Late-Breaker: Upadacitinib Demonstrates Superiority Over Dupilumab in All Ranked Secondary End Points of Head-to-Head AD Study

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A late-breaking session at the 2024 Revolutionizing Alopecia Areata, Vitiligo, and Eczema Conference in Chicago, Illinois, detailed follow-up data from the head-to-head LEVEL-UP (NCT05601882) study evaluating upadacitinib (AbbVie) versus dupilumab (Sanofi & Regeneron) for the treatment of adolescents and adults with moderate to severe atopic dermatitis who had inadequate response to systemic therapy or when systemic therapies were not advised. The late-breaking data demonstrates that upadacitinib showed superiority over dupilumab for all ranked secondary end points of LEVEL-UP, including complete skin clearance and rapid resolution of itching in patients with severe itch.¹

In LEVEL-UP, patients were randomized to receive upadacitinib 15mg starting dose or dupilumab per its label dose for 16 weeks (period 1), with a 16-week extension period to 32 weeks (period 2) for patients who did not achieve at least a 75% reduction in Eczema Area and Severity Index (EASI 75) from baseline at week 16. Patients who received upadacitinib 15mg were dose-escalated to 30mg starting from week 4 if they achieved at least EASI 50 or a <4-point improvement from baseline for their weekly rolling average of Worst Pruritus Numerical Rating Scale (WP-NRS) score. Patients who received upadacitinib 15mg and who did not achieve EASI 75 starting at week 8 were also dose-escalated to 30 mg.

The primary end point of LEVEL-UP was the simultaneous achievement of EASI 90 and WP-NRS 0/1 at week 16. The achievement of upadacitinib’s efficacy in the primary end point over dupilumab was announced in April 2024. Upadacitinib’s superiority began as early as week 4 and was maintained through week 16.²

"For years we focused on data for moderate efficacy endpoints, such as EASI 75 or NRS 4. LEVEL UP evaluated much more stringent composites of EASI 90 and NRS 0/1, which are very meaningful to patients. These LEVEL UP data show us that we can aim higher. The study showed very good efficacy overall, and across all subsets of patients examined in post-hoc analyses. That is, patients across different age groups and severity levels did very well with upadacitinib treatment. Taken together, upadacitinib has the potential to be highly effective across a wide array of patients with moderate-severe AD," Jonathan Silverberg, MD, PhD, MPH, professor of dermatology and director of clinical research at the George Washington University School of Medicine and Health Sciences and lead study investigator, told Dermatology Times.

In total, 920 patients (803 adults, 117 adolescents) were randomized to receive upadacitinib (n=458) or dupilumab (n=462). Patients who received upadacitinib achieved all ranked secondary endpoints, including:

• EASI 90 at week 16
• WP-NRS 0/1 at week 16
• Improvement in WP-NRS ≥4 at week 16
• WP-NRS 0/1at week 4
• WP-NRS 0/1 at week 2
• EASI 90 at week 4
• EASI 75 at week 2
• EASI 100 at week 16

"What’s unique about LEVEL UP is that it evaluates simultaneous achievement of near complete skin clearance, and little to no itch in adults and adolescents with moderate to severe atopic dermatitis,” Silverberg said Silverberg in a previous interview with Dermatology Times.

Additionally, the superiority of upadacitinib over dupilumab began as early as week one and was maintained through week 16 for patients achieving WP-NRS 0/1.

"Atopic dermatitis is a complex disease with activation of multiple immune pathways that contribute to the signs and symptoms of disease. Biologics are targeted treatments that work outside the cell targeting two of the many signaling pathways implicated in AD pathogenesis. Whereas upadacitinib, a selective oral JAK1 inhibitor, works inside cells and rapidly inhibits downstream signaling of multiple key signaling pathways implicated in AD pathogenesis. The broader mechanism of upadacitinib likely contributes to the deeper level of treatment response observed in the LEVEL UP study and other studies of upadacitinib in moderate-severe AD," said Silverberg.

Severe adverse events and adverse events leading to discontinuation of study treatment were similar between the upadacitinib and dupilumab groups, with no difference in the proportion of serious adverse events. No deaths were reported in either patient group. Additionally, no malignancies, adjudicated major adverse cardiac events, or adjudicated venous thromboembolic events were reported in either patient group.

“Treatment of moderate-to-severe AD with UPA initiated at 15mg and dose-escalated to 30mg based on clinical response demonstrated superiority versus DUPI for the primary endpoint of simultaneous achievement EASI 90 and WP-NRS 0/1 at week 16, and all ranked secondary endpoints....Achievement of stringent itch and skin targets may optimize overall disease control for patients with moderate-to-severe atopic dermatitis,” wrote Silverberg et al.

References

1. Silverberg J, Bunick C, Hong C, et al. Efficacy and safety of upadacitinib vs dupilumab in adults and adolescents with moderate-to-severe atopic dermatitis: results of an open-label, efficacy assessor-blinded head-to-head phase 3b/4 study (Level Up). Poster presented at: 2024 Revolutionizing Alopecia Areata, Vitiligo, and Eczema Conference; June 8-10, 2024; Chicago, IL.

2. New data show Rinvoq (upadacitinib) demonstrated superiority versus Dupixent (dupilumab) across primary and all secondary endpoints in an open-label head-to-head atopic dermatitis study. News release. AbbVie. April 25, 2024. Accessed June 10, 2024. https://news.abbvie.com/2024-04-25-New-Data-Show-RINVOQ-R-upadacitinib-Demonstrated-Superiority-Versus-DUPIXENT-R-dupilumab-Across-Primary-and-All-Secondary-Endpoints-in-an-Open-Label-Head-to-Head-Atopic-Dermatitis-Study