Treatment with the Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) maintains a favorable long-term benefit-risk profile through 76 weeks in adolescents with moderate to severe atopic dermatitis, according to an analysis of three phase III randomized trials. The findings, published in JAMA Dermatology, highlight the potential of upadacitinib as a valuable treatment option for this patient population.
Efficacy Outcomes
At week 76, the Measure Up 1, Measure Up 2, and AD Up trials showed that 84-89% of adolescents taking upadacitinib 15 mg achieved at least a 75% reduction in the Eczema Area and Severity Index score (EASI-75). Similarly, 83-96% of adolescents taking the 30-mg dose reached the same milestone, according to researchers led by Amy S. Paller, MD, of the Feinberg School of Medicine at Northwestern University in Chicago.
Both doses of upadacitinib also met the study's other two co-primary endpoints at week 76: a score of clear or almost clear with at least 2 grades of improvement on the Validated Investigator Global Assessment for Atopic Dermatitis and a minimum 4-point improvement from baseline on the Worst Pruritus Numerical Rating Scale for those with a score of 4 points or higher at baseline.
Clinical Context and Unmet Needs
Given the significant negative impacts of atopic dermatitis on the quality of life among adolescents, including increased suicidality, the authors emphasized the ongoing need for effective treatments available to this population.
Shoshana Marmon, MD, PhD, of New York Medical College in Valhalla, noted the importance of medication adherence, regular monitoring, infection prevention, and awareness of potential side effects when initiating JAK inhibitors, especially in younger patients.
Safety Profile
Overall, acne and nausea were the most common adverse events (AEs) associated with upadacitinib. Acne primarily manifested as inflammatory papules, pustules, and comedones involving the face. Nausea was reported by 2.4% to 4.5% of patients across the three trials, with exposure-adjusted rates of 2.9 per 100 patient-years with the 15-mg dose and 1.1 per 100 patient-years with the 30-mg dose.
Long-term outcomes were consistent with the known AE profile of upadacitinib. In Measure Up 1, Measure Up 2, and AD Up, rates of herpetic infection were 4.0, 1.9, and 1.1 events per 100 patient-years, respectively, and rates of creatine kinase elevations were 11.6, 11.0, and 7.1 events per 100 patient-years. No new safety signals were observed with either dose.
All opportunistic infections were mild or moderate events of eczema herpeticum (EH). The increased risk of EH among patients with atopic dermatitis is likely due to impaired epidermal barrier function, according to Paller and team.
"No consistent dose relationship of exposure-adjusted event rates was observed for any AEs, severe AEs, or AEs leading to treatment discontinuation" between the two upadacitinib doses across the three studies, the researchers wrote.
Expert Commentary
Sonya Kenkare, MD, of Illinois Dermatology Institute in Hinsdale, stated that "this JAK inhibitor is a promising addition to the treatment armamentarium that dermatologists will have at their fingertips for adolescent patients. As with any JAK inhibitor, patients will need to be appropriately screened for their candidacy for this drug and monitored for adverse events."
She added, "The adverse events like infections and herpes zoster are manageable, and patients should be warned about these and other potential risks of this drug."
Study Details
The analysis involved 542 adolescents (52.4% girls) with moderate to severe atopic dermatitis. Data were gathered from August 2018 to April 2022. Across the three trials, patients were randomized 1:1:1 to receive once-daily oral upadacitinib 15 mg or 30 mg, or placebo, either alone (Measure Up 1 and Measure Up 2) or with topical corticosteroids (AD Up) for 16 weeks. At week 16, placebo patients in all studies were re-randomized to receive 15 mg or 30 mg of upadacitinib.
For patients previously treated with placebo (with or without topical corticosteroids) during weeks 1 to 16 in all three studies, response rates increased after the switch to upadacitinib, then plateaued, and were maintained through week 76, similar to patients who continued with upadacitinib, Paller and colleagues noted.
One unexpected finding in the AD Up study was that at week 76, fewer patients achieved EASI-75 with the 30-mg dose versus the 15-mg dose, potentially because "concomitant use of topical corticosteroids was no longer required starting at the week 52 visit," the authors suggested.
