Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: Analysis of the 3-Year Phase 3 Rising Up Study

Detailed methods were previously reported [16, 17]. In brief, Rising Up (NCT03661138) was a 3-year, phase 3 study to evaluate the safety and efficacy of upadacitinib treatment for moderate-to-severe AD in adolescents (aged 12 to < 18 years, weight ≥ 40 kg) and adults (aged 18–75 years) in Japan. All 42 study sites were in Japan. Patients were randomized 1:1:1 to receive, in combination with TCS, upadacitinib 15 mg, upadacitinib 30 mg, or placebo from baseline to week 16. Randomization was stratified according to baseline disease severity [moderate (validated Investigator Global Assessment for Atopic Dermatitis, vIGA-AD™) score of 3 versus severe vIGA-AD score of 4] and age (< 18 years versus 18–40 years versus > 40 years). Patients who were randomized to placebo at baseline were rerandomized 1:1 at week 16 to receive either upadacitinib 15 mg or 30 mg; rerandomization at week 16 was stratified by ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) from baseline at week 16 (“yes” versus “no”) and age at baseline (< 18 years versus 18–40 years versus > 40 years). All treatment arms were blinded from weeks 0–16 (double-blind period) and weeks 16–52 (blinded extension period) and were open label from weeks 52–160 (open-label period). All patients were required to follow a step-down regimen of concomitant TCS therapy during the double-blind period [15, 16]; briefly, application of a medium-potency TCS to areas with active lesions was required once daily for a maximum of three consecutive weeks. After 3 weeks or once the lesions were clear or almost clear, a low-potency TCS was required once daily for 7 days and then stopped if lesions remained clear. If lesions returned or persisted after 7 days of low-potency TCS, the step-down approach was repeated until lesions resolved or until local or systemic TCS toxicity was observed. Concomitant TCS use was optional (administered per investigator discretion) after week 16 through the end of the study. The study was conducted in accordance with the protocol, International Council for Harmonisation guidelines, and applicable regulations, guidelines, and ethical principles originating from the Declaration of Helsinki. The study protocol was reviewed and approved by an institutional review board [16, 17]. Patients provided written informed consent before screening or undergoing study-specific procedures [16, 17].

Safety was assessed by monitoring adverse events (AEs), serious adverse events (SAEs), adverse events leading to discontinuation, and adverse events of special interest (AESIs) through up to 3 years (week 160) of continuous upadacitinib treatment; for comparison, 2-year (week 112 cutoff date: 11 August 2021) safety data are also presented [16, 17]. Relatedness to study drug was determined at the discretion of the investigator. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in EASI (EASI 75/90), achievement of clear or almost clear on the vIGA-AD (vIGA-AD 0/1) with at least two grades of reduction from baseline, and ≥ 4-point improvement (reduction) from baseline on the Worst Pruritus Numerical Rating Scale (WP-NRS) among patients with WP-NRS scores ≥ 4 at baseline.

AEs were summarized using Medical Dictionary for Regulatory Activities system organ class and preferred terms (version 25.0). Statistical analyses were performed using SAS version 9.4 or higher (SAS Institute, Cary, NC). Exposure-adjusted incidence rates were calculated as the number of patients with at least one event divided by the total number of patient-years for patients at risk of an event (n/PY) to account for differences in upadacitinib exposure across cohorts (the exposure for PY was counted from the first dose of study drug to the time when an event occurred); incidence rates are also presented as the number of patients with events per 100 patient-years (n/100 PY) [17]. Exposure-adjusted event rates [the number of events per 100 patient-years (E/100 PY)] were also calculated through the end of the study. Efficacy data were analyzed using two approaches for handling missing data: observed cases (OC) and nonresponder imputation (NRI). The OC analysis does not impute values for missing evaluations; patients without an evaluation at a scheduled visit will be excluded from the OC analysis for that visit. The NRI analysis categorizes any patient without an evaluation during a specific visit window as a nonresponder for that visit; the exception is if the patient is a responder both before and after a specific visit window and the patient then will be categorized as a responder for that visit. The 3-year efficacy results were descriptively summarized and no hypothesis testing was performed.

Of the 272 patients randomized in the study, 264 (97.1%) completed the double-blind period, and 230 (87.1%) of the 264 who entered the blinded extension/open-label periods completed the study (Fig. 1). A total of 29 adolescents were randomized; 28 adolescents completed the double-blind period, and 21 adolescents completed the study (12 in the upadacitinib 15 mg group and 9 in the upadacitinib 30 mg group). As previously reported, baseline demographics and characteristics were generally balanced across cohorts in the overall population (Table 1) and in the adolescent population (Supplementary Table 1) [16, 17]. The median exposure to upadacitinib was 3.1 years (range 0.04–3.1 years) in both of the continued upadacitinib treatment groups.

Among patients who were randomized to receive upadacitinib at baseline, improvement in skin clearance observed at week 16 was generally sustained through the end of the study (Figs. 3, 4). In the OC analysis, the proportion of patients achieving EASI 75 at week 160 was 72.7% with upadacitinib 15 mg and 77.0% with upadacitinib 30 mg, and the proportion of patients achieving EASI 90 at week 160 was 40.3% with upadacitinib 15 mg and 59.5% with upadacitinib 30 mg. Results for both EASI 75 and EASI 90 responses by NRI analysis were generally consistent with the OC analysis. Among patients who switched from placebo to upadacitinib at week 16, substantial improvements in EASI scores were also observed by the first visit after initiation of upadacitinib treatment; responses improved continuously until reaching a plateau that was sustained through the end of the study with either upadacitinib dose (Supplementary Figs. 1, 2).

The proportion of patients achieving vIGA-AD 0/1 was substantially higher with either upadacitinib dose than with placebo during the double-blind period, and vIGA-AD 0/1 response rates in the continued upadacitinib groups were sustained through the end of the study (Fig. 5). At week 160 by OC analysis, 39.0% and 50.0% of patients, respectively, achieved vIGA-AD 0/1 with continuous upadacitinib 15 mg and 30 mg treatment. Among patients who switched from placebo to upadacitinib at week 16, vIGA-AD 0/1 responses increased substantially within 8 weeks of initiating upadacitinib treatment and were generally maintained through the end of the study with either upadacitinib dose (Supplementary Fig. 3).

Itch was also substantially reduced in patients receiving upadacitinib within 1–8 weeks of initiating treatment and remained low through the end of the study (Fig. 6). In the OC analysis, 51.3% and 55.4% of patients with WP-NRS scores ≥ 4 at baseline achieved a ≥ 4-point improvement in WP-NRS scores at week 160 with upadacitinib 15 mg and 30 mg, respectively; similar results were observed by NRI analysis. Among patients who switched from placebo to upadacitinib at week 16, rapid improvements in itch were reported by the first visit after initiation of upadacitinib treatment, and these responses remained durable through the end of the study with either upadacitinib dose (Supplementary Fig. 4).

Efficacy responses in the adult population were consistent with those in the overall study population (Supplementary Figs. 5, 6, 7, 8). In the adolescent population, upadacitinib treatment also led to substantial skin clearance and itch reduction, with generally similar trends as in the overall population; however, the data should be interpreted with caution as higher variability was observed owing to the small sample size.

The mean proportion of days in which patients were not receiving concomitant TCS therapy during the study was greater among patients receiving upadacitinib compared with placebo and was generally higher for patients receiving upadacitinib 30 mg versus those receiving upadacitinib 15 mg (Fig. 7A). From baseline through week 16, the mean (SD) percentage of TCS-free days was 23.7% (29.2) with upadacitinib 15 mg, 27.7% (30.9) with upadacitinib 30 mg, and 4.1% (10.0) with placebo. Among patients who received upadacitinib, the mean proportion of TCS-free days increased during the double-blind period (when the TCS regimen was required) and peaked between weeks 4 and 16 for patients who received upadacitinib 15 mg and between weeks 12 and 16 for patients who received upadacitinib 30 mg; the proportion then decreased over the next several weeks when TCS use was optional per investigator discretion. The mean proportion of TCS-free days generally remained stable from weeks 88–160 with upadacitinib 15 mg and from weeks 52–160 with upadacitinib 30 mg. Over the course of the study (up to 160 weeks of exposure), the mean (SD) percentage of TCS-free days was 13.1% (22.8) with upadacitinib 15 mg and 21.2% (32.3) with upadacitinib 30 mg.

The mean proportion of days in which patients were TCS free and also achieved EASI 75 generally followed a similar pattern for all treatment groups (Fig. 7B). From baseline up to week 16, the mean (SD) percentage of days in which patients were TCS free and still achieved EASI 75 was 16.3% (25.4) in the upadacitinib 15 mg arm and 21.9% (27.7) in the upadacitinib 30 mg arm compared with 0.4% (1.8) in the placebo arm. Over 160 weeks of exposure, the mean (SD) percentage of days in which patients were TCS free and still achieved EASI 75 was 11.0% (20.0) with upadacitinib 15 mg and 18.5% (29.7) with upadacitinib 30 mg. Similar trends were observed among patients who switched from placebo to upadacitinib at week 16 (Supplementary Fig. 9A, B).