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

Detailed methods have been described previously [13]. Briefly, this ongoing phase 3 study (Rising Up, NCT03661138) was designed to evaluate the safety and efficacy of upadacitinib for the treatment of moderate-to-severe AD in adolescents (aged 12 to < 18 years, weight ≥ 40 kg) and adults (aged 18–75 years) in Japan. There were 42 study sites, all of which were in Japan. Patients were randomized 1:1:1 to receive either upadacitinib 15 mg, upadacitinib 30 mg, or placebo with concomitant topical corticosteroids for all arms from baseline to week 16 (double-blind period). Randomization was stratified according to baseline disease severity [validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 3 (moderate) versus 4 (severe)] and age (< 18 versus 18–40 versus > 40 years of age). Patients who received placebo during the double-blind period were rerandomized 1:1 at week 16 to receive either upadacitinib 15 mg or 30 mg; treatment was blinded from weeks 16–52 (blinded extension period) and open-label from week 52 up to week 160 (open-label phase). Starting at the week 16 visit, the use of any concomitant topical medication for AD was no longer required and was administered per investigator discretion. 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 and patients provided written informed consent before screening or undergoing study-specific procedures [13].

Safety assessments, exploratory efficacy endpoints, and statistical analyses through week 24 were previously reported [13]. In this 2-year interim analysis, safety and efficacy were evaluated through the 112-week cutoff date (11 August 2021). Short-term safety was reported as number (percent) of patients, while long-term safety was calculated as exposure-adjusted incidence rates [the number of patients with at least one event per 100 patient-years (n/100 PY)] to account for differences in upadacitinib exposure across treatment arms. Long-term safety data were censored with exposure only counted until the event. Exposure-adjusted event rates [calculated as the number of events per 100 patient-years (E/100 PY)] were also calculated through 52 weeks and 112 weeks of continuous upadacitinib treatment. Efficacy assessments included at least 75% and at least 90% improvement from baseline in Eczema Area and Severity Index (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) on the Worst Pruritus Numerical Rating Scale (WP-NRS) in patients with WP-NRS scores ≥ 4 at baseline. Long-term efficacy data are reported using the observed cases approach (i.e., all observed data up to drug discontinuation were included and no imputation was applied for missing data). Data were descriptively reported, and hypothesis testing was not performed.

Among the 272 patients enrolled in the study, 242 were still ongoing at the time of data cutoff (120 in the upadacitinib 15 mg group and 122 in the upadacitinib 30 mg group; Fig. 1). A total of 29 adolescents were randomized, and 23 adolescents were still ongoing at the time of data cutoff (12 in the upadacitinib 15 mg group and 11 in the upadacitinib 30 mg group). Baseline demographics and characteristics were generally balanced across treatment groups in both the overall population [13] (Table 1) and in adolescents (Table S1).

Overall, similar safety profiles were observed between the upadacitinib 15 mg group and upadacitinib 30 mg group through the week 112 data cutoff date (Table 2). The most common adverse events (AEs) with long-term upadacitinib treatment continued to be acne, nasopharyngitis, and herpes zoster. All cases of acne were mild or moderate in severity; one case of acne in the upadacitinib 30 mg group led to study drug discontinuation. Rates of acne, herpes zoster, increased blood creatine phosphokinase levels, and tinea pedis were slightly higher in the upadacitinib 30 mg group than in the 15 mg group. Rates for other common AEs were generally similar between the two upadacitinib treatment groups with some variability likely owing to the small sample size. Long-term incidence rates (n/100 PY) for severe AEs and AEs leading to discontinuation were similar between the two upadacitinib treatment groups. The rate of serious AEs was numerically higher with upadacitinib 15 mg than with upadacitinib 30 mg, likely owing to the small number of reports or simply a chance finding; no patterns in the type or timing of events were observed. There were no deaths during the interim analysis period. Similar patterns were observed for exposure-adjusted event rates (E/100 PY) through week 52 and week 112 (Table S2).

Long-term incidence rates of AEs were lower in adolescents than in the overall study population and were consistent with the previously reported safety profile for adolescents; no new safety findings were reported (Table S3).

Similar to the 16-week placebo-controlled period, incidence rates of AEs of special interest were generally low at week 112 for both doses of upadacitinib (Table 3). All opportunistic infections (excluding tuberculosis and herpes zoster) were eczema herpeticum (Kaposi’s varicelliform eruption), aside from one onset of Pneumocystis jirovecii pneumonia. In the upadacitinib 15 mg group, six serious infections were reported and included appendicitis, Pneumocystis jirovecii pneumonia, herpes zoster, cellulitis, septic shock, and enteritis infectious; all cases were severe. All serious infections in the upadacitinib 15 mg group except cellulitis and septic shock were considered by the investigator as having a reasonable possibility of being related to study drug, and all had resolved as of the data cutoff date. In the upadacitinib 30 mg group, four serious infections were reported (one event of appendicitis, one event of herpes simplex, and two events of herpes zoster); all cases were severe, all were considered by the investigator as having a reasonable possibility of being related to study drug, and all had resolved as of the data cutoff date. Most cases of herpes zoster were non-serious, did not lead to treatment discontinuation, and involved one or two dermatomes. Most hepatic disorders were elevations in transaminase levels. Incidence rates of anemia, neutropenia, and elevations in creatine phosphokinase levels remained higher with upadacitinib 30 mg than with upadacitinib 15 mg. All laboratory-related AEs were generally mild or moderate in severity and were non-serious; few led to treatment discontinuation. One case of grade 1 rectal cancer was reported in the upadacitinib 15 mg group on study day 793 (patient age at onset, 38 years); the case resolved after the excision of the tumor, and was considered unrelated to study drug by the investigator. A 22-year-old male patient experienced a major adverse cardiovascular event (cerebellar hemorrhage) on study day 65, and assessed by the investigator as possibly related to study drug. There continued to be no cases of gastrointestinal perforation, active tuberculosis, or venous thromboembolic events. Clinical laboratory parameters were generally similar through 112 weeks of treatment (Table 4) Exposure-adjusted event rates for AEs of special interest at week 52 and week 112 are presented in Table S4.

Among adolescents, AEs of special interest were reported infrequently (≤ three cases) with no new safety findings relative to the overall study population (Table S5). A single event of serious infection (appendicitis, possibly related to study drug) was reported in an adolescent receiving upadacitinib 15 mg. In addition to the appendicitis, two serious AEs were reported in adolescents receiving upadacitinib 15 mg: one event of concussion due to an accident and one event of irritable bowel syndrome, both considered to be unrelated to the study drug by the investigator. Two events of herpes zoster were reported in adolescents receiving upadacitinib 30 mg. No malignancies, adjudicated major adverse cardiovascular events, or venous thromboembolic events were reported.

In patients randomized to receive upadacitinib at baseline, improvements in EASI scores observed by week 16 were sustained through 112 weeks of treatment (Fig. 2) At week 112, 69.5% and 74.4% of patients achieved EASI 75 with upadacitinib 15 mg and 30 mg, respectively (Fig. 2A), while 37.8% and 56.4% of patients achieved EASI 90 (Fig. 2B). Patients who switched from placebo to upadacitinib at week 16 also showed substantial improvements in EASI scores within 8 weeks that remained high and durable through week 112, regardless of upadacitinib dose; at week 112, 66.7% and 85.4% of patients achieved EASI 75 with upadacitinib 15 mg and 30 mg, respectively, and 36.1% and 56.1% of patients achieved EASI 90.

Response rates for vIGA-AD 0/1 were numerically greater for patients treated with either dose of upadacitinib than for patients receiving placebo, and vIGA-AD 0/1 response rates were maintained through week 112 in all upadacitinib treatment groups (Fig. 3). At week 112, 32.9% and 46.2% of patients achieved vIGA-AD 0/1 with continuous upadacitinib 15 mg and 30 mg, respectively; among patients who switched from placebo to upadacitinib at week 16, 27.8% and 36.6% of patients achieved vIGA-AD 0/1 at week 112 with upadacitinib 15 mg and 30 mg, respectively.

Patients receiving upadacitinib also showed substantial reductions in WP-NRS scores within as early as 1 week of treatment that were maintained long term (Fig. 4). At week 112, 44.4% and 56.4% of patients with WP-NRS scores ≥ 4 at baseline achieved a ≥ 4-point improvement in WP-NRS scores with continuous upadacitinib 15 mg and 30 mg, respectively. Among patients who switched from placebo to upadacitinib at week 16, 44.4% and 63.4% of patients achieved a ≥ 4-point improvement in WP-NRS scores at week 112 with upadacitinib 15 mg and 30 mg, respectively.

Adolescents also experienced substantial skin clearance and itch reduction that generally followed similar trends as the overall population; however, higher variability was observed owing to the small sample size, and the data should be interpreted with caution (Figs. S1–S3).