Chronic spontaneous urticaria (CSU) affects approximately 1% of the global population and is often challenging to manage.^1,2 First-line treatment typically involves second-generation H1 antihistamines (H1-AH), administered at doses up to four times the standard recommendation, but only around half of patients achieve adequate symptom control.³ Until recently, treatment options for those who remained symptomatic were limited.³ This highlights an unmet need for additional targeted therapies.³ Recently, the United States (US) Food and Drug Administration (FDA) approved dupilumab, the first new targeted treatment for CSU in over a decade, for patients aged 12 and older who remain symptomatic despite antihistamine use.

CSU is a distressing skin condition characterized by unpredictable outbreaks of hives and severe itching, often persisting for ≥6 weeks without an identifiable cause.³ Dupilumab, a monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling, has recently been approved for the treatment of CSU.^3,4 The FDA's decision was supported by two pivotal phase 3 clinical trials (LIBERTY-CSU CUPID study A and study C), which demonstrated that dupilumab significantly reduced symptoms of itch and hives compared to placebo in patients with CSU inadequately controlled by H1-AH.^3,5

LIBERTY-CSU CUPID study A and study C were randomized, double-blind, placebo-controlled trials conducted as replicate studies.^3,5 They aimed to evaluate the efficacy and safety of dupilumab as an add-on therapy to standard-of-care antihistamines compared to antihistamines alone in patients aged six years and older who remained symptomatic despite the use of antihistamines.^3,5 Throughout the 24-week treatment period, participants received a loading dose followed by 300mg dupilumab biweekly (adolescent patients <60kg and children >30kg received a reduced dose of 200mg) or matching placebos.^3,5 The primary endpoint was the change in itch severity from baseline at week 24, measured by the weekly Itch Severity Score (ISS7, 0-21 scale).^3,5 Key secondary endpoints included changes in both itch and hives, measured by the Urticaria Activity Score (UAS7, 0-42 scale), as well as the safety endpoints.^3,5

In study A (n=138), dupilumab showed statistically significant symptom improvements over placebo in both UAS7 and ISS7.³ The least squares (LS) mean change in UAS7 was -20.5 for dupilumab vs. -12.0 for placebo, showing a difference of 8.5 points (p=0.0003).³ Besides, dupilumab resulted in a 4.2-point greater reduction in ISS7 compared to placebo (p=0.0005).³

A higher proportion of dupilumab-treated patients achieved well-controlled CSU symptoms (45.7% vs. 23.5%; OR=2.8; p=0.0075), complete resolution of CSU symptoms (31.4% vs. 13.2%; OR=2.9; 95% CI: 1.2-7.2; p=0.0199).³ Similarly, in study C (n=151), dupilumab led to meaningful reductions in itch and hives at 24 weeks.5 The LS mean change in ISS7 was -8.6 for dupilumab compared to -6.1 for placebo, with a treatment difference of -2.5 (p=0.02).5 For UAS7, dupilumab showed a more significant improvement (-15.9) compared to placebo (-11.2), resulting in a difference of -4.7 (p=0.02).5 Additionally, a higher percentage of patients treated with dupilumab achieved well-controlled disease status (41% vs. 23%; OR=2.7; p=0.005) and complete response (30% vs. 18%; OR=2.7; p=0.02) compared to those receiving placebo.⁵

In terms of safety, the incidence of treatment-emergent adverse events (TEAEs) was similar between the dupilumab and placebo groups across the studies.^3,5 Study B (n=108) provided additional safety data and evaluated dupiliumab in patients aged 12 years and older who were inadequate responders or intolerant to anti-IgE therapy and symptomatic despite antihistamine use.³ In the pooled data from study A and study B of the LIBERTY-CSU CUPID phase 3 program, 57.3% of dupilumab-treated patients and 56.6% of placebotreated patients experienced TEAEs.3 In study C, the incidence was 53% for both groups.⁵ The safety profile was consistent with that observed in other indications of dupilumab, with no new safety concerns identified in the CSU population.^3,5

In conclusion, the FDA approval of dupilumab for CSU represents a significant milestone in the management of this challenging condition. With this, dupilumab expands its therapeutic reach, now FDA-approved for diseases such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, prurigo nodularis, CSU, and chronic obstructive pulmonary disease.⁴