to upadacitinib oral treatment is not fully characterized. OBJECTIVES: Assess the effect of upadacitinib withdrawal on skin clearance and itch improvement in adult patients with moderate-to-severe AD and evaluate the kinetics of recovery on rescue treatment. METHODS: Data from a phase 2b randomized, placebo-controlled trial (NCT02925117) of upadacitinib in patients with moderate-to-severe AD were analysed. Patients were randomized 1:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg or placebo, and then at Week 16, patients were re-randomized 1:1 to receive the same dose of upadacitinib (upadacitinib 30 mg for patients initialized to placebo) or placebo. From Week 20, those who experienced loss of response defined as Eczema Area and Severity Index <50% improvement from baseline (EASI 50) received rescue treatment with upadacitinib 30 mg. RESULTS: Patients who withdrew from upadacitinib experienced a rapid loss of skin clearance response, while those who switched from placebo to upadacitinib gained response. Loss of skin clearance response occurred within 4 weeks and worsening of itch occurred within 5 days. In patients who originally received placebo or a lower dose of upadacitinib leading to a loss of EASI response, rescue treatment with upadacitinib 30 mg resulted in rapid recovery or improvement of both skin and itch responses; most patients who were re-randomized to placebo achieved EASI 75 and IGA 0/1 by 8 weeks of rescue treatment. No new safety risks were observed. CONCLUSIONS: Continuous treatment with upadacitinib is suggested to maintain skin clearance and antipruritic effects.

Efficacy and safety of switching from dupilumab to upadacitinib versus continuous upadacitinib in moderate-to-severe atopic dermatitis: Results from an open-label extension of the phase 3, randomized, controlled trial (Heads Up).

BACKGROUND: Characterization of upadacitinib use and switching from dupilumab to upadacitinib among patients with moderate-to-severe atopic dermatitis (AD) is needed. OBJECTIVE: To evaluate the long-term safety and efficacy of continuous upadacitinib 30 mg and switching to upadacitinib after 24 weeks of dupilumab. METHODS: Adults who completed the phase 3b clinical trial of oral upadacitinib 30 mg vs injectable dupilumab 300 mg (Heads Up) and entered a 52-week open-label extension (OLE) (NCT04195698) were included. All patients received 30-mg upadacitinib during the open-label period. We report results of a prespecified interim OLE 16-week analysis. RESULTS: Patients (n = 239) continuing upadacitinib maintained high levels of skin and itch response. Patients (n = 245) switching from dupilumab experienced additional incremental improvements in clinical responses within 4 weeks of starting upadacitinib. Most patients who did not achieve adequate clinical responses with dupilumab did so with upadacitinib. The safety profile of upadacitinib up to 40 weeks (week 16 of OLE) was consistent with previous phase 3 AD studies, with no new safety risks observed. LIMITATIONS: Open-label study design. CONCLUSIONS: Clinical responses are maintained with continuous upadacitinib through 40 weeks and patients regardless of prior dupilumab response experienced improved outcomes when switched to upadacitinib. No new safety risks were observed.

Population pharmacokinetic and exposure-response modelling to inform upadacitinib dose selection in adolescent and adult patients with atopic dermatitis.

AIMS: First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates that may impact upadacitinib pharmacokinetics. Second, the exposure-response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure-response relationship and dose selection for patients with AD were evaluated. METHODS: A two-compartment model with combined first- and zero-order absorption adequately characterized the upadacitinib concentration-time profiles in 911 healthy volunteer adolescent and adult participants with AD who received upadacitinib 15 or 30 mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure-efficacy and safety relationships, and simulations were performed based on final exposure-response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS. RESULTS: Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase the upadacitinib area under the plasma concentration-time curve from time zero to 24 h after dosing (AUC24 ) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC24 compared to male participants. Participants with AD were predicted to have 18% higher AUC24 compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8-14%) with the upadacitinib 30 mg once-daily regimen compared to 15 mg once-daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure-dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure-response models. CONCLUSION: The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.

Efficacy and Safety of Upadacitinib Treatment in Adolescents With Moderate-to-Severe Atopic Dermatitis: Analysis of the Measure Up 1, Measure Up 2, and AD Up Randomized Clinical Trials.

Importance: Atopic dermatitis onset usually occurs in childhood. Persistence of disease into adolescence and adulthood is common. It is important to evaluate new treatment options in adolescents because of the high unmet need in this population. Objective: To assess the efficacy and safety of upadacitinib to treat moderate-to-severe atopic dermatitis in adolescents. Design, Setting, and Participants: Prespecified analysis of adolescents enrolled in 3 randomized, double-blind, placebo-controlled phase 3 clinical trials in more than 20 countries across Europe, North and South America, Oceania, the Middle East, and the Asia-Pacific region from July 2018 through December 2020. Participants were adolescents aged 12 to 17 years with moderate-to-severe atopic dermatitis. Data analysis was performed from April to August 2021. Interventions: Patients were randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo alone (Measure Up 1 and Measure Up 2) or with topical corticosteroids (AD Up). Main Outcomes and Measures: Safety and efficacy, including at least a 75% improvement in the Eczema Area and Severity Index from baseline and validated Investigator Global Assessment for Atopic Dermatitis score of 0 (clear) or 1 (almost clear) at week 16 (coprimary end points). Results: A total of 552 adolescents (290 female; 262 male) were randomized. Mean (SD) age was 15.4 (1.8), 15.5 (1.7), and 15.3 (1.8) years for adolescents in Measure Up 1, Measure Up 2, and AD Up, respectively. In Measure Up 1, Measure Up 2, and AD Up, respectively, a greater proportion of adolescents (% [95% CI]) achieved at least 75% improvement in the Eczema Area and Severity Index at week 16 with upadacitinib 15 mg (73% [63%-84%], 69% [57%-81%], 63% [51%-76%]), and upadacitinib 30 mg (78% [68%-88%], 73% [62%-85%], 84% [75%-94%]), than with placebo (12% [4%-20%], 13% [5%-22%], 30% [19%-42%]; nominal P < .001 for all comparisons vs placebo). Similarly, a greater proportion of adolescents treated with upadacitinib achieved a validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 at week 16 and improvements in quality of life with upadacitinib than with placebo. Upadacitinib was generally well tolerated in adolescents. Acne was the most common adverse event, and all acne events were mild or moderate. Conclusions and Relevance: In this analysis of 3 randomized clinical trials, upadacitinib was an effective treatment for adolescents with moderate-to-severe atopic dermatitis, with an acceptable safety profile. Trial Registration: ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1), NCT03607422 (Measure Up 2), and NCT03568318 (AD Up).

Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: 2-Year Interim Results from the Phase 3 Rising Up Study.

INTRODUCTION: Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. METHODS: Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS). RESULTS: A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n = 120; UPA30, n = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112. CONCLUSION: UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.

Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials.

BACKGROUND: Acne is the most frequent adverse event associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: To characterize the adverse event of acne associated with upadacitinib. METHODS: This was a post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials of upadacitinib, alone (NCT03569293 and NCT03607422) or in combination with topical corticosteroids (NCT03568318). Data included were from the 16-week placebo-controlled period. RESULTS: Over 16 weeks, 84 of 857 (9.8%), 131 of 864 (15.2%), and 19 of 862 (2.2%) patients randomized to receive upadacitinib 15 mg, upadacitinib 30 mg, and placebo, respectively, experienced acne. All cases of acne, except 1, were mild/moderate in severity; 2 patients discontinued treatment due to moderate acne. Acne occurred at higher rates among younger, female, and non-White patients. Acne required no intervention in 40.5% and 46.6% of patients receiving upadacitinib 15 and 30 mg, respectively; most remaining cases were managed with topical antibiotics, benzoyl peroxide, and/or retinoids. Acne also had no impact on patient-reported outcomes. LIMITATIONS: This study was relatively short in duration and had a small patient population. CONCLUSIONS: Acne associated with upadacitinib for atopic dermatitis treatment is usually mild/moderate in severity and managed with topical therapies or no intervention.

Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network Meta-analysis.

INTRODUCTION: The comparative efficacy of targeted systemic therapies for moderate to severe atopic dermatitis (AD) has not been systematically assessed using recent phase 3 data. This network meta-analysis assesses the comparative efficacy of targeted systemic therapies without the addition of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) in adults with moderate to severe AD. METHODS: The systematic literature review searched through 17 May 2021 for phase 3/4 trials with upadacitinib, interleukin-4 (IL-4), interleukin-13 (IL-13), or JAK inhibitors compared with placebo or active intervention for adults and adolescents with moderate to severe AD with inadequate response to TCS/TCI or for whom TCS/TCI was medically inadvisable, without restrictions on year or region. Researchers assessed data using PRISMA guidelines. The proportion of patients achieving trial co-primary endpoints [Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and reduction of ≥ 2 points from baseline; proportion of patients achieving Eczema Area and Severity Index (EASI) improvement ≥ 75% from baseline (EASI-75)]; EASI improvement ≥ 90% from baseline (EASI-90); and ≥ 4-point improvement on Pruritus Numerical Rating Scale from baseline (ΔNRS ≥ 4) were evaluated using Bayesian network meta-analysis. RESULTS: Of 3415 initially identified records, network meta-analysis (NMA) ultimately included 6 records representing 9 unique studies. Two upadacitinib trials were also included. Eleven clinical trials including 6254 patients were analyzed. Upadacitinib 30 mg daily was the most efficacious therapy across all endpoints at the primary endpoint (week 12 or 16) and at earlier timepoints, followed by upadacitinib 15 mg daily and abrocitinib 200 mg daily. DISCUSSION: Many factors need to be considered for treatment selection for AD. These findings can help healthcare providers when personalizing a patient's treatment. CONCLUSION: Upadacitinib 30 mg daily, upadacitinib 15 mg daily, and abrocitinib 200 mg daily may be the most efficacious targeted systemic therapies over 12-16 weeks of therapy in AD.

A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.

BACKGROUND: Systemic atopic dermatitis treatments that have acceptable safety are needed. OBJECTIVE: To evaluate the safety of the oral Janus kinase inhibitor upadacitinib in combination with topical corticosteroids (TCSs) for the treatment of atopic dermatitis. METHODS: In this phase 3, double-blind study (Rising Up), Japanese patients (12-75 years) with moderate-to-severe atopic dermatitis were randomized in a 1:1:1 ratio to receive 15 mg of upadacitinib + TCS, 30 mg of upadacitinib + TCS, or a placebo + TCS (rerandomized in a 1:1 ratio to receive either 15 or 30 mg of upadacitinib + TCS at week 16). Adverse events and laboratory data were assessed for safety. RESULTS: In 272 treated patients, the serious adverse event rates were similar for 15- and 30-mg upadacitinib + TCS at week 24 (15 mg, 56%; 30 mg, 64%) but greater than those for placebo + TCS (42%). Acne (all mild or moderate; none leading to discontinuation) occurred more frequently with upadacitinib + TCS (15 mg, 13.2%; 30 mg, 19.8%) than with placebo + TCS (5.6%). Furthermore, herpes zoster infection (4.4% vs 0%), anemia (1.1% vs 0%), neutropenia (4.4% vs 1.1%), and creatine phosphokinase elevations (2.2% vs 1.1%) occurred more frequently with 30-mg upadacitinib + TCS than with 15-mg upadacitinib + TCS; none of these events were reported with placebo + TCS. No thromboembolic events, malignancies, gastrointestinal perforations, active tuberculosis, or deaths occurred. LIMITATIONS: The limitations included a small sample size and short observation period as well as nongeneralizability of the results beyond Japanese populations. CONCLUSIONS: The results were generally consistent with those of previous reports; no new safety risks were detected.

Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial.

IMPORTANCE: Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement. OBJECTIVE: To assess the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD. DESIGN, SETTING, AND PARTICIPANTS: Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population. INTERVENTIONS: Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week. MAIN OUTCOMES AND MEASURES: The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug. RESULTS: Of 924 patients screened, 348 (183 men [52.6%]; mean [SD] age, 36.6 [14.6] years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men [56.4%]; mean [SD] age, 36.9 [14.1] years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 (P = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean [SE], 31.4% [1.7%] vs 8.8% [1.8%]; P < .001), achievement of EASI75 as early as week 2 (152 [43.7%] vs 60 [17.4%]; P < .001), and achievement of EASI100 at week 16 (97 [27.9%] vs 26 [7.6%]; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab. CONCLUSIONS AND RELEVANCE: During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03738397.

Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.

BACKGROUND: Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting. FINDINGS: Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4-60·2] for the upadacitinib 15 mg group; 63·4% [57·1-69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9-53·9] for the upadacitinib 15 mg group; 59·6% [53·1-66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2-46·4] for the upadacitinib 15 mg group; 53·6% [47·2-60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8-40·2] for the upadacitinib 15 mg group; 47·4% [41·0-53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients). INTERPRETATION: Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit-risk profile in adolescents and adults with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Exposure-Response Analyses for Upadacitinib Efficacy in Subjects With Atopic Dermatitis-Analyses of Phase 2b Study to Support Selection of Phase 3 Doses.

Upadacitinib is a selective Janus kinase 1 inhibitor that was recently approved for treatment of rheumatoid arthritis and is currently being evaluated for treatment of several other autoimmune diseases, including atopic dermatitis (AD). The relationships between upadacitinib plasma exposure and efficacy (assessed as Eczema Area Severity Index [EASI]-75, EASI-90, and Investigator Global Assessment [IGA] 0/1) in subjects with moderate to severe atopic dermatitis were characterized using the data from 167 subjects who were enrolled in a phase 2b dose-ranging study. Subjects were randomized to receive once daily doses of monotherapy treatment with upadacitinib extended-release 7.5, 15, or 30 mg or placebo for 16 weeks. Logistic regression models were developed and utilized to simulate efficacy for upadacitinib with an approximate phase 3 sample size. Based on exposure-response models, 15 mg once daily is predicted to achieve EASI-75, EASI-90, and IGA 0/1 responses in 48%, 26%, and 29% of subjects, respectively, compared with placebo responses of 9%, 2%, and 2%, respectively, whereas 30 mg once daily is predicted to provide an additional approximately 20% greater efficacy for these end points relative to 15 mg once daily. These analyses supported the selection of upadacitinib doses that are being evaluated in ongoing global phase 3 studies in atopic dermatitis.

The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis.

BACKGROUND: An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization. OBJECTIVES: To develop an IGA scale, training module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability. METHODS: Expert dermatologists participated in the development of the validated IGA for AD (vIGA-ADTM). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination. RESULTS: Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W [Kendall's W], 0.809; intraclass correlation [ICC], 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification. LIMITATIONS: Ratings were assessed on photographs. CONCLUSION: A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed.

Baseline Characteristics from UNITE: An Observational, International, Multicentre Registry to Evaluate Hidradenitis Suppurativa (Acne Inversa) in Clinical Practice.

BACKGROUND: Hidradenitis suppurativa (HS), also known as acne inversa, is a recurring, painful, chronic, and sometimes disfiguring inflammatory skin disease. OBJECTIVES: Our objective was to report the baseline clinical characteristics, natural history, and associated outcomes of patients with HS from the ongoing, prospective, non-interventional UNITE registry that is collecting data regarding the natural history and associated outcomes of HS. METHODS: Patients with inflammatory HS lesions were enrolled, including adolescents (aged 12 to < 18 years) and adults (aged ≥ 18 years). None had participated in previous or current originator-adalimumab studies/registries. Patients received treatment consistent with site-specific, routine clinical practice. HS disease status was assessed by HS lesions and disease flare; treatment and outcomes data were collected at enrolment and every 6 months for ≤ 4 years. RESULTS: Enrolment (N = 594; 89.1% adults; 10.9% adolescents) occurred from 29 October 2013 to 29 December 2015 at 73 sites in 12 countries. At baseline, the majority were female (69.7%) and White (81.2%), had moderate-to-severe disease (Hurley stage II or III; 93.3%), and had undergone prior procedures/surgery for HS (68.7%). In total, 61.6% of adults and 49.2% of adolescents were obese; 40.2% of patients reported current tobacco use. Scarring due to lesions occurred in 91.2% of patients. The prevalence of comorbidities of interest was as follows: depression (13.3%), other psychiatric disorders (9.6%), inflammatory bowel disease (2.7%), diabetes (9.1%), and polycystic ovary syndrome (5.2%). CONCLUSIONS: In this population from the UNITE HS registry, obesity and smoking were common, and disease burden was high, manifesting as multiple lesions, scarring, surgical history, and considerable comorbidities.

A Genetic Variant in the BCL2 Gene Associates with Adalimumab Response in Hidradenitis Suppurativa Clinical Trials and Regulates Expression of BCL2.

Hidradenitis suppurativa is a chronic skin disease with a significant genetic component and prevalence from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency or the U.S. Food and Drug Administration for the management of moderate to severe hidradenitis suppurativa. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the most extensive two phase 3 hidradenitis suppurativa clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with minor allele frequency > 5% and identified one single linkage disequilibrium block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism, rs59532114; P = 2.35E-08). Bioinformatic analysis and functional genomics experiments suggested a correlation of the most strongly associated single-nucleotide polymorphism minor allele with increased BCL2 gene and protein expressions in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight a pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients with hidradenitis suppurativa.

Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions. OBJECTIVE: We sought to evaluate the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate to severe atopic dermatitis. METHODS: In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate to severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary end point was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment. RESULTS: Patients (N = 167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n = 42; placebo, n = 41); 166 were analyzed for safety (each upadacitinib group, n = 42; placebo, n = 40). The mean (SE) primary efficacy end point was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P = .03, <.001, and <.001). Serious adverse events occurred in 4.8% (2 of 42), 2.4% (1 of 42), and 0% (0 of 42) of upadacitinib groups (vs 2.5% [1 of 40] for placebo). CONCLUSIONS: A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.