touchDERMATOLOGY coverage of data presented at AAAAI/WAO 2025:
The treatment landscape for chronic spontaneous urticaria (CSU) is poised for change, with a growing wave of therapies currently under investigation for patients who remain refractory to H1-antihistamines.
While the approval of omalizumab has been a key advancement, some patients do not adequately respond, underscoring the need for additional options. Dupilumab, a monoclonal antibody that targets interleukin (IL)-4 and IL-13, has shown promise, with recent phase III trial data demonstrating its efficacy in reducing symptoms.
At this year’s American Academy of Allergy, Asthma and Immunology (AAAAI)/ World Allergy Organization (WAO) Joint Congress (San Diego, CA, USA; 28 February–3 March 2025), findings from the pooled analysis of two phase III trials (LIBERTY-CSU CUPID Study A and Study C; ClinicalTrials.gov identifier: NCT04180488) investigating dupilumab in omalizumab-naïve patients with CSU were presented.
To learn more about the results, what they tell us about dupilumab and how they could impact clinical practice, we were delighted to speak with study investigator, Professor Thomas Casale (University of South Florida, Tampa, FL, USA).
Q. What are the biggest challenges or gaps in the current treatment landscape for CSU?
That’s a great question. I believe there are several gaps. One of the most surprising is that many people aren’t diagnosed with urticaria quickly—it often goes unrecognized.
The second is whether patients who are diagnosed with urticaria are receiving the most appropriate treatment. Many individuals manage their symptoms on their own or seek care from a primary physician, who may prescribe an H1-antihistamine. However, even at four times the licensed dose, antihistamines provide relief for only about 50% of patients. Then, as a result of this, many patients can experience a significant impact on their quality of life. As you can imagine, if you’re planning on heading out to a social event and then all of a sudden you have an episode where you have hives and/or swelling on your face, lips or anywhere else on your body, it can be a huge problem. The itchiness and the hives can also keep you up at night, so you don’t sleep as well, which can then further impair your quality of life.
Another very interesting finding in the last few months was a publication indicating that individuals with urticaria have an increased risk of mortality. This is partly due to the psychological burden of the condition, including depression and anxiety, that often stems from the unpredictability of flare-ups—basically, not knowing when they will occur, how severe they will be and how they might affect daily life, such as your ability to socialize, go to work or attend school.
Q. If a patient is diagnosed and initiated on H1-antihistamines but does not respond, what are the next steps?
Currently, according to guidelines, the next treatment option is omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody that was approved in 2014 for the treatment of CSU. This has been a significant breakthrough for many patients. However, we also know that some individuals do not respond to omalizumab and others are slow responders. For instance, patients with a high body mass index (BMI) or very low IgE levels tend to have a less effective or delayed response to omalizumab. Therefore, there is a need for additional treatment options beyond omalizumab for patients who remain refractory to antihistamines.
Q. Could you outline the key objectives and design of the LIBERTY-CSU CUPID studies A and C?
The LIBERTY-CSU CUPID studies A and C are two independent, yet highly similar, 24-week, randomized, placebo-controlled, double-blind, phase III clinical trials evaluating dupilumab treatment in patients who are omalizumab-naïve. These trials enrolled individuals with CSU lasting at least 6 months and presenting with significant symptoms. To qualify, participants needed to have a high burden of hives and itchiness.
When examining the enrolled patient populations, they were very similar across both studies and align with what we have seen in other recent urticaria trials. Most participants were female and many were borderline overweight or obese.
On average, the time since their first diagnosis of urticaria was just over 6 years, indicating that these patients had been living with the condition for a long time. They all had a high burden of disease, as measured by three primary parameters: the Itch Severity Score over 7 days, Hives Severity Score (HSS7), and the Urticaria Activity Score over 7 days (UAS7), which combines both itch and hive severity scores.
Essentially, the results from the two studies could be pooled because the patient populations and study objectives were largely the same and the results could be used to better assess dupilumab as a potential new therapy for urticaria.
Q. What impact did adding dupilumab have on treatment outcomes for these patients?
The pooled dataset analysis revealed that, by the end of the 24-week treatment period, dupilumab had led to significant reductions in both the primary and secondary endpoints, with improvements observed in the ISS7 and UAS7 versus placebo.
What was particularly impressive was that approximately twice as many patients receiving dupilumab, compared to those on placebo, achieved a UAS7 score of ≤6, indicating well-controlled disease. Only half as many patients in the placebo group achieved that level of improvement. Furthermore, about twice as many patients receiving dupilumab had a UAS7 score of zero, which indicates complete resolution of their urticaria.
Q. What were the findings regarding the safety and tolerability of dupilumab compared to placebo?
There were no unexpected or untoward allergic reactions to the drug or to any other treatments administered alongside the active treatment. Overall, patients tolerated dupilumab well. Unlike some other conditions treated with dupilumab, there were no significant issues with conjunctivitis, which seems to track more closely with atopic dermatitis. So generally, dupilumab was found to be well tolerated and safe.
By combining the results of both studies, a strong regulatory package can now be submitted to the FDA and EMA for their assessment of dupilumab as a potential additional therapy.
Q. If approved for use in CSU, how do you see dupilumab fitting into the current treatment paradigm?
I cannot predict exactly what new guidelines may say as new therapies are approved, but to me dupilumab would be in line with omalizumab. Meaning that if a patient does not respond to a licensed dose of antihistamines, they are then placed on a higher dose, up to four times the dose of antihistamines. If they still do not improve, they would now have two treatment options, either omalizumab or dupilumab.
In another study also presented at the AAAAI/WAO Joint Congress, dupilumab’s clinical effectiveness was shown to be independent of patient BMI, which could make it a preferred choice over omalizumab for some clinicians, as omalizumab may be less effective or slower-acting in patients with a high BMI.
Click here for the full abstract.
Further content in urticaria.
Associated abstract: Casale T, Saini S, Bernstein J, et al. Dupilumab Improves Itch And Urticaria Activity In Patients With Chronic Spontaneous Urticaria: Pooled Results From Two Phase 3 Trials (LIBERTY-CSU CUPID Study A and Study C). J Allergy Clin Immunol. 2025;155(Suppl.):Abstract L02.
Disclosures: Prof. Thomas Casale has served as a consultant for Sanofi, Genentech, Regeneron, Novartis, Jasper and Celldex. Additionally, he has participated in the Speaker’s Bureau for Sanofi, Regeneron and Genentech.
This content has been developed independently by Touch Medical Media for touchDERMATOLOGY and is not affiliated with the AAAAI or the WAO. Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. No endorsement of unapproved products or unapproved uses is either made or implied by mention of these products or uses by Touch Medical Media or any sponsor. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Interviewer/Editor: Gina Furnival
Cite: Pooled Phase III Data Reinforce Dupilumab’s Efficacy in H1-Antihistamine Refractory CSU. touchDERMATOLOGY, March 3 2025.
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