Total eosinophil count as a biomarker for therapeutic effects of upadacitinib in atopic dermatitis over 48 weeks

Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines - interleukin-4 (IL-4), IL-5 and IL-13 - represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma - atopic dermatitis and chronic sinusitis with nasal polyps - supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.

Question Are the efficacy and safety of oral upadacitinib superior to subcutaneous dupilumab in adults with moderate-to-severe atopic dermatitis (AD)? Findings This randomized, blinded, head-to-head comparator clinical trial of 692 patients with moderate-to-severe AD demonstrated clinically meaningful skin clearance and itch relief, with statistically significant superiority for upadacitinib compared with dupilumab. There were no new safety signals reported for either upadacitinib or dupilumab. Meaning Upadacitinib provides superior and more rapid skin clearance and itch relief with tolerable safety compared with dupilumab in patients with moderate-to-severe AD. Importance Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement. Objective To assess the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD. Design, Setting, and Participants Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population. Interventions Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week. Main Outcomes and Measures The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug. Results Of 924 patients screened, 348 (183 men [52.6%]; mean [SD] age, 36.6 [14.6] years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men [56.4%]; mean [SD] age, 36.9 [14.1] years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 ( P  = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean [SE], 31.4% [1.7%] vs 8.8% [1.8%]; P  < .001), achievement of EASI75 as early as week 2 (152 [43.7%] vs 60 [17.4%]; P  < .001), and achievement of EASI100 at week 16 (97 [27.9%] vs 26 [7.6%]; P  < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab. Conclusions and Relevance During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals. Trial Registration ClinicalTrials.gov Identifier: NCT03738397 This randomized clinical trial assesses the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis.