LEVEL UP Study Shows Benefits of Switching From Dupilumab to Upadacitinib in AD

Over the past decade, treatment options for moderate to severe AD have expanded to include targeted systemic therapies such as biologics and Janus kinase (JAK) inhibitors. Despite these advances, a significant proportion of patients fail to achieve optimal disease control, prompting questions around treatment sequencing and switching strategies in routine practice.¹

Upadacitinib (UPA), an oral selective JAK1 inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting IL-4 and IL-13 signaling, are both widely approved for moderate to severe AD. Prior head-to-head and real-world studies have suggested more rapid and, in some cases, greater efficacy with UPA compared with DUPI, particularly for itch relief and higher levels of skin clearance. The phase 3b/4 LEVEL UP study was designed to further explore these differences and to address a clinically relevant scenario: how patients with an inadequate response to initial therapy respond to a structured treatment switch.

The recently published period 2 results of LEVEL UP focus on patients who did not achieve at least 75% improvement in Eczema Area and Severity Index (EASI 75) after 16 weeks of initial treatment (period 1). These patients entered an additional 16-week period in which those originally assigned to DUPI were switched directly, without washout, to UPA 15 mg once daily, with protocol-defined escalation to 30 mg based on clinical response. Patients initially treated with UPA either continued their dose or escalated to 30 mg as needed.²

Study design and population

LEVEL UP is a global, randomized, open-label study with blinded efficacy assessment, enrolling adolescents (≥12 years) and adults under 65 years with long-standing, moderate to severe AD inadequately controlled by prior systemic therapy. Period 2 included 355 patients, of whom 208 switched from DUPI to UPA. Baseline disease severity at entry into period 2 remained clinically significant, with mean EASI scores above 13 and ongoing moderate itch, reflecting persistent disease despite prior advanced therapy.

Efficacy after switching from DUPI to UPA

Following the switch, clinically meaningful improvements were observed across multiple outcomes. By week 32 (16 weeks after switching), nearly 80% of patients in the DUPI → UPA group achieved EASI 75, with 58.7% reaching EASI 90 and approximately 20% achieving complete skin clearance (EASI 100). Importantly, improvements were not limited to skin signs. Measures of itch showed rapid benefit, with more than half of patients achieving a ≥4-point reduction in Worst Pruritus Numerical Rating Scale (WP-NRS) within 4 weeks of switching.

A stringent composite endpoint—simultaneous achievement of EASI 90 and minimal itch (WP-NRS 0/1), often referred to as minimal disease activity—was met by 26.8% of patients by week 32. Notably, early responses were seen as soon as 4 weeks after the switch, underscoring the relatively rapid onset of UPA in this population. Dose escalation played a role for some patients, with just under half requiring escalation to 30 mg; however, most patients who achieved minimal disease activity were maintained on the 15 mg dose.

Safety and tolerability

The safety profile observed during period 2 was consistent with previously reported data for upadacitinib. Approximately half of patients experienced a treatment-emergent adverse event, most commonly nasopharyngitis, acne, upper respiratory tract infection, or AD flare. Rates of acne were lower than those reported in earlier phase 3 trials. Serious adverse events were uncommon, and no new safety signals emerged. There were no reports of malignancy, major adverse cardiovascular events, venous thromboembolism, or serious infections in the DUPI → UPA group. Adolescent safety findings were similar to those in adults.

Clinical context and implications

These findings add to a growing body of evidence supporting treatment modification in patients with inadequate response to biologic therapy. Therapeutic inertia is increasingly recognized as a barrier to achieving treatment goals in AD. Consensus recommendations, including the AHEAD treat-to-target framework, suggest reassessing response within 3–6 months and considering escalation or switching if agreed targets are not met.

The LEVEL UP period 2 data are notable for their pragmatic design: no washout period, initiation at a lower UPA dose with escalation as needed, and clinically relevant endpoints that reflect both skin clearance and itch control. While the open-label design and lack of a comparator arm in period 2 limit definitive conclusions, blinded efficacy assessment and a sizable patient population strengthen the findings.

Conclusion

In patients with moderate to severe AD who did not achieve adequate disease control after 16 weeks of dupilumab, switching to upadacitinib led to substantial improvements in skin clearance and itch for many patients, with a safety profile consistent with prior studies. These results support upadacitinib as a viable and effective option when initial biologic therapy fails to meet treatment targets, aligning with contemporary treat-to-target strategies in AD management.

References

1. Prados-Carmona A, Navarro Triviño FJ, Husein-ElAhmed H, Ruiz-Villaverde R. Comparative real-world effectiveness and safety of biologics and JAK inhibitors in atopic dermatitis: short- and medium-to-long-term analysis from a regional healthcare network in southern Spain. Front Med (Lausanne). 2025;12:1658843. Published 2025 Oct 24. doi:10.3389/fmed.2025.1658843
2. Bunick CG, Magnolo N, Moore A, et al. Switching from dupilumab to upadacitinib in adults and adolescents with moderate-to-severe atopic dermatitis after inadequate response to dupilumab: eefficacy and safety results from period 2 of phase 3b/4 study (LEVEL UP). Am J Clin Dermatol. Published online January 14, 2026. doi:10.1007/s40257-025-01003-0