Upadacitinib, a selective, reversible Janus kinase (JAK) inhibitor with established efficacy for moderate to severe atopic dermatitis (AD) was found safe and well-tolerated for long-term treatment in adults and adolescents with AD, according to integrated safety data from double-blind, placebo-controlled phase 2b and 3 studies published in The Journal of Allergy and Clinical Immunology.
Investigators pooled data from the double-blind period of 4 studies (1 phase 2b and 3 global phase 3 studies) reporting safety outcomes for upadacitinib in patients with moderate to severe AD, and used the data to assess placebo-controlled safety through 16 weeks, referred to as the 16-Week analysis. They pooled data from patients who received at least 1 upadacitinib dose (15 or 30 mg) in 3 ongoing phase 3 studies to assess long-term safety, referred to as the All Upadacitinib Exposure analysis. Safety outcomes included treatment-emergent adverse events (TEAEs), defined as adverse events with onset after the first dose and within 30 days after the last dose of the study drug or as of the data cutoff date. Investigators also looked at adverse events of special interest (AESIs).
Adverse event rates were presented as exposure-adjusted event rates (EAERs) or exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PYs) for the entire treatment period to adjust for potentially different follow-up durations. For the 16-Week analysis, EAERs and EAIRs were specified using the Cochran-Mantel-Haenszel method adjusting for study. For the All Upadacitinib Exposure analysis, investigators developed an overview of TEAEs in exposure-adjusted rates for all treatment groups together with 95% exact Poisson CI for each treatment group.
There were a total of 2707 patients, including 343 adolescents, randomly assigned 1:1 to upadacitinib or placebo for the 16-Week analysis. There were 2485 patients, including 333 adolescents, in the All Upadacitinib Exposure analysis with 1239 receiving 15 mg and 1246 receiving 30 mg of upadacitinib, respectively. The majority of patients in both groups were White men. The mean duration of exposure for this group for 15 mg was 405 days and for 30 mg was 415 days, with a maximum exposure of 818 days for both groups, respectively. The majority (<60%) of patients in both dosing groups received treatment for 52 weeks or more.
In the 16-Week analysis, EAERs for TEAEs were higher for upadacitinib compared with placebo, and rates of serious AEs and AEs leading to treatment discontinuation were numerically lower in both upadacitinib groups than placebo. The most frequently reported TEAE (>5%) was acne, followed by nasopharyngitis, upper respiratory tract infection, headache, elevated blood creatinine phosphokinase (CPK), and oral herpes. Acne was most common in adolescents and adults younger than 40 years of age.
Serious AEs were infrequent (<2.6 per 100 PY), with serious infection being the most common. Serious infection EAERs were similar between placebo and upadacitinib groups in the 16-Week analysis and between the 15- and 30-mg groups in the All Upadacitinib Exposure analysis.
The most common AE leading to treatment discontinuation in all treatment groups was worsening AD. Serious AEs, severe AEs, and AEs leading to treatment discontinuation were higher in patients aged 65 years and older. The only serious infection in 2 or more patients in the 16-week analysis was appendicitis, and the most common serious infections in the All Upadacitinib Exposure analysis were eczema herpeticum among patients receiving 15 mg and pneumonia and coronavirus infection among patients receiving 30 mg. No patient in the 16-Week analysis experience adjucated major adverse cardiovascular events (MACE), and in the All Upadacitinib Exposure analysis the EAIRs of MACE were 0.1 per 100 PY among those treated with 15 mg and fewer than 0.1 per 100 PY among those treated with 30 mg. No patients receiving upadacitinib in the 16-Week analysis had a VTE, and the VTE events reported in the All Upadacitinib Exposure analysis had an EAIR of less than 0.1 per 100 PY. All patients with a VTE had at least 1 risk factor for thrombosis.
The study was limited by its 1-year duration while AD patients are usually treated for many years, so results may not reflect real-world data. In addition, the majority of patients were White, thus limiting the “generalizability of the results to patients of other racial or ethnic groups.”
Although the risks for MACE and VTE in patients treated with upadacitinib were very low in this analysis, the study authors noted that “as upadacitinib and other JAK inhibitors are prescribed in the real-world setting to a larger number of patients with AD and for longer duration, a risk for MACE and VTE or other safety signals in patients with AD emerge over time.” They therefore recommended evaluating AD patients, especially elderly or those with cardiovascular risk factors, when initiating JAK inhibitors.
Disclosure: Several of the study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.
Guttman-Yassky E, Thyssen JP, Silverberg JI, et al. Safety of upadacitinib in moderate-to-severe atopic dermatitis: an integrated analysis of phase 3 studies. J Allergy Clin Immunol. Published online October 1, 2022. doi:10.1016/j.jaci.2022.09.023