Key Points
Question
Is the efficacy of upadacitinib maintained with long-term treatment with an acceptable adverse event profile in adolescents with moderate to severe atopic dermatitis?
Findings
In this study using data from 3 large, global phase 3 randomized clinical trials including 542 adolescents, once-daily upadacitinib (15 mg or 30 mg) with or without topical corticosteroids was effective in treating moderate to severe atopic dermatitis, with responses maintained through 76 weeks of treatment. No new risks were observed.
Meaning
The current analysis of 3 randomized clinical trials found that treatment with upadacitinib had a favorable long-term benefit-risk profile through 76 weeks in adolescents with moderate to severe atopic dermatitis.
This study using data from 3 phase 3 randomized clinical trials evaluates the efficacy and adverse events of upadacitinib in adolescent patients with moderate to severe atopic dermatitis through 76 weeks.
Abstract
Importance
The Measure Up 1, Measure Up 2, and AD Up studies demonstrated the efficacy and adverse events of upadacitinib through 52 weeks in adults and adolescents with atopic dermatitis (AD); however, longer-term outcomes (longer than 1 year) in adolescents have not previously been available.
Objective
To evaluate the efficacy and adverse events of upadacitinib in adolescent patients with moderate to severe AD through 76 weeks.
Design, Setting, and Participants
The Measure Up 1, Measure Up 2, and AD Up trials are ongoing double-blind, placebo-controlled phase 3 randomized clinical trials including adolescents (aged 12 to 17 years) with moderate to severe AD. Data were collected from August 2018 to April 2022, and data were analyzed from June 2022 to September 2023.
Interventions
Adolescents were randomized 1:1:1 to receive once-daily oral upadacitinib, 15 mg; upadacitinib, 30 mg; or placebo, either alone (Measure Up 1 and Measure Up 2 trials) or with topical corticosteroids (AD Up). At week 16, placebo-treated patients were rerandomized to receive upadacitinib, 15 mg, or upadacitinib, 30 mg, daily.
Main Outcomes and Measures
Coprimary end points assessing efficacy included achievement of 75% reduction or more in the Eczema Area and Severity Index Score (EASI-75) from baseline, Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear (0) or almost clear (1) with 2 grades or more of improvement, and Worst Pruritus Numerical Rating Scale (WP-NRS) improvement of 4 points or greater through week 76 for participants with a WP-NRS score of 4 points or higher at baseline.
Results
From all studies, 542 adolescents were included; of these, 284 (52.4%) were female. At week 76, among patients in the Measure Up 1, Measure Up 2, and AD Up trials, EASI-75 was achieved by 89.1%, 84.4%, and 87.8% of adolescents taking upadacitinib, 15 mg, respectively, and by 96.1%, 93.6%, and 82.7% of adolescents taking upadacitinib, 30 mg, indicating maintenance or improvement of EASI-75 across 76 weeks with upadacitinib. Efficacy measured by achievement of vIGA-AD score of 0 or 1 and WP-NRS improvement of 4 points or more from baseline was similarly maintained or improved through week 76 for adolescents taking upadacitinib, 15 mg or 30 mg. Long-term outcomes in Measure Up 1, Measure Up 2, and AD Up participants were consistent with the known adverse event profile of upadacitinib (herpetic infection: 4.0, 1.9, and 1.1 events per 100 patient-years, respectively; creatine kinase elevation: 11.6, 11.0, and 7.1 events per 100 patient-years); no new signals were observed with either dose.
Conclusions and Relevance
In this study assessing 3 randomized clinical trials, long-term treatment of adolescents with moderate to severe AD with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 76 weeks.
Trial Registrations
Measure Up 1 trial: ClinicalTrials.gov Identifier: NCT03569293; Measure Up 2 trial: NCT03607422; AD Up trial: NCT03568318
Introduction
Atopic dermatitis (AD) is a common chronic inflammatory skin disease, characterized by eczematous morphology and intense pruritus.1,2 The age of onset of AD is variable and can occur at any point in life, with the highest incidence of onset in childhood.2,3 Prevalence of AD is estimated at 20% in children, with 10% to 20% of cases persisting into adolescence, during which prevalence rates range from 5% to 20%, varying based on geographic location.3,4,5 Adolescents with AD experience impacts to quality of life that are shared with other age groups, like increased reports of depression and anxiety. Given the importance of psychosocial development during adolescence, AD also impacts identity, relationship building, self-esteem, and school performance.2,6,7,8 Further, development of autonomy and independence during adolescence can impact adherence and risk-taking behaviors that can challenge treatment plans. Additionally, there are reports of increased suicidal behavior in adolescents with AD.9 Given its negative impacts to adolescent quality of life, there remains a need for treatments available to this population.
In addition to the use of nonprescription moisturizers, topical therapies are the mainstay for AD, especially corticosteroids, but also inhibitors of calcineurin, phosphodiesterase-4, and Janus kinase (JAK). Patients with moderate to severe AD who do not respond adequately to topical therapies or are intolerant of them may have to advance to treatments such as phototherapy or systemic therapies. Until the last decade, conventional immunosuppressants (ie, cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, and prednisone) were the only option for systemic therapy. Biologics (initially dupilumab) transformed AD care, and most recently, JAK inhibitors have been approved by the US Food and Drug Administration for moderate to severe AD.10,11,12,13,14
Upadacitinib is an oral, once-daily selective small-molecule JAK inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2. It is approved in many jurisdictions, including the European Union, Japan, Canada, and the US, for the treatment of moderate to severe AD in patients 12 years and older.15 In 3 large double-blind, placebo-controlled, multicenter phase 3 randomized clinical trials (RCTs; Measure Up 1, Measure Up 2, and AD Up trials), once-daily upadacitinib, 15 mg or 30 mg, was superior to placebo alone (Measure Up 1 and Measure Up 2 trials) or with topical corticosteroids (AD Up trial) through 16 weeks in adults and adolescents with moderate to severe AD,16,17 which was sustained through 52 weeks in the blinded extension phases of the studies.18,19
The objective of the current study was to assess the efficacy of upadacitinib, 15 mg and 30 mg, with or without topical corticosteroids in adolescents aged 12 to 17 years with moderate to severe AD through 76 weeks.
Methods
Study Design and Patients
Full methodology for the Measure Up 1, Measure Up 2, and AD Up studies, including study dates and size, inclusion and exclusion criteria, randomization, and blinding as well as details about the end points assessed have been published previously.17 Briefly, all 3 studies are ongoing parallel, double-blind, placebo-controlled, global multicenter phase 3 RCTs with a double-blind treatment period of 16 weeks and a blinded extension of 244 weeks. The trial protocols and statistical analysis plans of the Measure Up 1, Measure Up 2, and AD Up trials can be found in Supplement 1, Supplement 2, and Supplement 3, respectively.
The main studies for Measure Up 1, Measure Up 2, and AD Up included adolescents aged 12 to 17 years and adults aged 18 to 75 years with moderate to severe AD. An additional adolescent substudy to recruit more adolescent patients was also implemented in all 3 RCTs. Independent ethics committees or institutional review boards approved the study protocols, informed consent (and assent, where applicable) forms, and recruitment materials before patient enrollment. This study was conducted in accordance with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. Patients or their parents or legal guardians provided written informed consent before screening. Data were collected from August 2018 to April 2022, and data were analyzed from June 2022 to September 2023.
Procedures
At baseline, patients in the Measure Up 1 and Measure Up 2 studies were randomized 1:1:1 to receive a once-daily extended-release tablet of oral upadacitinib, 15 mg or 30 mg, or placebo. In the AD Up study, in addition to upadacitinib, 15 mg, upadacitinib, 30 mg, or placebo, all patients were treated with concomitant topical corticosteroids. In all 3 studies, after the visit at week 16, patients in the placebo groups were rerandomized to receive upadacitinib, 15 mg, or upadacitinib, 30 mg, while patients previously in the upadacitinib, 15 mg and 30 mg, groups continued at the same dose for the duration of the trial. Use of any concomitant topical therapy for AD was permitted per investigator discretion starting at week 16 in the Measure Up 1 and Measure Up 2 studies and starting at week 52 in the AD Up study.
Assessments
Efficacy end points for skin clearance were assessed by achievement of 75% or more, 90% or more, or 100% reduction in the Eczema Area and Severity Index (EASI-75, EASI-90, and EASI-100, respectively) and Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 or 1 with 2 grades or greater reduction from baseline across 76 weeks. Clinically meaningful itch improvement was evaluated as a 4-point improvement or greater from baseline on the Worst Pruritus Numerical Rating Scale (WP-NRS) in patients with WP-NRS scores of 4 points or higher at baseline. WP-NRS was assessed daily, and weekly rolling average scores were used through week 16; WP-NRS was assessed at study visits only thereafter (weeks 20, 24, 32, 40, 52, 64, and 76). Events were assessed as treatment-emergent adverse events (AEs) in all patients who received 1 or more doses of the study drug. All AEs presented were treatment emergent, unless otherwise noted. AE outcomes for all 3 studies have been published previously.15,18
Statistical Analysis
Efficacy was assessed in the intention-to-treat adolescent population, which was defined as all adolescents randomized in the main study or adolescent substudy. All efficacy end points were summarized using the observed cases approach, ie, all observed data up to the data cutoff date or premature discontinuation from the study drug were included and no missing data imputation was applied. AE analyses and methodology for all 3 RCTs have been published previously.18,20 All analyses were conducted using SAS version 9.4 (SAS Institute).
Results
Patients
Demographic and baseline disease characteristics are included in eTable 1 in Supplement 4 and have been published previously.21 A total of 179, 180, and 183 adolescent patients aged 12 to 17 years were included from the Measure Up 1, Measure Up 2, and AD Up studies, respectively. At baseline, a total of 181 patients were randomized to upadacitinib, 15 mg (63, 58, and 60 in Measure Up 1, Measure Up 2, and AD Up, respectively), 180 to upadacitinib, 30 mg (58, 62, and 60), and 181 to placebo (58, 60, and 63) alone (Measure Up 1 and 2) or with topical corticosteroids (AD Up). At week 16, patients in the placebo groups from all studies were rerandomized to upadacitinib, 15 mg (28, 26, and 29, respectively), and upadacitinib, 30 mg (26, 29, and 30). Patient disposition information is provided in eTable 4 and eFigure 2 in Supplement 4.
Efficacy
In adolescents receiving upadacitinib, 15 mg or 30 mg, either with or without topical corticosteroids during the first 16 weeks, the EASI-75 response rate was generally sustained or improved through week 76 with continued treatment for all 3 studies. Adolescents who switched from placebo to upadacitinib, 15 mg or 30 mg, after week 16 experienced improvements in achievement of EASI-75, reaching similar proportions as adolescents who started treatment with upadacitinib, 15 mg or 30 mg, at the beginning of the study. The proportion of patients achieving EASI-75 at week 76 was higher for the upadacitinib, 30 mg, group compared with the upadacitinib, 15 mg, group in both the Measure Up 1 and Measure Up 2 trials. However, in the AD Up study, the proportion of patients achieving EASI-75 at week 76 in the upadacitinib, 30 mg, group was numerically lower compared with the upadacitinib, 15 mg, group. Concomitant use of topical corticosteroids was no longer required starting at the week 52 visit, and this may have contributed to this unique outcome in the AD Up study (Figure 1).
Figure 1. Proportion of Adolescents Achieving EASI-75, EASI-90, and EASI-100 Across 76 Weeks.
Analyses were conducted in the intention-to-treat population using the observed case approach. EASI indicates Eczema Area and Severity Index; TCS, topical corticosteroids. Error bars indicate 95% CIs.
The proportion of patients achieving more stringent skin clearance measures of EASI-90 and EASI-100 increased and were generally maintained or improved beyond week 16 through week 76 for all 3 studies. These efficacy parameters of deeper responses were achieved in a numerically higher proportion of adolescents taking upadacitinib, 30 mg. Similarly, the proportion of patients achieving a vIGA-AD of 0 or 1 was generally maintained or increased through week 76 for adolescents who continued or switched to either upadacitinib, 15 mg or 30 mg, across all 3 studies (Figure 1; Figure 2; eTable 2 in Supplement 4).
Figure 2. Proportion of Adolescents Achieving Validated Investigator Global Assessment for Atopic Dermatitis Score of 0 or 1 Over 76 Weeks.
Analyses were conducted in the intention-to-treat population using the observed case approach. NA indicates not applicable; TCS, topical corticosteroids. Error bars indicate 95% CIs.
The proportion of adolescents achieving a WP-NRS improvement of 4 points or greater was greater in adolescents treated with upadacitinib, 15 mg, and upadacitinib, 30 mg, compared with placebo through week 16. After the week 16 visit, response rates were maintained through week 76 for patients continuing upadacitinib. Switching to upadacitinib, 15 mg, or upadacitinib, 30 mg, from placebo resulted in a similar trajectory as patients who continued with upadacitinib, with increases in response rates, which plateaued and were maintained through week 76.
Integrated efficacy data of Measure Up 1 and Measure Up 2 for all patients treated with upadacitinib, 15 mg (n = 121; 72 [59.5%] female; mean [SD] age, 15.3 [1.9] years), or upadacitinib, 30 mg (n = 120; 56 [46.7%] female; mean [SD] age, 15.7 [1.7] years), supports conclusions from the individual studies (eFigure 1 in Supplement 4).
AEs
Both doses of upadacitinib were generally safe and well-tolerated in adolescents after long-term exposure through 76 weeks. No consistent dose relationship of exposure-adjusted event rates was observed for any AEs, severe AEs, or AEs leading to treatment discontinuation between the 2 upadacitinib doses across the 3 studies (Table). Most AEs of special interest were reported infrequently. Serious infections were reported in 5 patients or fewer in each treatment arm for all 3 studies. All opportunistic infections were events of eczema herpeticum (EH), and most were nonserious, mild or moderate in severity, and generally did not lead to study drug discontinuation. A smaller number of EH events were reported in the upadacitinib, 30 mg, group (1 event) compared with the upadacitinib, 15 mg, group (8 events) for the Measure Up 1 and AD Up studies. Except for the Measure Up 2 study, herpes zoster was reported more frequently with upadacitinib, 30 mg, compared with upadacitinib, 15 mg. Similar to adults, most events of herpes zoster reported in adolescents involved a single dermatome. One event of medulloblastoma, deemed by the investigator as not related to the study drug, was reported in a 15-year-old boy who received upadacitinib, 15 mg. No adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, active tuberculosis, lymphoma, kidney dysfunction, nonmelanoma skin cancer (NMSC), or adjudicated gastrointestinal perforation were seen in adolescents during the long-term treatment period.
Table. Treatment-Emergent Adverse Events (AEs) During Administration of Upadacitinib in Adolescents Through Week 76.
| Measure | No. (Events per 100 PY) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Measure Up 1 | Measure Up 2 | AD Up | |||||||
| Upadacitinib, 15 mg (n = 94) | Upadacitinib, 30 mg (n = 91) | Total (n = 185) | Upadacitinib, 15 mg (n = 84) | Upadacitinib, 30 mg (n = 91) | Total (n = 175) | Upadacitinib, 15 mg, plus TCS (n = 89) | Upadacitinib, 30 mg, plus TCS (n = 90) | Total (n = 179) | |
| Exposure-adjusted rate per 100 PY | 174.4 | 186.4 | 360.9 | 153.2 | 166.1 | 319.2 | 171.4 | 180.3 | 351.6 |
| AEs | |||||||||
| Any treatment-emergent AE | 348 (204.6) | 390 (221.9) | 738 (213.4) | 342 (223.2) | 346 (208.4) | 688 (215.5) | 444 (259.1) | 421(233.5) | 865 (246.0) |
| Severe AEs | 17 (10.0) | 17 (9.7) | 34 (9.8) | 28 (18.3) | 24 (14.5) | 52 (16.3) | 26 (15.2) | 13 (7.2) | 39 (11.1) |
| Serious AEs | 7 (4.1) | 7 (4.0) | 14 (4.0) | 16 (10.4) | 8 (4.8) | 24 (7.5) | 12 (7.0) | 7 (3.9) | 19 (5.4) |
| AEs leading to discontinuation of study drug | 6 (3.5) | 7 (4.0) | 13 (3.8) | 5 (3.3) | 9 (5.4) | 14 (4.4) | 7 (4.1) | 4 (2.2) | 11 (3.1) |
| Deaths | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| AEs of special interest | |||||||||
| Serious infections | 2 (1.2) | 5 (2.8) | 7 (2.0) | 5 (3.3) | 2 (1.2) | 7 (2.2) | 7 (4.1) | 2 (1.1) | 9 (2.6) |
| Opportunistic infection excluding tuberculosis and herpes zoster | 5 (2.9) | 0 | 5 (1.4) | 1 (0.7) | 3 (1.8) | 4 (1.3) | 4 (2.3) | 1 (0.6) | 5 (1.4) |
| Herpes zoster | 3 (1.8) | 11 (6.3) | 14 (4.0) | 3 (2.0) | 3 (1.8) | 6 (1.9) | 1 (0.6) | 3 (1.7) | 4 (1.1) |
| Active tuberculosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Possible malignancy | 1 (0.6) | 0 | 1 (0.3) | 0 | 0 | 0 | 0 | 0 | 0 |
| Malignancy | 1 (0.6) | 0 | 1 (0.3) | 0 | 0 | 0 | 0 | 0 | 0 |
| NMSC | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Malignancy other than NMSC | 1 (0.6) | 0 | 1 (0.3) | 0 | 0 | 0 | 0 | 0 | 0 |
| Lymphoma | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hepatic disorder | 9 (5.3) | 3 (1.7) | 12 (3.5) | 5 (3.3) | 8 (4.8) | 13 (4.1) | 11 (6.4) | 4 (2.2) | 15 (4.3) |
| Adjudicated gastrointestinal perforation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Anemia | 5 (2.9) | 1 (0.6) | 6 (1.7) | 3 (2.0) | 2 (1.2) | 5 (1.6) | 8 (4.7) | 1 (0.6) | 9 (2.6) |
| Neutropenia | 2 (1.2) | 6 (3.4) | 8 (2.3) | 2 (1.3) | 4 (2.4) | 6 (1.9) | 7 (4.1) | 13 (7.2) | 20 (5.7) |
| Lymphopenia | 0 | 0 | 0 | 2 (1.3) | 0 | 2 (0.6) | 0 | 0 | 0 |
| CPK elevation | 21 (12.3) | 19 (10.8) | 40 (11.6) | 16 (10.4) | 19 (11.4) | 35 (11.0) | 5 (2.9) | 20 (11.1) | 25 (7.1) |
| Kidney dysfunction | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Adjudicated MACE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Adjudicated VTE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Change from baseline height at 76-wk visit (95% CI) | 3.0 (2.1-3.9) | 2.4 (1.6-3.3) | NA | 2.7 (1.7-3.7) | 2.0 (1.1-3.0) | NA | 2.6 (1.7-3.6) | 3.0 (2.0-3.9) | NA |
Abbreviations: CPK, creatine phosphokinase; MACE, major adverse cardiovascular event; NA, not applicable; NMSC, nonmelanoma skin cancer; PY, patient-year; TCS, topical corticosteroid; VTE, venous thromboembolic event.
Acne was the most common AE (AD Up and Measure Up 2 trials) or second most common AE (Measure Up 1 trial); most acne events were mild in severity and rarely led to treatment discontinuation. Acne presentation consisted of inflammatory papules, pustules, and comedones and primarily involved the face. In the Measure Up 1, Measure Up 2, and AD Up trials, nausea was reported in 3 of 91 (3.3%), 2 of 84 (2.4%), and 4 of 89 (4.5%), respectively, of patients in the upadacitinib, 15 mg, group and 2 of 84 (2.4%), 5 of 91 (5.5%), and 4 of 90 (4.4%) for upadacitinib, 30 mg, group. Based on the exposure-adjusted rate per 100 patient-years (PY), nausea was reported as an exposure-adjusted rate of 0.6 per 100 PY and 1.3 per 100 PY for those taking upadacitinib, 15 mg, alone in the Measure Up 1 and Measure Up 2 studies, respectively, and 0.6 per 100 PY for patients taking upadacitinib, 30 mg, alone in Measure Up 2; nausea was not reported for Measure Up 1 patients taking upadacitinib, 30 mg, alone up to 76 weeks of follow-up. For those patients taking upadacitinib combined with topical therapy, exposure-adjusted rates of nausea in the upadacitinib, 15 mg, and upadacitinib, 30 mg, groups were 2.9 per 100 PY and 1.1 per 100 PY, respectively. Allergic conjunctivitis was reported during the double-blind period in 1 patient in the Measure Up 1 placebo group (assessed as possibly related to study drug by investigator); there were no reports of allergic conjunctivitis in the upadacitinib, 15 mg, and upadacitinib, 30 mg, groups during this period in the 3 studies. The long-term exposure-adjusted allergic conjunctivitis rate for patients taking upadacitinib, 15 mg, were 0.6 per 100 PY and 0.7 per 100 PY for Measure Up 1 and Measure Up 2, respectively, while the long-term rates were 0.6 per 100 PY for both Measure Up 1 and Measure Up 2 in the upadacitinib, 30 mg, arm. No events of allergic conjunctivitis were reported in the AD Up trial up to the week 76 visit.
Incidence and characteristics of laboratory-related AEs (ie, anemia, neutropenia, lymphopenia, transaminitis, and creatine phosphokinase elevations) were consistent with those observed in adults and the known profile of upadacitinib. Laboratory-related abnormalities were transient and rarely resulted in severe AEs or permanent discontinuation of study drug. Cases of neutropenia included 2 that were graded as grade 3 or higher for patients taking upadacitinib, 30 mg (1 in Measure Up 1 and 1 in Measure Up 2), and none for upadacitinib, 15 mg (eTable 3 in Supplement 4). There were no reports of discontinuation of the study drug resulting from neutropenia. There were 2 events of rhabdomyolysis, both observed in boys and preceded by increased physical activity or exercise, with 1 instance being serious and leading to study drug discontinuation. Height measurement up to week 76 did not suggest that upadacitinib treatment had notable impact on the growth of adolescents (Table). Long-term outcomes up to 76 weeks for upadacitinib, 15 mg, and upadacitinib, 30 mg, with or without topical corticosteroids in moderate to severe AD were consistent with the known AE profile of upadacitinib.18,21 No new signals were observed in adolescents following up to 76 weeks of exposure compared with the known AE profile of upadacitinib.
Discussion
In the Measure Up 1, Measure Up 2, and AD Up studies, a greater proportion of adolescents treated with upadacitinib, 15 mg, or upadacitinib, 30 mg, achieved EASI-75, EASI-90, EASI-100, and a vIGA-AD score of 0 or 1 compared with those in placebo groups, with or without topical corticosteroids, at week 16. Responses of participants continuing upadacitinib were maintained up to week 76, when more than 70% of adolescents continuing with upadacitinib, 15 mg, or upadacitinib, 30 mg, achieved EASI-75. For patients previously treated with placebo (with or without topical corticosteroids) during weeks 1 to 16 of all 3 studies, response rates increased after the switch to upadacitinib, plateaued, and were maintained through week 76, as in patients who continued with upadacitinib. The proportion of adolescents achieving EASI-90 and EASI-100 also increased across 76 weeks for groups continuing with upadacitinib, 15 mg, and upadacitinib, 30 mg, and those who switched from placebo to either upadacitinib, 15 mg, or upadacitinib, 30 mg. While the difference in the proportions of patients achieving at least EASI-75 between the 2 upadacitinib treatment groups is small, the difference between the 2 doses becomes more pronounced over time in the more stringent efficacy end points, such as EASI-90 and vIGA-AD score of 0 or 1, showing that there is a difference in long-term efficacy between upadacitinib, 15 mg, and upadacitinib, 30 mg.
Notably, adolescents in the placebo or placebo plus topical corticosteroids group showed steady improvement in vIGA-AD score of 0 or 1 after switching to upadacitinib, 15 mg, or upadacitinib, 30 mg, after the week 16 visit until plateau was reached, after which point responses were maintained through week 76, which was a similar trajectory as patients continuing upadacitinib treatment from the first 16 weeks of the study. These results mirror those for achievement of WP-NRS improvement of 4 points or greater, where adolescents in the upadacitinib groups had week 16 response rates maintained through week 76 and improvements in pruritus among patients who switched from placebo to upadacitinib until plateau, then response rates were maintained through week 76. Improvements were numerically higher in those who switched to upadacitinib, 30 mg, vs those who switched to upadacitinib, 15 mg (Figure 3; eTable 2 in Supplement 4).
Figure 3. Proportion of Adolescents Achieving Worst Pruritus Numerical Rating Scale Improvement of 4 Points or More Across 76 Weeks.
Analyses were conducted in the intention-to-treat population using the observed case approach. NA indicates not applicable; TCS, topical corticosteroids. Error bars indicate 95% CIs.
Results of the current studies demonstrate that upadacitinib use in adolescents was similar to results for adults reported in prior studies, in which responses achieved at week 16 for measures of EASI-75, EASI-90, EASI-100, vIGA-AD score of 0 or 1, and WP-NRS improvement of 4 points or more for patients with a baseline score of 4 or higher were improved in adults and adolescents treated with upadacitinib, 15 mg, and upadacitinib, 30 mg, and maintained through week 52 in the Measure Up 1, Measure Up 2, and AD Up studies.18,20 For more stringent measures of skin clearance (EASI-90 and EASI-100) in the current study, adolescents taking upadacitinib, 30 mg, had numerically higher proportions compared with those taking upadacitinib, 15 mg, which is consistent with reports in adults through week 52.18
A higher incidence of EH was found in Measure Up 1 and AD Up but not in Measure Up 2. Previous studies have reported that individuals with active AD have a higher risk of developing EH compared with those without AD, likely due to impairments in epidermal barrier function commonly seen in patients with AD.22 Moreover, only areas affected by active AD have been noted to exhibit EH, with no impact to skin unaffected by AD. Topical calcineurin inhibitors have been noted to mildly increase the risk of developing EH in patients with AD, although this was not observed with dupilumab.23 At the time of this publication, the impact of upadacitinib on the mechanism by which EH occurs is not yet understood.
Clinicians should remain vigilant in checking the varicella (and, less likely, shingles) vaccine and exposure status in patients taking upadacitinib. Due to both of the 2 rhabdomyolysis events appearing to be associated with increased physical exertion, there is value in the adequate education of adolescents taking upadacitinib about the importance for proper hydration while exercising or engaging in any physically strenuous activity.
Long-term AE outcomes up to 76 weeks for upadacitinib, 15 mg, and upadacitinib, 30 mg, with or without topical corticosteroids in moderate to severe AD were consistent with what was observed previously in the AD studies.18,20 No new signals were observed in adolescents following up to 76 weeks of exposure compared with the known AE profile of upadacitinib.
Limitations
This study has limitations. The number of adolescents included in this analysis is relatively small compared with the sample size of adult studies, which may limit characterization of the AEs and efficacy of upadacitinib in this age group (12 to 17 years). Additionally, this study was limited to patients 12 years and older and with a body weight of 40 kg or greater; therefore, the efficacy and AEs in patients younger than 12 years or with a body weight less than 40 kg remains unknown.
Conclusions
In summary, these results through 76 weeks demonstrated that upadacitinib, with a favorable benefit-risk profile, was an effective long-term treatment option for adolescents with moderate to severe AD.
Measure Up 1 Trial Protocol and Statistical Analysis Plan
Measure Up 2 Trial Protocol and Statistical Analysis Plan
AD Up Trial Protocol and Statistical Analysis Plan
eTable 1. Demographics and Baseline Characteristics of Adolescents in the Measure Up 1, Measure Up 2, and AD Up Studies
eTable 2. Proportion of Adolescents Achieving EASI-75, EASI-90, EASI-100, vIGA-AD 0/1, and WP-NRS Improvement ≥4 at Week 76 (ITT Adolescent Population, OC Approach)
eTable 3. Potentially Clinically Significant Laboratory Values During Administration of Upadacitinib in Adolescents in Measure Up 1, Measure Up 2, and AD Up at Week 76
eTable 4. Detailed Subject Disposition During Blinded Extension Period Through Week 76
eFigure 1. Proportion of Adolescents Achieving (A) EASI-75, EASI-90, and EASI-100, (B) vIGA-AD 0/1, and (C) WP-NRS Improvement ≥4 Across 76 Weeks (Integrated Measure Up 1 and Measure Up 2 Data, OC Approach)
eFigure 2. Patient Flow Diagram for Patients Who Entered the Blinded Extension (BE) Study
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Measure Up 1 Trial Protocol and Statistical Analysis Plan
Measure Up 2 Trial Protocol and Statistical Analysis Plan
AD Up Trial Protocol and Statistical Analysis Plan
eTable 1. Demographics and Baseline Characteristics of Adolescents in the Measure Up 1, Measure Up 2, and AD Up Studies
eTable 2. Proportion of Adolescents Achieving EASI-75, EASI-90, EASI-100, vIGA-AD 0/1, and WP-NRS Improvement ≥4 at Week 76 (ITT Adolescent Population, OC Approach)
eTable 3. Potentially Clinically Significant Laboratory Values During Administration of Upadacitinib in Adolescents in Measure Up 1, Measure Up 2, and AD Up at Week 76
eTable 4. Detailed Subject Disposition During Blinded Extension Period Through Week 76
eFigure 1. Proportion of Adolescents Achieving (A) EASI-75, EASI-90, and EASI-100, (B) vIGA-AD 0/1, and (C) WP-NRS Improvement ≥4 Across 76 Weeks (Integrated Measure Up 1 and Measure Up 2 Data, OC Approach)
eFigure 2. Patient Flow Diagram for Patients Who Entered the Blinded Extension (BE) Study
Data Sharing Statement