Key Points
Question
What is the efficacy, safety, and tolerability of upadacitinib—an oral, selective Janus kinase inhibitor—in adults and adolescents with severe alopecia areata (AA)?
Findings
In 2 phase 3 randomized clinical trials including 1281 adults and 118 adolescents with severe AA receiving 15- or 30-mg upadacitinib once daily met the primary end point of at least 80% scalp hair coverage at week 24 (defined as Severity of Alopecia Tool score ≤20). In addition, multiplicity-controlled secondary end points were met, including complete scalp hair regrowth, improvement in eyebrow and eyelash hair, and health-related quality of life measures at week 24; no new safety events were identified.
Meaning
These results demonstrate the potential of upadacitinib as a treatment option for adults and adolescents with severe AA.
Abstract
Importance
Alopecia areata (AA) is a chronic, systemic immune-mediated disease characterized by nonscarring hair loss. Many patients do not experience improvements with available treatment options and only ritlecitinib is approved for adolescent patients; therefore, there remains a clear unmet need for additional and improved systemic therapies.
Objective
To evaluate the efficacy and safety of upadacitinib—an oral selective Janus kinase inhibitor—in adult and adolescent patients with severe AA.
Design, Setting, and Participants
This global clinical program included 2 parallel phase 3 replicate randomized clinical trials (UP-AA1 and UP-AA2) conducted from October 2023 to July 2025, to evaluate upadacitinib in adolescent and adult patients (age 12 to <64 years old) with severe AA, defined as a Severity of Alopecia Tool (SALT) score of 50 or greater. Both trials included a 24-week placebo-controlled, double-blinded treatment period (period A) and a 28-week blinded extension treatment period (period B). Data were analyzed from July 2025 to October 2025.
Interventions
Eligible patients were randomized 2:2:1 to once daily 15- or 30-mg upadacitinib or matching placebo.
Main Outcomes and Measures
Achievement of (multiplicity controlled) SALT score of 20 or less at week 24. Multiplicity-controlled secondary efficacy end points included achievement of improvements in clinician-reported outcomes for eyebrows and eyelashes; achievement of SALT scores of 20 or less at weeks 4, 8, and 12; achievement of SALT score of 10 or less; SALT score 0 at week 24; patients’ global impression of change of AA score of much better or moderately better at weeks 4 and 24; and other AA-specific health-related quality of life measures at week 24.
Results
A total of 1399 patients were randomized (mean [range] age, 36 [12-64] years; 826 female [59.0%]), 676 patients from the UP-AA1 and 723 patients from the UP-AA2, to either 15-mg upadacitinib (270 and 289 patients, respectively), 30-mg upadacitinib (271 and 289), or placebo (135 and 145). Their mean (SD) SALT score was 83.9 (18.9) at baseline. The proportion of patients who achieved SALT score of 20 or less at week 24 was significantly higher for the 15-mg upadacitinib (122 [45.2%] and 129 [44.6%]) and the 30-mg upadacitinib (149 [55.0%] and 157 [54.3%]) groups, respectively, than for the placebo (2 [1.5%] and 5 [3.4%]) group. The safety profile of both doses was similar in adults and adolescents and consistent with approved indications; no new safety findings were identified. Treatment-emergent adverse events reported by more than 5% of patients in any treatment group were upper respiratory tract infection, acne, elevated blood creatine phosphokinase, and nasopharyngitis. Across both studies, treatment-emergent serious adverse events occurred in 9 (1.6%), 13 (2.3%), and 1 (0.4%) of patients receiving 15-mg upadacitinib , 30-mg upadacitinib, or placebo, respectively.
Conclusions and Relevance
In these 2 parallel phase 3 replicate randomized clinical trials, upadacitinib demonstrated a positive benefit-risk profile in adults and adolescents with severe AA. Upadacitinib may be a potentially effective treatment option for this patient population.
Trial Registration
ClinicalTrials.gov Identifier: NCT06012240
These 2 parallel phase 3 replicate randomized clinical trials evaluate the efficacy and safety of upadacitinib in adult and adolescent patients with severe alopecia areata.
Introduction
Alopecia areata (AA) is a chronic, systemic immune-mediated disease, characterized by nonscarring hair loss, ranging from isolated patches on the scalp to complete scalp, facial, and body hair loss. With an estimated global prevalence of 2%, AA has a profound psychosocial burden on patients. Conventional off-label treatments have variable and limited efficacy, especially in severe cases.
The Janus kinases (JAKs) family of intracellular tyrosine kinases plays a critical role in innate and adaptive immunity, making them targets for the treatment of inflammatory diseases including AA. Several reports have evaluated the use of JAK inhibitors as treatment for AA. Currently, the JAK inhibitors baricitinib, ritlecitinib, and deuruxolitinib are the only approved treatments for patients with severe AA. Many patients have not achieved the primary efficacy end point of SALT score of 20 or less (≤20% scalp hair loss) in clinical trials (≤35% for each trial across study treatment groups) and only ritlecitinib is approved for adolescent patients—there remains a clear unmet need for additional and improved systemic therapies.
Upadacitinib, an oral, selective, reversible JAK inhibitor that more potently inhibit JAK1 compared to JAK2, JAK3, and tyrosine kinase 2, is approved in multiple countries for the treatment of several inflammatory conditions. These 2 parallel replicate phase 3 randomized clinical trials assess the efficacy, safety, and tolerability of upadacitinib for the treatment of adults and adolescents with severe AA.
Methods
Both trials were conducted in accordance with the International Conference for Harmonization guidelines, applicable regulations, and the Declaration of Helsinki. Adult patients and parents/legal guardians of adolescent patients provided written informed consent before screening. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol is available in Supplement 1 and the statistical analysis plans are available in Supplement 2 for study 1 and Supplement 3 for study 2.
Trial Participants
Eligible patients were adolescents (age 12-17 years; weight ≥30 kg) or adults (age 18 to <64 years) with severe AA, defined as having a Severity of Alopecia Tool (SALT) score of 50 or greater for scalp hair loss at screening and baseline, no spontaneous scalp hair regrowth during the past 6 months, and a current episode of AA of less than 8 years (no lower limit). Full eligibility criteria are in eTable 1 in Supplement 4. Patient race and ethnicity were self-reported or investigator observed.
Trial Design and Treatment
UP-AA1 and UP-AA2 are replicate, global, randomized, double-blinded, placebo-controlled, phase 3 multicenter clinical trials conducted from October 2023 to July 2025. UP-AA1 was conducted at 112 clinical centers in 25 countries; UP-AA2 was conducted at 125 clinical centers in 28 countries. Both studies comprised a 35-day screening period, a 24-week placebo-controlled, double-blind treatment period (period A), and a 28-week blinded extension treatment period (period B).
In period A, patients were randomized 2:2:1 to receive oral 15-upadacitinib, 30-mg upadacitinib, or placebo, once daily for 24 weeks. Patients were stratified by baseline age (adults, ≥18 years compared with adolescents, 12 to younger than 18 years), baseline SALT score of severe AA (SALT score <95) vs very severe AA (SALT score ≥95), and baseline AA episode duration (<3 years vs ≥3 years, respectively). Efficacy was reported at weeks 4, 8, 12, and 24. Safety was reported through week 24 in period A.
Randomization was performed using an interactive response technology system according to a randomization schedule generated by randomization specialists. During period A of UP-AA1 and UP-AA2, all personnel with direct oversight of the conduct and management of the trial (with the exception of the drug supply management team), the investigator, study site personnel, and the patients were blinded to all participants’ treatment. To maintain the blinding, the upadacitinib and placebo tablets in UP-AA1 and UP-AA2 were identical in appearance.
Outcomes
Efficacy
The primary efficacy end point (multiplicity-controlled) was SALT score of 20 or less, defined as 20% or less scalp hair loss, at week 24. Multiplicity-controlled secondary efficacy end points included improvements in clinician-reported outcomes (ClinRO) for eyebrows and eyelashes. ClinRO measure for eyebrow hair loss and for eyelash hair loss of 0 (full coverage for eyebrows; continuous line for eyelash) or 1 (minimal gaps) at week 24 with a 2-point or greater improvement (reduction) from baseline among patients with baseline score of 2 or greater; SALT scores of 20 or less at weeks 4, 8, and 12; SALT score of 10 or less (≤10% scalp hair loss) at week 24; SALT score 0 (complete scalp hair regrowth) at week 24; patients’ global impression of change of AA (PaGIC-AA) score of 1 (much better) or 2 (moderately better) at weeks 4 and 24; patient-reported outcome (PRO) for scalp hair assessment 0 (no missing hair; 0%) or 1 (limited, 20%) with 2-point or greater improvement (reduction) from baseline at week 24 among patients with baseline score of 3 or greater; change from baseline in AA symptom impact scale (AASIS)—interference subscale and symptoms subscale scores at week 24; change from baseline in Skindex-16 AA emotions domain score and functioning domain score at week 24; Hospital Anxiety And Depression Scale (HADS-A [anxiety] and HADS-D [depression]) scores less than 8 at week 24 among patients with HADS-A or HADS-D of 8 or greater at baseline.
Safety
Safety was assessed by adverse event (AE) monitoring, physical examination, vital signs, and clinical laboratory assessments, including hematology, chemistry, urinalysis, liver function tests, and lipid parameters. Treatment-emergent AEs (TEAEs) in period A were defined as any AE that began or worsened on or after the first dose of study treatment in period A, and through 30 days after the last dose date in period A for patients who did not continue into period B. For patients who continued into period B, TEAEs were defined as any AE occurring 30 days after the last dose date in period A, or 1 day before the first dose date in period B, whichever came first.
Sample Size
Approximately 600 adult patients per study were planned to be randomized to 15-mg upadacitinib, 30-mg upadacitinib, or placebo in a 2:2:1 ratio in UP-AA1 and UP-AA2 (240 patients per upadacitinib dose and 120 for placebo). The planned sample size was estimated to provide sufficient power (more than 90%) to assess the primary end point to detect a treatment difference of 19.5% in either upadacitinib doses vs placebo using a 2-sided significance level of .05.
Statistical Analyses
Data from UP-AA1 and UP-AA2 were analyzed independently. The primary analyses for all efficacy end points in period A were conducted after all continuing patients in the study completed the 24-week, double-blinded period. All tests were 2-sided at an α level of .05. Efficacy analyses were conducted on the intention-to-treat (ITT) population, defined as all patients who were randomized at baseline. No statistical testing was performed to compare 15-mg to 30-mg upadacitinib.
The use of confounding medication for AA that could impact the evaluation of the respective end point or premature discontinuation of study drug was considered an intercurrent event. For binary end points, the Cochran-Mantel-Haenszel test was used for analyses, with nonresponder imputation (NRI) to handle data after intercurrent events and missing data. For continuous end points, analysis of covariance (ANCOVA) was used for analyses, with return to baseline to handle data after intercurrent events and multiple imputation to handle missing data.
Safety analyses were performed on safety data for patients in period A who received at least 1 dose of study drug and were summarized descriptively. For all safety analyses, baseline was defined as the last nonmissing measurement on or before the date of the first dose of study treatment. Missing safety data were not imputed.
All statistical analyses were carried out using SAS, version 9.4 or higher, (SAS Institute Inc) from July to October 2025. An external data monitoring committee oversaw the studies.
Results
Patient Disposition and Characteristics
Between November 30, 2023, and July 8, 2025, in UP-AA1, 676 patients were randomized 2:2:1 to receive 15-mg upadacitinib once daily (n = 270), 30-mg upadacitinib once daily (n = 271), or placebo once daily (n = 135). All patients were included in the efficacy analysis and in the safety analysis (Figure 1A).
Figure 1. CONSORT Diagram of Included Patients.
ITT indicates intention-to-treat.
Between October 11, 2023, and June 13, 2025, in UP-AA2, 723 patients were randomized 2:2:1 to 15-mg upadacitinib once daily (n = 289), 30-mg upadacitinib (n = 289), or placebo once daily (n = 145). All patients were included in the efficacy analysis. Two patients who were randomized but did not receive treatment were not included in the safety analysis (Figure 1B).
Treatment discontinuation during period A was low overall (UP-AA1, 39 patients [5.8%]; UP-AA2, 38 patients [5.3%]). The main reasons were withdrawal from treatment by patient and lost to follow up (Figure 1).
Demographic and baseline disease characteristics were generally well balanced among treatment groups in both studies (Table 1). There were 118 adolescent patients (age 12-17 years) enrolled across the 2 studies.
Table 1. Baseline Demographics and Disease Characteristics of Participants in the Analysis of Upadacitinib for Severe Alopecia Areata (AA) .
| Characteristic | No. (%) | |||||||
|---|---|---|---|---|---|---|---|---|
| UP-AA1 | UP-AA2 | |||||||
| Placebo | 15-mg UPA | 30-mg UPA | Total | Placebo | 15-mg UPA | 30-mg UPA | Total | |
| Participants, No. | 135 | 270 | 271 | 676 | 145 | 289 | 289 | 723 |
| Female | 79 (58.5) | 156 (57.8) | 156 (57.6) | 391 (57.8) | 81 (55.9) | 174 (60.2) | 180 (62.3) | 435 (60.2) |
| Male | 56 (41.5) | 114 (42.2) | 115 (42.4) | 285 (42.2) | 64 (44.1) | 115 (39.8) | 109 (37.7) | 288 (39.8) |
| Age, mean (SD), y | 34.6 (12.2) | 34.9 (13.7) | 35.1 (13.1) | 34.9 (13.2) | 37.2 (14.0) | 37.5 (13.6) | 36.0 (12.9) | 36.8 (13.4) |
| Age group, y | ||||||||
| <18 | 13 (9.6) | 25 (9.3) | 26 (9.6) | 64 (9.5) | 10 (6.9) | 23 (8.0) | 21 (7.3) | 54 (7.5) |
| ≥18 to <40 | 74 (54.8) | 144 (53.3) | 148 (54.6) | 366 (54.1) | 72 (49.7) | 134 (46.4) | 146 (50.5) | 352 (48.7) |
| ≥40 | 48 (35.6) | 101 (37.4) | 97 (35.8) | 246 (36.4) | 63 (43.4) | 132 (45.7) | 122 (42.2) | 317 (43.8) |
| Race and ethnicitya | ||||||||
| Asian | 49 (36.3) | 91 (33.7) | 98 (36.2) | 238 (35.2) | 45 (31.0) | 60 (20.8) | 70 (24.2) | 175 (24.2) |
| Black | 7 (5.2) | 22 (8.1) | 13 (4.8) | 42 (6.2) | 9 (6.2) | 16 (5.5) | 14 (4.8) | 39 (5.4) |
| White | 77 (57.0) | 148 (54.8) | 151 (55.7) | 376 (55.6) | 89 (61.4) | 206 (71.3) | 194 (67.1) | 489 (67.6) |
| Other | 2 (1.5) | 9 (3.3) | 9 (3.3) | 20 (3.0) | 2 (1.4) | 7 (2.4) | 11 (3.8) | 20 (2.8) |
| Not Hispanic or Latino | 126 (93.3) | 240 (88.9) | 246 (90.8) | 612 (90.5) | 129 (89.0) | 254 (87.9) | 250 (86.5) | 633 (87.6) |
| Geographic region | ||||||||
| Asia | 44 (32.6) | 80 (29.6) | 84 (31.0) | 208 (30.8) | 38 (26.2) | 46 (15.9) | 61 (21.1) | 145 (20.1) |
| Europe | 44 (32.6) | 89 (33.0) | 83 (30.6) | 216 (32.0) | 58 (40.0) | 120 (41.5) | 117 (40.5) | 295 (40.8) |
| North America | 31 (23.0) | 69 (25.6) | 71 (26.2) | 171 (25.3) | 30 (20.7) | 73 (25.3) | 69 (23.9) | 172 (23.8) |
| South or Central America | 4 (3.0) | 12 (4.4) | 11 (4.1) | 27 (4.0) | 5 (3.4) | 19 (6.6) | 18 (6.2) | 42 (5.8) |
| Other | 12 (8.9) | 20 (7.4) | 22 (8.1) | 54 (8.0) | 14 (9.7) | 31 (10.7) | 24 (8.3) | 69 (9.5) |
| BMI, mean (SD) | 25.6 (5.4) | 25.8 (5.3) | 26.1 (6.0) | 25.9 (5.6) | 25.9 (4.9) | 26.5 (5.8) | 25.3 (5.0) | 25.9 (5.3) |
| AA duration since onset, mean (SD) [IQR], y | 12.7 (11.1) [4.2-20.6] | 11.6 (12.1) [3.0-16.0] | 10.9 (11.0) [3.3-15.7] | 11.5 (11.4) [3.3-16.7] | 9.9 (9.3) [2.7-14.4] | 11.6 (11.4) [3.7-16.0] | 12.4 (11.4) [4.7-17.3] | 11.6 (11.0) [3.8-16.1] |
| AA current episode duration, mean (SD) [IQR], y | 3.0 (2.2) [1.0-4.7] | 3.1 (2.3) [1.1-4.7] | 3.0 (2.2) [1.1-4.9] | 3.0 (2.2) [1.1-4.8] | 3.2 (2.2) [1.3-5.0] | 3.0 (2.2) [1.1-4.7] | 3.1 (2.3) [1.1-5.2] | 3.1 (2.2) [1.1-4.9] |
| AA current episode ≥3 y | 58 (43.0) | 115 (42.6) | 113 (41.7) | 286 (42.3) | 67 (46.2) | 126 (43.6) | 126 (43.6) | 319 (44.1) |
| SALT score, mean (SD) [IQR] | 84.4 (18.1) [67.4-100.0] | 84.0 (18.8) [64.9-100.0] | 83.8 (18.9) [65.4-100.0] | 84.0 (18.7) [65.2-100.0] | 82.3 (20.0) [60.4-100.0] | 84.7 (18.7) [67.0-100.0] | 83.6 (19.2) [62.5-100.0] | 83.8 (19.2) [62.3-100.0] |
| AA severity | ||||||||
| Severe (SALT score <95) | 70 (51.9) | 138 (51.1) | 135 (49.8) | 343 (50.7) | 70 (48.3) | 136 (47.1) | 134 (46.4) | 340 (47.0) |
| Very severe (SALT score ≥95) | 65 (48.1) | 132 (48.9) | 136 (50.2) | 333 (49.3) | 75 (51.7) | 153 (52.9) | 155 (53.6) | 383 (53.0) |
| Alopecia totalis or universalisb,c | 52 (38.5) | 89 (33.0) | 98 (36.2) | 239 (35.4) | 54 (37.2) | 102 (35.3) | 100 (34.6) | 256 (35.4) |
| Alopecia universalis | 35 (25.9) | 71 (26.3) | 71 (26.2) | 177 (26.2) | 40 (27.6) | 79 (27.3) | 85 (29.4) | 204 (28.2) |
| ClinRO eyebrow hair loss severity ≥2 | 87 (64.4) | 170 (63.0) | 178 (65.7) | 435 (64.3) | 93 (64.1) | 192 (66.4) | 197 (68.2) | 482 (66.7) |
| ClinRO eyelash hair loss severity ≥2 | 72 (53.3) | 151 (55.9) | 145 (53.7) | 368 (54.5) | 82 (56.6) | 166 (57.4) | 158d (54.9) | 406 (56.2) |
| AASIS score, mean (SD) | ||||||||
| Symptoms subscale | 3.4 (2.1) | 3.3 (2.1) | 3.4 (2.1) | 3.3 (2.1) | 3.3 (2.1) | 3.3 (2.1) | 3.3 (2.1) | 3.3 (2.1) |
| Respondents, No. | 133 | 266 | 268 | 667 | 143 | 288 | 285 | 716 |
| Interference subscale | 3.5 (3.0) | 3.5 (2.9) | 2.9 (2.6) | 3.3 (2.8) | 3.0 (2.7) | 2.9 (2.8) | 3.1 (2.8) | 3.0 (2.8) |
| Respondents, No. | 133 | 266 | 267 | 666 | 142 | 288 | 285 | 715 |
| Skindex-16 AA score, mean (SD) | ||||||||
| Emotions domain | 69.2 (29.3) | 68.0 (29.5) | 64.3 (30.0) | 66.7 (29.7) | 64.8 (28.0) | 65.5 (29.0) | 65.3 (29.3) | 65.3 (28.9) |
| Respondents, No. | 133 | 266 | 268 | 667 | 143 | 288 | 285 | 716 |
| Functioning domain | 51.2 (32.8) | 51.4 (32.7) | 46.9 (31.1) | 49.5 (32.1) | 46.4 (30.1) | 45.3 (31.7) | 47.4 (30.4) | 46.4 (30.8) |
| Respondents, No. | 133 | 266 | 268 | 667 | 143 | 288 | 285 | 716 |
| Prior AA systemic medication | 91 (67.4) | 175 (64.8) | 178 (65.7) | 444 (65.7) | 98 (67.6) | 173 (59.9) | 186 (64.4) | 457 (63.2) |
Abbreviations: AASIS, Alopecia Areata Symptom Impact Scale; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); ClinRO, clinician-reported outcome; SALT, Severity of Alopecia Tool; UPA, upadacitinib.
Patient race and ethnicity were self-reported or investigator observed; other included American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and multiracial.
Alopecia totalis is hair loss across the entire scalp.
Alopecia universalis is entire-body hair loss, including eyebrows and lashes.
No./total No. (158 of 288) due to 1 missing patient for the analysis.
In UP-AA1, 343 patients (50.7%) had severe AA (SALT score, <95) and 333 (49.3%) had very severe AA (SALT score, ≥95) at baseline. Mean (SD; range) AA disease duration since onset was 11.5 (11.4; 60.9-0.3) years and mean (SD; range) AA current episode duration was 3.0 (2.2; 8.0-0.08) years. In UP-AA2, 340 patients (47.0%) had severe AA (SALT score, <95) and 383 (53.0%) had very severe AA (SALT score, ≥95) at baseline. Mean (SD; range) AA disease duration since onset was 11.6 (11.0; 54.9-0.3) years and mean (SD; range) AA current episode duration was 3.1 (2.2; 8.0-0.1) years (Table 1).
Efficacy
Both studies met the primary end point of SALT score of 20 or less at week 24 (P < .001 for all doses; all 95% CIs are available in Table 2; Figure 2). The proportion of patients who achieved a SALT score of 20 or less at week 24 was significantly greater for 15-mg upadacitinib (UP-AA1, 122 of 270 patients [45.2%]; UP-AA2, 129 of 289 patients [44.6%]) and 30-mg upadacitinib (UP-AA1, 149 of 271 [55.0%]; UP-AA2, 157 of 289 [54.3%]) compared with placebo (UP-AA1, 2 of 135 [1.5%]; UP-AA2, 5 of 145 [3.4%]) (Table 2; Figure 2; eFigure 2 in Supplement 4). The number of patients achieving the response was calculated based on the nonresponder imputation (NRI) approach. Sensitivity analyses of the primary end point, including multiple imputation and tipping point analysis, showed consistent results with the primary approach (ie, NRI), with nominal P ≤ .001.
Table 2. Primary and Secondary End Points in Trials of Upadacitinib for Severe Alopecia Areata (AA).
| End point | Visit, wk | UP-AA1 trial | UP-AA2 trial | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Placebo (n = 135), response (No.) [95% CI] | 15-mg UPA (n = 270) | 30-mg UPA (n = 271) | Placebo (n = 145), response (No.) [95% CI] | 15-mg UPA (n = 289) | 30-mg UPA (n = 289) | ||||||||||
| Response (No.) [95% CI] | Difference (95% CI)a | P value | Response (No.) [95% CI] | Difference (95% CI)a | P value | Response (No.) [95% CI] | Difference (95% CI)a | P value | Response (No.) [95% CI] | Difference (95% CI)a | P value | ||||
| Primary efficacy | |||||||||||||||
| SALT score ≤20, % (No.) | 24 | 1.5 (2) [0 to 3.5] | 45.2 (122) [39.2 to 51.1] | 43.8 (37.6 to 49.9) | <.001 | 55.0 (149) [49.1 to 60.9] | 53.5 (47.4 to 59.5) | <.001 | 3.4 (5) [0.5 to 6.4] | 44.6 (129) [38.9 to 50.4] | 41.0 (34.9 to 47.1) | <.001 | 54.3 (157) [48.6 to 60.1] | 50.7 (44.3 to 57.0) | <.001 |
| Secondary efficacy | |||||||||||||||
| SALT score ≤10, % (No.) | 24 | 0.7 (1) [0 to 2.2] | 35.2 (95) [29.5 to 40.9] | 34.5 (28.8 to 40.2) | <.001 | 45.8 (124) [39.8 to 51.7] | 45.0 (38.9 to 51.0) | <.001 | 2 (1.4) [0 to 3.3] | 36.0 (104) [30.5 to 41.5] | 34.3 (28.9 to 39.8) | <.001 | 47.1 (136) [41.3 to 52.8] | 45.4 (39.4 to 51.4) | <.001 |
| SALT score ≤20, % (No.) | 12 | 0.7 (1) [0 to 2.2] | 20 (54) [15.2 to 24.8] | 19.3 (14.4 to 24.2) | <.001 | 28.0 (76) [22.7 to 33.4] | 27.6 (22.1 to 33.1) | <.001 | 2.1 (3) [0 to 4.4] | 21.1 (61) [16.4 to 25.8] | 18.9 (13.9 to 23.9) | <.001 | 30.4 (88) [25.1 to 35.8] | 28.5 (22.8 to 34.2) | <.001 |
| ClinRO for eyebrow hair loss of 0 or 1 with a ≥2-point improvement from BL, % (No./total)b | 24 | 1.1 (1/87) [0 to 3.4] | 40.6 (69/170) [33.2 to 48.0] | 39.7 (32.0 to 47.4) | <.001 | 61.8 (110/178) [54.7 to 68.9] | 60.9 (53.6 to 68.2) | <.001 | 3.2 (3/93) [0 to 6.8] | 41.7 (80/192) [34.7 to 48.6] | 38.1 (30.4 to 45.9) | <.001 | 58.9 (116/197) [52.0 to 65.8] | 55.7 (48.0 to 63.4) | <.001 |
| ClinRO for eyelash hair loss of 0 or 1 with a ≥2-point improvement from BL, % (No./total)b | Week 24 | 5.6 (4/72) [0.3 to 0.8] | 43.7 (66/151) [35.8 to 51.6] | 37.9 (28.3 to 47.5) | <.001 | 58.6 (85/145) [50.6 to 66.6] | 52.7 (43.2 to 62.2) | <.001 | 3.7 (3/82) [0 to 7.7] | 42.8 (71/166) [35.2 to 50.3] | 38.9 (30.5 to 47.4) | <.001 | 61.4 (97/158) [53.8 to 69.0] | 57.7 (49.1 to 66.3) | <.001 |
| SALT75, % (No.)c | 24 | 1.5 (2) [0 to 3.5] | 45.9 (124) [40 to 51.9] | 44.5 (38.3 to 50.7) | <.001 | 56.1 (152) [50.2 to 62.0] | 54.4 (48.4 to 60.5) | <.001 | 2.8 (4) [0.1 to 5.4] | 47.1 (136) [41.3 to 52.8] | 44.1 (38.0 to 50.2) | <.001 | 53.6 (155) [47.9 to 59.4] | 50.6 (44.4 to 56.9) | <.001 |
| SALT90, % (No.)d | 24 | 0.7 (1) [0 to 2.2] | 30.7 (83) [25.2 to 36.2] | 30 (24.5 to 35.5) | <.001 | 42.4 (115) [36.6 to 48.3] | 41.5 (35.5 to 47.5) | <.001 | 0.7 (1) [0 to 2.0] | 33.6 (97) [28.1 to 39.0] | 32.6 (27.3 to 37.9) | <.001 | 46.7 (135) [41.0 to 52.5] | 45.7 (39.9 to 51.5) | <.001 |
| % Change from baseline in SALT score, LS mean (SE) | 24 | −5.1 (3.1) [−11.2 to .0] | −56.1 (2.2) [−60.3 to −51.8] | −51.0 (3.8) [−58.4 to −43.5] | <.001 | −63.1 (2.2) [−67.4 to −58.8] | −58.0 (3.8) [−65.4 to −50.5] | <.001 | −4.8 (3.1) [−10.8 to 1.2] | −55.7 (2.2) [−60.1 to −51.4] | −50.9 (3.8) [−58.3 to −43.5] | <.001 | −63.7 (2.2) [−68.1 to −59.3] | −58.8 (3.8) [−66.3 to −51.4] | <.001 |
| PaGIC-AA score of 1 or 2, % (No.)e | 24 | 6.7 (9) [2.5 to 0.9] | 67.8 (183) [62.2 to 73.4] | 61.1 (54.3 to 68.0) | <.001 | 75.3 (204) [70.1 to 80.4] | 68.5 (62.0 to 75.0) | <.001 | 7.6 (11) [3.3 to 11.9] | 64.7 (187) [59.2 to 70.2] | 56.8 (50 to 63.7) | <.001 | 75.1 (217) [70.1 to 80.1] | 67.4 (60.9 to 73.9) | <.001 |
| PRO for Scalp Hair Assessment 0/1 with ≥2-point improvement from BL, % (No./total)f | 24 | 2.4 (3/124) [0 to 5.1] | 42.4 (106/250) [36.3 to 48.5] | 39.8 (33.2 to 46.4) | <.001 | 52.6 (132/251) [46.4 to 58.8] | 50.3 (43.7 to 56.9) | <.001 | 4.5 (6/132) [1.0 to 8.1] | 39.5 (104/263) [33.6 to 45.5] | 34.4 (27.8 to 41.0) | <.001 | 53.1 (138/260) [47.0 to 59.1] | 48.3 (41.3 to 55.2) | <.001 |
| Change from baseline in AASIS Interference Subscale score, LS mean (SE) | 24 | −0.4 (0.2) [−0.8 to −0.0] | −1.4 (0.1) [−1.6 to −1.1] | −1.0 (0.2) [−1.5 to −0.6) | <.001 | −1.7 (0.1) [−2.0 to −1.5] | −1.3 (0.2) [−1.8 to −0.9] | <.001 | −0.2 (0.2) [−0.5 to 0.2] | −1.4 (0.1) [−1.6 to −1.1] | −1.2 (0.2) [−1.6 to −0.8] | <.001 | −1.3 (0.1) [−1.5 to −1.0] | −1.1 (0.2) [−1.5 to −0.7] | <.001 |
| Change from baseline in AASIS Symptom Subscale score, LS mean (SE) | 24 | −0.3 (0.1) [−0.6 to −0.0] | −1.6 (0.1) [−1.8 to −1.4] | −1.3 (0.2) [−1.6 to −0.9) | <.001 | −2.0 (0.1) [−2.2 to −1.8] | −1.7 (0.2) [−2.0 to −1.3] | <.001 | −0.2 (0.1) [−0.5 to 0.0] | −1.5 (0.1) [−1.7 to −1.3] | −1.2 (0.2) [−1.6 to −0.9] | <.001 | −1.7 (0.1) [−1.9 to −1.5] | −1.4 (0.2) [−1.8 to −1.1] | <.001 |
| Change from baseline in Skindex-16 AA Emotions Domain score, LS mean (SE) | 24 | −14.6 (2.4) [−19.2 to −9.9] | −30.1 (1.7) [−33.4 to −26.8] | −15.5 (2.9) [−21.2 to −9.8] | <.001 | −36.2 (1.7) [−39.5 to −32.9] | −21.6 (2.9) [−27.3 to −16.0] | <.001 | −10.4 (2.3) [−14.8 to −5.9] | −31.3 (1.6) [−34.5 to −28.1] | −20.9 (2.8) [−26.4 to −15.5] | <.001 | −34.4 (1.6) [−37.6 to −31.2] | −24.0 (2.8) [−29.5 to −18.6] | <.001 |
| Change from baseline in Skindex-16 AA Functioning Domain score, LS mean (SE) | 24 | −9.3 (2.2) [−13.6 to −5.0] | −21.5 (1.5) [−24.5 to −18.6] | −12.3 (2.6) [−17.4 to −7.1] | <.001 | −24.6 (1.5) [−27.6 to −21.6] | −15.3 (2.6) [−20.5 to −10.1] | <.001 | −7.0 (2.0) [−10.9 to −3.2] | −22.5 (1.4) [−25.3 to −19.8] | −15.5 (2.4) [−20.2 to −10.7] | <.001 | −23.4 (1.4) [−26.2 to −20.6] | −16.3 (2.4) [−21.1 to −11.6] | <.001 |
| HADS-A <8 and HADS-D <8, % (No./total)g | 24 | 24.6 (16/65) [14.1 to 35.1] | 34.5 (49/142) [26.7 to 42.3] | 10.7 (−2.2 to 23.6) | .103 | 42.9 (48/112) [33.7 to 52.0] | 18.8 (5.2 to 32.4) | .007 | 22.7 (15/66) [12.6 to 32.8] | 35.8 (43/120) [27.3 to 44.4] | 14.2 (1.3 to 27.0) | .031 | 30.4 (42/138) [22.8 to 38.1] | 8.5 (−3.7 to 20.7) | .170 |
| SALT score 0, % (No.) | 24 | 0 | 14.1 (38) [9.9 to 18.2] | 14.1 (10 to 18.2) | <.001 | 20.3 (55) [15.5 to 25.1] | 20.4 (15.6 to 25.2) | <.001 | 0.7 (1) [0 to 2.0] | 13.1 (38) [9.3 to 17.0] | 12.2 (8.4 to 16.1) | <.001 | 22.5 (65) [17.7 to 27.3] | 21.8 (16.8 to 26.7) | <.001 |
| SALT score ≤20, % (No.) | 8 | 1.5 (2) [0 to 3.5] | 7.0 (19) [4.0 to 10.1] | 5.6 (2.0 to 9.2) | .002 | 11.4 (31) [7.6 to 15.2] | 10.3 (6.0 to 14.6) | <.001 | 2.1 (3) [0 to 4.4] | 8.7 (25) [5.4 to 11.9] | 6.4 (2.6 to 10.3) | .001 | 12.1 (35) [8.3 to 15.9] | 10.1 (5.8 to 14.4) | <.001 |
| PaGIC-AA score of 1 or 2, % (No.)e | 4 | 1.5 (2) [0 to 3.5] | 8.5 (23) [5.2 to 11.8] | 7.0 (3.1 to 10.9) | <.001 | 7.4 (20) [4.3 to 10.5] | 5.8 (2.1 to 9.6) | .002 | 2.8 (4) [0.1 to 5.4] | 5.9 (17) [3.2 to 8.6] | 3.0 (−0.8 to 6.7) | .12 | 11.8 (34) [8.1 to 15.5] | 9.1 (4.5 to 13.6) | <.001 |
| SALT score ≤20, % (No.) | 4 | 1.5 (2) [0 to 3.5] | 0.4 (1) [0 to 1.1] | −1.1 (−3.3 to 1.0) | .31 | 0.4 (1) [0 to 1.1] | −1.1 (−3.3 to 1.1) | .32 | 0 | 0.7 (2) [0 to 1.6] | 0.7 (−0.3 to 1.6) | .16 | 0.3 (1) [0 to 1.0] | 0.4 (−0.3 to 1.0) | .31 |
Abbreviations: ANCOVA, analysis of covariance; AASIS, Alopecia Areata Symptom Impact Scale; BL, baseline; ClinRO, clinician-reported outcome; HADS-A, Hospital Anxiety and Depression Scale−Anxiety; HADS-D, Hospital Anxiety and Depression Scale−depression; LS, least square; NRI, nonresponder imputation; PaGIC-AA, patients’ global impression of change of AA; PBO, placebo; RTB-MI, return-to-baseline incorporating multiple imputation; SALT, Severity of Alopecia Tool; UPA, upadacitinib.
The 95% CIs for adjusted difference and P values were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata based on NRI approach for binary end point, and ANCOVA model adjusted based on RTB-MI approach for continuous end points. SALT score of 20 or less was defined as less than or equal to 20% scalp hair loss; score of 10 or less was defined as less than or equal to 10% scalp hair loss; and score of 0 was defined as 0% scalp hair loss. The ClinRO for eyebrow hair loss is comprised of the following response options: 0, eyebrows have full coverage and no areas of hair loss; 1, minimal gaps in eyebrow hair and even distribution; 2, significant gaps in eyebrow hair or distribution is not even; and 3, no notable eyebrows. The ClinRO for eyelash hair loss is comprised of the following response options: 0, eyelashes form a continuous line along the eyelids on both eyes; 1, minimal gaps and the eyelashes are evenly spaced along the eyelids on both eyes; 2, significant gaps along the eyelids or the eyelashes are not evenly spaced along the eyelids; and 3, no notable eyelashes.
Adjusted difference vs PBO.
Among patients with baseline score of 2 or greater.
At least a 75% improvement (decrease) from baseline in SALT score.
At least a 90% improvement (decrease) from baseline in SALT score
Score of 1 is much better and 2 is moderately better.
Among patients with baseline score of 3 or greater.
Among patients with HADS-A of 8 or greater or HADS-D of 8 or greater at baseline.
Figure 2. Line Graph of Primary End Point—Achievement of SALT Score 20 or Less at Week 24.
SALT score of 20 or less was defined as less than or equal to 20% scalp hair loss.
SALT indicates Severity of Alopecia Tool; UPA, upadacitinib.
aP ≤ .01.
bP ≤ .001. P values generated from week 8 were statistically significant at the prespecified 2-sided .05 level with multiplicity adjustment. P values were calculated according to the Cochran-Mantel-Haenszel test adjusted for strata based on nonresponder imputation approach.
In both studies, significantly greater proportions of patients taking upadacitinib, whether 15 mg (UP-AA1, 95 of 270 patients [35.2%]; UP-AA2, 104 of 289 [36.0%]) or 30 mg (UP-AA1, 124 of 271 patients [45.8% ]; UP-AA2, 136 of 289 [47.1%]), achieved SALT score of 10 or less at week 24 compared with placebo (UP-AA1, 1 of 135 [0.7%]; UP-AA2, 2 of 145 [1.4%]; P < .001 for all with 95% CIs available in Table 2; eFigure 4 in Supplement 4). Likewise, significantly greater proportions of patients taking 15-mg upadacitinib (UP-AA1, 38 of 270 patients [14.1%]; UP-AA2, 38 of 289 [13.1%]) and 30-mg upadacitinib (UP-AA1, 55 of 271 patients [20.3%]; UP-AA2, 65 of 289 [22.5%]) achieved the most stringent end point of SALT score of 0 at week 24 compared with placebo (UP-AA1, 0 of 135; UP-AA2, 0 of 145 [0.7%]; P < .001 for all, with 95% CIs available in Table 2; eFigure 4 in Supplement 4).
In both studies, responses to both doses were observed as early as week 8 for SALT score of 20 or less. For SALT score 10 or less and SALT score of 0, responses were observed as early as week 8 (UP-AA1, 30 mg; UP-AA2, 15 mg and 30 mg) and week 12 (UP-AA1, 15 mg; UP-AA2, 15 mg and 30 mg; eFigure 4 in Supplement 4).
Significantly greater proportions of patients with baseline score of 2 or greater achieved ClinRO measure for eyebrow hair loss of 0 or 1 with a 2-point or greater improvement from baseline at week 24 on 15-mg upadacitinib (UP-AA1, 69 of 170 patients [40.6%]; UP-AA2, 80 of 192 [41.7% ]) and 30 mg (UP-AA1, 110 of 178 patients [61.8%]; UP-AA2, 116 of 197 [58.9%]) compared with placebo (UP-AA1, 1 of 87 patients [1.1%]; UP-AA2, 3 of 93 [3.2%]; P < .001 for all; eFigure 3 in Supplement 4). Likewise, significantly greater proportion of patients with baseline score of 2 or greater achieved ClinRO measure for eyelash hair loss of 0 or 1 with a 2-point or greater improvement from baseline at week 24 on 15-mg upadacitinib (UP-AA1, 66 of 151 patients [43.7%]; UP-AA2, 71 of 166 [42.8%]) and 30 mg (UP-AA1, 85 of 145 patients [58.6%]; UP-AA2, 97 of 158 [61.4%]) compared with placebo (UP-AA1, 4 of 72 patients [5.6%]; UP-AA2, 3 of 82 [3.7%]; P < .001 for all; eFigure 3 in Supplement 4).
Responses to both doses were observed as early as week 8 for ClinRO measure for eyebrow hair loss of 0 or 1 with a 2-point or greater improvement from baseline compared to placebo (eFigure 3 in Supplement 4). For upadacitinib, 30 mg, responses were observed as early as week 8 for improvement in eyelash hair loss (eFigure 3 in Supplement 4).
In both studies, both upadacitinib doses demonstrated significantly greater improvement (reduction) from baseline in AASIS interference subscale score and symptoms subscale score, and in Skindex-16 AA emotions and functioning domain scores compared with placebo at week 24 compared with placebo (P < .001 for all with 95% CIs in Table 2).
At week 24 in UP-AA1, a significantly greater proportion of patients taking 30-mg upadacitinib and achieved HADS-A of less than 8 and HADS-D less than 8 among patients with HADS-A of 8 or greater or HADS-D of 8 or greater at baseline vs placebo in the overall study population (Table 2). For patients taking 15-mg upadacitinib in both studies and taking 30 mg in UP-AA2, the improvement in HADS-A less than 8 and HADS-D less than 8 among patients with HADS-A of 8 or greater or HADS-D of 8 or greater at baseline vs placebo did not meet statistical significance (Table 2).
At week 24 for both studies, both doses led to improved PaGIC-AA scores (1 or 2) and scalp hair assessment (0 or 1 with 2-point or greater improvement [reduction] among patients with baseline score ≥3) vs placebo (eFigure 4 and eTable 2 in Supplement 4).
Patients receiving 30-mg upadacitinib consistently achieved numerically greater response rates than patients receiving 15-mg upadacitinib for the primary end point and most secondary end points (Table 2). Adolescents generally showed a numerically better treatment effect than the overall study population (eTable 4 and 5 and eFigures 9-12 in Supplement 4). Efficacy results from the pooled patient population are provided in eTable 2 in Supplement 4.
Safety
In UP-AA1 and UP-AA2, TEAEs were numerically higher for 30-mg upadacitinib compared to 15-mg upadacitinib or placebo (Table 3; eTable 3 in Supplement 4). In the pooled patient population across UP-AA1 and UP-AA2, treatment-emergent serious adverse events (SAEs) occurred in 1.6% and 2.3% of patients taking 15-mg and 30-mg upadacitinib, respectively, and 0.4% on placebo (Table 3). Discontinuations due to TEAEs occurred in 0.9% and 1.4% of patients taking 15- and 30-mg upadacitinib, respectively, and none taking placebo (Table 3). In UP-AA1, 3 patients discontinued upadacitinib due to an SAE—breast cancer in the 15-mg group and rhabdomyolysis and elective abortion in the 30-mg group (eTable 3 in Supplement 4). In UP-AA2, 2 patients taking 30-mg upadacitinib discontinued study drug due to an SAE (streptococcal pneumonia and vertebral artery stenosis; eTable 3 in Supplement 4). Three SAEs (staphylococcal cellulitis, streptococcal pneumonia, and urinary tract infection) were considered by the investigator to have a reasonable possibility of being related to the study drug.
Table 3. Overview of Treatment-Emergent Adverse Events (TEAEs) in the Safety Analysis Set (Integrated Safety for UP-AA1 and UP-AA2 Trials).
| TEAE | Participants, No. (%) | ||
|---|---|---|---|
| Placebo (n = 280) | 15-mg UPA (n = 557) | 30-mg UPA (n = 560) | |
| Any TEAE | 160 (57.1) | 349 (62.7) | 376 (67.1) |
| SAEs | 1 (0.4) | 9 (1.6) | 13 (2.3) |
| AEs leading to discontinuation of study drug | 0 | 5 (0.9) | 8 (1.4) |
| Deaths | 0 | 0 | 0 |
| AEs reported in >5% of patients in any treatment group | |||
| Acne | 10 (3.6) | 65 (11.7) | 91 (16.3) |
| Nasopharyngitis | 26 (9.3) | 67 (12.0) | 67 (12.0) |
| Upper respiratory tract infection | 33 (11.8) | 53 (9.5) | 74 (13.2) |
| Blood creatine phosphokinase increased | 11 (3.9) | 29 (5.2) | 37 (6.6) |
| AESIs | |||
| Serious infections | 1 (0.4) | 2 (0.4) | 4 (0.7) |
| Opportunistic infection excluding TB and herpes zoster | 0 | 0 | 0 |
| Active tuberculosis | 0 | 0 | 0 |
| Herpes zoster | 1 (0.4) | 4 (0.7) | 6 (1.1) |
| Malignant neoplasm | 0 | 1 (0.2)a | 0 |
| Hepatic disorder | 5 (1.8) | 15 (2.7) | 18 (3.2) |
| Adjudicated GI perforations | 0 | 0 | 0 |
| Anaemia | 1 (0.4) | 4 (0.7) | 4 (0.7) |
| Neutropenia | 1 (0.4) | 12 (2.2) | 22 (3.9) |
| Lymphopenia | 1 (0.4) | 1 (0.2) | 5 (0.9) |
| Kidney dysfunction | 0 | 0 | 0 |
| Elevated CPK | 11 (3.9) | 29 (5.2) | 37 (6.6) |
| Adjudicated MACE | 0 | 0 | 0 |
| Adjudicated VTE | 0 | 1 (0.2)b | 0 |
| Bone fractures | 1 (0.4) | 3 (0.5) | 3 (0.5) |
| Retinal detachment | 1 (0.4) | 1 (0.2) | 0 |
| Serious hypersensitivity reactions | 0 | 0 | 0 |
Abbreviations: AE, adverse event; AESI, adverse events of special interest; CPK, creatine phosphokinase; GI, gastrointestinal; MACE, major adverse cardiovascular event; SAE, serious adverse event; TB, tuberculosis; UPA, upadacitinib; VTE, venous thromboembolic event
One malignant neoplasm (breast cancer) was reported in the 15-mg UPA group in UP-AA1.
One patient with multiple risk factors reported VTE while taking 15-mg UPA in UP-AA2.
The most commonly reported TEAEs were upper respiratory tract infection (placebo, 11.8%; 15-mg upadacitinib, 9.5%; 30-mg upadacitinib, 13.2%), acne (placebo, 3.6%; 15-mg upadacitinib, 11.7%; 30-mg upadacitinib, 16.3%), elevated blood creatine phosphokinase ( placebo, 3.9%; 15-mg upadacitinib, 5.2%; 30-mg upadacitinib, 6.6%), and nasopharyngitis (placebo, 9.3%; 15-mg upadacitinib, 12.0%; 30-mg upadacitinib, 12.0%).
The incidences of adverse events of special interest and of serious infections are reported in Table 3 and eTable 3 in Supplement 4. No serious infections were reported in adolescent patients receiving upadacitinib (eTable 6 in Supplement 4). No deaths were reported in either study. In UP-AA1, a case of breast cancer was reported for a patient taking 15-mg upadacitinib, approximately 4 months after initiating study drug in a 50- to 55-year-old patient with preexisting nodules observed on mammogram results (eTable 3 in Supplement 4). In UP-AA2, 1 case of venous thromboembolism was reported for a patient taking 15-mg upadacitinib approximately 4 months after initiating study drug in a 20- to 30-year-old patient with multiple risk factors, including Down syndrome, hypothyroidism, congenital heart defects, taking combined oral contraception, and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 (eTable 3 in Supplement 4). The SAE of rhabdomyolysis was reported in a patient with a relevant medical history of alcohol use, intravenous methamphetamine use, and severe exercise with dehydration preceding the event; the patient recovered after intravenous rehydration. No cases of active tuberculosis, adjudicated gastrointestinal perforation, major adverse cardiovascular events, kidney dysfunction, or serious hypersensitivity were reported with upadacitinib treatment in either study (Table 3).
Discussion
In both UP-AA1 and UP-AA2, both doses of upadacitinib were superior to placebo in achieving the primary end point of SALT score 20 or less at week 24 in an adult and adolescent patient population diagnosed with severe AA. Both doses of upadacitinib also showed superiority to placebo in most multiplicity-controlled secondary end points, including but not limited to SALT score of 0 (complete scalp hair regrowth), improvement in ClinRO measures for eyebrow and eyelash hair loss, and improvement in health-related quality of life measures at week 24. Differentiation from placebo was observed quickly after treatment initiation, as the primary end point of SALT score 20 or less was met by both upadacitinib doses beginning at week 8.
In addition to the primary end point of SALT score of 20 or less, a key consideration in our study was the inclusion of more stringent SALT score outcomes, specifically SALT score 10 or less and SALT score of 0. Patients treated with upadacitinib met SALT scores of 10 or less and 0—end points that demonstrate deeper levels of scalp hair regrowth that are shown to be associated with significant improvements in psychosocial outcomes across multiple measures. Complete hair regrowth with upadacitinib treatment, demonstrated by the achievement of SALT score of 0 at week 24, showed statistical significance over placebo—a result that was not assessed as a key ranked end point in the primary analyses for the currently approved oral JAK inhibitors. Recent data from global assessment studies show that complete scalp hair regrowth (SALT score of 0) is different in gradation (complete hair restoration) from more limited hair restoration. This distinction supports the concept of SALT score of 0 as a meaningful and aspirational goal in terms of an outcome measure of successful treatment for AA.
Patients treated with both doses of upadacitinib also experienced significant improvement in patient impression of change as well as multiple facets of health-related quality of life. In a disease often associated with sizable psychosocial and emotional burden, translation of clinical responses (hair regrowth) into meaningful patient-reported improvements becomes imperative to deem a treatment to be efficacious.
Upadacitinib is currently approved for multiple indications, including AD, which is noted as a comorbidity in patients with AA. The rapidity and depth of response have the potential to position upadacitinib as a valuable treatment option for patients with severe AA.
The safety profile of both doses of upadacitinib through 24 weeks was generally consistent across both studies, similar in adolescents and adults, and consistent with that observed in atopic dermatitis and other approved indications. No new safety risks were observed.
Strengths and Limitations
With a combined total of 1397 patients, including 118 adolescents, UP-AA1 and UP-AA2 represent a robust phase 3 program of an oral JAK inhibitor in AA. It is noteworthy that the efficacy of baricitinib, deuruxolitinib, and ritlecitinib at week 24 continued to rise over time, and generally no plateau of treatment effect was observed with upadacitinib at week 24 either. Data through week 52 and beyond will reveal the efficacy and safety of upadacitinib in AA over longer treatment periods. Furthermore, a third study is being conducted to assess long-term efficacy and safety and upadacitinib dose adjustments based on clinical response targets at week 52 of UP-AA1 and UP-AA2.
Limitations include the exclusion of patients with a current AA episode duration of more than 8 years, exclusion of preadolescents (who may be affected by AA) and adults older than 64 years, and a predominance of White participants (>50%) despite the diversity of the trial population.
Conclusions
In these 2 parallel phase 3 replicate randomized clinical trials, the 24-week double-blinded period A of UP-AA1 and UP-AA2 demonstrated the superiority of both 15-mg and 30-mg upadacitinib compared with placebo in adult and adolescent patients with severe AA. The safety profile of both doses of upadacitinib through week 24 was consistent with that observed in approved indications. These findings suggest that upadacitinib may be an effective therapeutic option for adults and adolescents with severe AA.
Trial Protocol
SAP for Study 1
SAP for Study 2
eFigure 1. Study design
eFigure 2. Primary end point – achievement of SALT score ≤20 at week 24
eFigure 3. Achievement of ClinRO end points
eFigure 4. Achievement of SALT score ≤10, SALT score of 0, and PAGIC-AA score of 1/2
eFigure 5. Achievement of primary end point (SALT score ≤20) over time
eFigure 6. Achievement of ClinRO end points over time
eFigure 7. Achievement of SALT score ≤10 and SALT score of 0 over time
eFigure 8. Achievement of PaGIC-AA score of 1 or 2 over time
eTable 1. Eligibility criteria
eTable 2. Primary and secondary end points, pooled data
eTable 3. Overview of treatment-emergent adverse events, pooled data
eTable 4. Primary and ranked secondary end points for adult and adolescent patients
eTable 5. Primary and ranked secondary end points (pooled data) in adult and adolescent subgroups
eTable 6. Overview of treatment-emergent adverse events in adult and adolescent subgroups
eFigure 9. Achievement of SALT score ≤20 through week 24 in adult and adolescent subgroups
eFigure 10. Achievement of SALT score ≤10 and SALT score of 0 in adult and adolescent subgroups
eFigure 11. Achievement of ClinRO end points in adult and adolescent subgroups
eFigure 12. Achievement of PaGIC-AA score of 1 or 2 in adult and adolescent subgroups
eAppendix 1. List of Investigators and Institutions by Country
eAppendix 2. Ethics Statement
Nonauthor Collaborators
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
Trial Protocol
SAP for Study 1
SAP for Study 2
eFigure 1. Study design
eFigure 2. Primary end point – achievement of SALT score ≤20 at week 24
eFigure 3. Achievement of ClinRO end points
eFigure 4. Achievement of SALT score ≤10, SALT score of 0, and PAGIC-AA score of 1/2
eFigure 5. Achievement of primary end point (SALT score ≤20) over time
eFigure 6. Achievement of ClinRO end points over time
eFigure 7. Achievement of SALT score ≤10 and SALT score of 0 over time
eFigure 8. Achievement of PaGIC-AA score of 1 or 2 over time
eTable 1. Eligibility criteria
eTable 2. Primary and secondary end points, pooled data
eTable 3. Overview of treatment-emergent adverse events, pooled data
eTable 4. Primary and ranked secondary end points for adult and adolescent patients
eTable 5. Primary and ranked secondary end points (pooled data) in adult and adolescent subgroups
eTable 6. Overview of treatment-emergent adverse events in adult and adolescent subgroups
eFigure 9. Achievement of SALT score ≤20 through week 24 in adult and adolescent subgroups
eFigure 10. Achievement of SALT score ≤10 and SALT score of 0 in adult and adolescent subgroups
eFigure 11. Achievement of ClinRO end points in adult and adolescent subgroups
eFigure 12. Achievement of PaGIC-AA score of 1 or 2 in adult and adolescent subgroups
eAppendix 1. List of Investigators and Institutions by Country
eAppendix 2. Ethics Statement
Nonauthor Collaborators
Data Sharing Statement
