Long-term Upadacitinib Safety in Moderate-to-Severe Atopic Dermatitis up to 7 Years: an Integrated Analysis with Over 9600 Patient-Years of exposure

Abstract

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous lesions, intense itch, and skin pain. The chronic nature of the disease requires safe and effective long term treatment options. Upadacitinib (UPA) is a Janus kinase inhibitor approved for the treatment of moderate-to-severe AD in adults and adolescents.

Materials and Methods Patients in the randomized, double-blind, multicenter, placebo-controlled, phase 3 Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and AD Up (NCT03568318) trials were pooled for analysis. Adolescents and adults (aged 12–75 years) with moderate-to-severe AD were randomized 1:1:1 to receive once-daily oral monotherapy with UPA 15 mg, UPA 30 mg, or placebo (Measure Up 1, Measure Up 2) or in conjunction with topical corticosteroids (AD Up). The first 16 weeks of each study were placebo-controlled, double-blinded with a blinded extension period of up to 524 weeks. Patients who were initially randomized to UPA maintained their original treatment. Patients initially randomized to placebo were rerandomized (1:1) to blinded UPA 15 mg or UPA 30 mg. Treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI) were assessed by exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period.

Results A total of 2683 patients were treated with either 15 mg (N = 1337) or 30 mg (N=1346) of UPA with a total of 9623.7 PYs of exposure. Overall rates for TEAEs were higher with UPA 30 mg than UPA 15 mg.  Serious AE, and AE leading to discontinuation were generally similar between UPA 15 mg and 30 mg. Rates of TEAEs leading to death remained low in both groups (both UPA 15 mg and 30 mg, 0.1 events per 100PY [E/100PY]). Rates of AESIs were: serious infections (UPA 15 mg, 2.2E/100PY; UPA 30 mg, 2.7 E/100 PY), herpes zoster (UPA 15 mg, 3.2 E/100PY; UPA 30 mg, 5.1 E/100PY), nonmelanoma skin cancer (NMSC; UPA 15 mg, 0.4 patients per 100 patient-years [n/100PY]; UPA 30 mg 0.5 n/100PY), malignancy excluding NMSC (UPA 15 mg, 0.3 n/100PY; UPA 30 mg, 0.4 n/100PY), adjudicated major adverse cardiovascular events (UPA 15 mg, 0.2 n/100PY; UPA 30 mg, < 0.1 n/100PY), and adjudicated venous thromboembolic events (UPA 15 mg, 0.1 n/100PY; UPA 30 mg, 0.2 n/100PY). Incidence rates for MACE, VTE and malignancy were similar or below background rates observed in real-world AD populations.

Conclusions This integrated analysis of three phase 3 trials with over 9600 patient-years of exposure demonstrates consistently low rates of adverse events of special interest throughout 7 years of upadacitinib treatment. Rates were generally similar between doses and did not exceed background incidence rates in real-world atopic dermatitis populations, supporting the established benefit-risk profile of upadacitinib for moderate-to-severe atopic dermatitis.