Dupilumab in Patients With Chronic Spontaneous Urticaria: Phase 3 LIBERTY-CSU CUPID Randomized Clinical Trials.

Importance: Chronic spontaneous urticaria (CSU) is an inflammatory disease characterized by recurrent pruritic hives and/or angioedema. Many patients with CSU remain symptomatic despite standard-of-care, histamine 1-receptor antagonist (H1-AH) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved in multiple disease states associated with type 2 inflammation. In the phase 3 LIBERTY-CSU CUPID-A trial, dupilumab significantly reduced itch and hives severity in anti-immunoglobulin E (IgE)-naive patients with CSU uncontrolled with H1-AH. However, a replicate trial (CUPID-C) was required per US Food and Drug Administration registration requirements. Objective: To further evaluate the efficacy and safety of dupilumab vs placebo in anti-IgE-naive patients with CSU uncontrolled by H1-AH. Design, Setting, and Participants: The LIBERTY-CSU CUPID-C (2022-2024) was a randomized, placebo-controlled, double-blind, 24-week phase 3 trial using the same trial design as CUPID-A (2019-2021). CUPID-A and CUPID-C were performed in 10 countries in Asia, Europe, and North and South America with anti-IgE-naive patients aged 6 to 80 years with CSU uncontrolled with H1-AH. Data were analyzed from August to September 2024. Interventions: Dupilumab or placebo. Main Outcomes and Measures: In CUPID-C and pooled CUPID-A and -C analyses, change from baseline at week 24 in Itch Severity Score over 7 days (ISS7) or Urticaria Activity Score over 7 days (UAS7), with the other as a key secondary end point, per regional regulatory requirements. Results: The CUPID-C analysis included 151 participants (mean [SD] age, 44.7 [16.9] years; 106 females [70.2%]), of whom 77 (51%) were taking H1-AH at a dosage higher than recommended, and 90 (59.6%) had a baseline UAS7 of 28 or greater. Significant improvements in ISS7 and UAS7 were observed with dupilumab vs placebo at week 24. Least squares mean (SE) changes were -8.64 (1.41) vs -6.10 (1.40), respectively (difference: -2.54 points [95% CI, -4.65 to -0.43]; P = .02) for ISS7 and -15.86 (2.66) vs -11.21 (2.65), respectively (difference: -4.65 points [95% CI, -8.65 to -0.65]; P = .02) for UAS7. CUPID-A and -C combined data (289 participants) demonstrated greater improvements in UAS7 and ISS7. Safety outcomes were generally consistent with the known dupilumab safety profile; 77 patients (53.5%) taking dupilumab vs 81 patients (55.9%) taking placebo reported treatment-emergent adverse events in the pooled analysis. Conclusions and Relevance: The CUPID-C randomized clinical trial confirmed CUPID-A findings, and pooled data demonstrated dupilumab significantly reduced urticaria activity by reducing itch and hives severity in anti-IgE-naive patients with CSU who remained symptomatic despite the use of H1-AH. Trial Registration: ClinicalTrials.gov Identifier: NCT04180488.