Efficacy and safety of upadacitinib dose escalation and reduction in adults with moderate-to-severe atopic dermatitis: results of a randomized blinded treat-to-target multicentre phase IIIb/IV study (Flex Up).
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BACKGROUND: Pivotal clinical trials have assessed the efficacy and safety of fixed-dose upadacitinib 15 mg (UPA15) and 30 mg (UPA30) once daily in atopic dermatitis (AD). OBJECTIVES: To assess the efficacy and safety of dose escalation to UPA30 and dose reduction to UPA15 based on a clinical response [90% reduction in Eczema Area and Severity Index (EASI 90)] after 12 weeks of treatment in adults with moderate-to-severe AD enrolled in a randomized blinded treat-to-target multicentre phase IIIb/IV study. METHODS: A total of 461 patients were randomized in a 1 : 1 ratio to receive oral doses of UPA15 (n = 229) or UPA30 (n = 232) once daily during the 12-week double-blinded period. At week 12, patients on UPA15 not achieving EASI 90 were dose escalated to UPA30 (UPA15/30); patients achieving ≥ EASI 90 continued on UPA15 (UPA15/15). Patients on UPA30 not achieving EASI 90 at week 12 continued on UPA30 (UPA30/30); patients achieving ≥ EASI 90 received a reduced dose of UPA15 (UPA30/15) for 12 additional weeks. The primary efficacy endpoint was EASI 90 achievement at week 24. Results were reported descriptively as observed. Safety outcomes were assessed. RESULTS: At week 24, of patients who received dose escalation (UPA15/30), 48.1% [n = 64/133; 95% confidence interval (CI) 39.6-56.6] achieved EASI 90; of patients who received a dose reduction (UPA30/15), 68.5% (n = 89/130; 95% CI 60.5-76.4) maintained EASI 90. Of patients who continued on their initial dose, 29.3% (n = 24/82; 95% CI 19.4-39.1) on UPA30/30 achieved EASI 90 and 74.6% (n = 53/71; 95% CI 64.5-84.8) on UPA15/15 maintained EASI 90. At week 24, 32.5% (n = 27/83; 95% CI 22.5-42.6) and 38.0% (n = 38/100; 95% CI 28.5-47.5) of patients on UPA15/30 and UPA30/15, respectively, achieved a worst pruritus numerical rating scale score of 0 or 1 (WP-NRS 0/1), and 20.7% (n = 17/82; 95% CI 12.0-29.5) and 35.0% (n = 35/100; 95% CI 25.7-44.3), respectively, achieved combined EASI 90 and WP-NRS 0/1. At week 24, treatment emergent adverse events were reported in 43.1% (n = 31/72; UPA15/15), 54.2% (n = 78/144; UPA15/30), 61.5% (n = 56/91; UPA30/30) and 48.9% (n = 65/133; UPA30/15) of patients. No malignancies, adjudicated venous thromboembolic events or deaths were reported. CONCLUSIONS: Treatment of moderate-to-severe AD with UPA15 or UPA30, with dose escalation or dose reduction based on achievement of the optimal treatment target of EASI 90 at week 12, demonstrated that both approaches support the achievement and maintenance of EASI 90 at week 24. Overall safety findings were consistent with the known UPA safety profile, with no new safety signals identified.