Dupilumab may have reduced itch severity and overall urticaria activity compared with placebo in patients with chronic spontaneous urticaria whose symptoms persisted despite histamine 1–receptor antagonist therapy, according to a recent clinical trial.

Chronic spontaneous urticaria (CSU) is characterized by recurrent pruritic wheals and angioedema lasting more than 6 weeks without an identifiable trigger. This condition currently affects approximately 0.5% to 1% of the global population and can disrupt sleep, daily activities, and quality of life. Standard treatment with histamine 1–receptor antagonists controls symptoms in about 50% of patients.

Trial Design and Population

In the study, researchers conducted the LIBERTY-CSU CUPID-C trial, a 24-week, multicenter, randomized, double-blind, placebo-controlled phase III study evaluating dupilumab in patients with CSU who remained symptomatic despite antihistamine therapy.

The researchers enrolled 151 patients aged 6 to 80 years across nine countries in North America, Europe, Asia, and South America. The participants had experienced urticaria symptoms for more than 6 months and continued to have active disease despite stable antihistamine treatment, including doses up to four times the recommended amount.

The researchers randomly assigned the patients to receive either dupilumab or placebo while continuing background antihistamines. Dosing was weight-based and administered subcutaneously every 2 weeks or every 4 weeks depending on patient weight.

At baseline, disease severity was substantial. The mean urticaria activity score over 7 days was approximately 28, and nearly 60% of the participants had severe disease activity. More than half were already taking antihistamines at doses higher than recommended.

Improvements in Itch and Hive Severity

The primary endpoint was change in itch severity over 7 days at week 24, with overall urticaria activity serving as a key secondary endpoint.

At week 24, dupilumab produced greater reductions in symptoms compared with placebo:

• Itch Severity Score over 7 days: −8.64 with dupilumab vs −6.10 with placebo

• Urticaria Activity Score over 7 days: −15.86 vs −11.21

• Hives Severity Score over 7 days: −7.27 vs −5.11.

Symptom improvement occurred early, beginning around week 3 and continuing through the 24-week treatment period.

Clinically meaningful responses were also more common in the dupilumab group. At week 24:

• 70% of the patients receiving dupilumab achieved at least a 5-point reduction in itch severity compared with 52% receiving placebo.

• 41% achieved well-controlled disease activity compared with 23% receiving placebo.

• 30% achieved complete disease control compared with 18% receiving placebo.

Findings From Pooled Trial Data

The researchers also conducted a pooled analysis combining data from the earlier LIBERTY-CSU CUPID-A trial and the CUPID-C study, increasing the sample size to 289 patients.

In the combined analysis, dupilumab continued to show greater improvement across key outcomes:

• Itch Severity Score: −9.94 vs −6.71

• Urticaria Activity Score: −19.29 vs −13.13

• Hives Severity Score: −9.29 vs −6.36.

Rates of disease control were also higher with dupilumab. In the pooled cohort, 43% of the dupilumab-treated patients achieved well-controlled disease compared with 23% of the placebo recipients. Complete disease control occurred in 31% vs 16%, respectively.

Based on pooled results, approximately 4 patients would need to receive dupilumab for 1 additional patient to achieve a clinically meaningful reduction in itch severity compared with placebo.

Safety Outcomes

Safety outcomes were similar between treatment groups. In the pooled analysis, 53% of the dupilumab-treated patients and 56% of the placebo recipients reported treatment-emergent adverse events.

The most frequently reported adverse events included:

• Nasopharyngitis

• CSU

• COVID-19 infections

• Injection-site erythema.

Serious adverse events occurred in 5% of the patients receiving dupilumab and 4% of those receiving placebo. One death occurred in the placebo group as a result of suicide.

Mechanistic Implications

Dupilumab blocks signaling through the shared receptor for interleukin-4 and interleukin-13, cytokines that drive type 2 inflammation. Type 2 inflammatory pathways are thought to contribute to mast cell activation and itch signaling in CSU.

The patients treated with dupilumab also experienced substantial reductions in serum immunoglobulin E concentrations, whereas levels remained stable in the placebo group.

Treatment responses were observed regardless of baseline serum immunoglobulin E levels.

Study Limitations

The researchers acknowledged several limitations. The 24-week study duration limited evaluation of long-term treatment durability. The number of pediatric participants was small, and the study population had limited racial and ethnic diversity, which may have affected generalizability.

Conclusion

The CUPID-C trial replicated findings from the earlier CUPID-A study and demonstrated consistent improvements in itch severity, hives severity, and overall disease activity among patients with CSU who remained symptomatic despite antihistamine therapy.

Lead study author Thomas B. Casale, MD, of the Division of Allergy and Immunology in the Department of Medicine at the University of South Florida, and colleagues wrote that the combined trial results “collectively reinforce the clinical benefits and safety profile of dupilumab for [histamine 1–receptor antagonist]−refractory and omalizumab-naive patients with CSU.”

Co-authors Thomas B. Casale, MD,  Sarbjit S. Saini, MD, Moshe Ben-Shoshan, MD, Ana M. Giménez-Arnau, MD, PhD, Jonathan A. Bernstein, MD, PhD, and Koremasa Hayama, MD, PhD, reported research funding, consulting fees, advisory roles, or honoraria from multiple pharmaceutical companies—including Sanofi, Regeneron Pharmaceuticals Inc, Novartis, Genentech, AstraZeneca, Amgen, Blueprint Medicines, Celldex, Escient Pharmaceuticals, and others. Co-authors Nikhil Amin, MD, Lacey B. Robinson, MD, MPH, Deborah Bauer, MS, and Paula Dakin, MBChB, reported equity holdings in Sanofi or Regeneron during the study; Elizabeth Laws, PhD, reported personal fees from Sanofi; Allen Radin, MD, reported equity in Regeneron and a pending patent related to CSU treatment; and Melanie Makhija, MD, reported employment with Sanofi. The study authors reported no other disclosures.

Source: JAMA Dermatology