Upadacitinib Outperforms Dupilumab in Landmark LEVEL UP Trial for Moderate-to-Severe Atopic Dermatitis
Key Insights
The phase 3b/4 LEVEL UP trial demonstrated upadacitinib's superior efficacy over dupilumab, with 19.9% versus 8.9% of patients achieving both EASI 90 and minimal itch at week 16 (P<.0001).
While treatment-emergent adverse events were more common with upadacitinib (65.3% vs 52.7%), rates of severe adverse events and treatment discontinuations remained comparable between both therapies.
Principal investigator Dr. Jonathan Silverberg emphasized these findings provide important context for clinical decision-making, highlighting upadacitinib's ability to address unmet needs in atopic dermatitis (search) treatment.
In the first head-to-head comparison of two leading atopic dermatitis (search) treatments, upadacitinib demonstrated significantly superior efficacy over dupilumab for patients with moderate-to-severe disease, according to comprehensive data from the LEVEL UP trial presented at the Revolutionizing Atopic Dermatitis (RAD) 2024 Annual Meeting.
The landmark phase 3b/4 multicenter, randomized, open-label, efficacy assessor-blinded study enrolled 920 patients aged 12 years and older, including 803 adults and 117 adolescents with moderate-to-severe atopic dermatitis (search) who had inadequate responses to systemic therapy or for whom such therapies were inadvisable.
Superior Efficacy Across Primary and Secondary Endpoints
Results revealed that upadacitinib significantly outperformed dupilumab for the trial's primary endpoint - the simultaneous achievement of a 90% or greater reduction in the Eczema Area and Severity Index (EASI 90) and a Worst Pruritus Numerical Rating Scale (WP-NRS) score of 0 or 1 at week 16. This composite endpoint was achieved by 19.9% of patients receiving upadacitinib compared to 8.9% of those receiving dupilumab (P<.0001).
When analyzing the individual components of the primary endpoint, upadacitinib maintained its superior performance:
- EASI 90 achievement: 40.8% with upadacitinib vs. 22.5% with dupilumab (P<.0001)
- WP-NRS of 0/1 achievement: 30.2% with upadacitinib vs. 15.5% with dupilumab (P<.0001)
"These data really provide important context in terms of superior efficacy for upadacitinib over dupilumab and potentially other biologics by extension," said principal investigator Jonathan Silverberg, MD, PhD, MPH, professor of dermatology and director of clinical research at the George Washington University School of Medicine and Health Science (search).
Study Design and Patient Population
The LEVEL UP trial, launched in 2022, randomized patients in a 1:1 ratio to receive either upadacitinib 15 mg once daily (458 patients) or dupilumab according to label information (462 patients). The study consisted of a 35-day screening period followed by two 16-week treatment periods. In the second treatment period, patients who did not achieve the primary endpoint during the first 16 weeks received upadacitinib as per protocol-defined criteria.
Both medications have established roles in the treatment landscape, with upadacitinib approved for moderate-to-severe atopic dermatitis (search) in 2022 and dupilumab in 2017.
Safety Considerations
Safety analysis revealed that treatment-emergent adverse events occurred more frequently with upadacitinib than dupilumab (65.3% vs. 52.7%). However, the incidence of severe adverse events and adverse events leading to treatment discontinuation were comparable between the two treatment arms.
Regarding infection risk, a single serious infection was reported with dupilumab, while none occurred with upadacitinib. Conversely, five opportunistic infections, all cases of eczema herpeticum (search), were reported with upadacitinib, while none occurred with dupilumab.
Clinical Implications for Treatment Selection
Dr. Silverberg emphasized the importance of these findings for clinical decision-making: "I'm a big believer in shared decision making and that we should offer options to patients and see what really resonates based on their preferences and goals."
He added that upadacitinib appears particularly well-positioned to address unmet needs in atopic dermatitis (search) treatment: "We certainly look for, or hope, for treatments that can get us to higher rates of patients achieving a clinical response across the treated patient population. Upadacitinib in particular is able to really fill a lot of those unmet needs."
The LEVEL UP trial provides dermatologists and patients with valuable comparative data to guide treatment decisions for moderate-to-severe atopic dermatitis (search), particularly for those who have not responded adequately to previous systemic therapies. These findings may influence clinical practice by offering clearer differentiation between these two advanced treatment options based on both efficacy and safety profiles.