Comparing novel treatments in chronic spontaneous urticaria: A critical appraisal of Bruton's tyrosine kinase inhibitors versus anti-cytokine biologics in clinical trials

To the Editor,

We have been following recent clinical trials focusing on new therapies to treat Chronic Spontaneous Urticaria (CSU). While current treatments can manage the debilitating symptoms, a significant number of patients do not achieve symptom control with available medications, including anti-IgE treatment.^{1, 2} New potential solutions to address this include Bruton's tyrosine kinase (BTK) inhibitors, targeting downstream signaling of the Immunoglobulin E high-affinity receptor,^{3, 4} and anti-cytokine biologics, targeting T2/alarmin-driven responses.⁵ However, available literature provides limited comparisons between newer CSU treatments.

We critically appraised the efficacy and safety of six randomized controlled clinical trials (RCTs), three focusing on BTK inhibitors and three on cytokine blockers, to provide insights into the more promising therapeutic options for CSU. Using the Arksey and O'Malley's framework, we systematically reviewed relevant trials. Our search across Embase and Ovid identified 473 studies from April 2019 to May 2024. A secondary search on ClinicalTrials.gov yielded 123 trials, 15 focusing on BTK inhibitors and cytokine blockers. Based on the CONSORT checklist for methodological quality,⁶ we selected trials scoring a minimum of 10 positive or partially met items out of 25. Six RCTs and two pharmaceutical releases (for trial NCT05107115, whose results were not published at the time of the search) were chosen (Figure 1A, Table 1).

Common inclusion criteria included CSU duration of at least 6 months and non-response to second-generation H1-antihistamines, while exclusion criteria included recent infections, other dermatological conditions, immunocompromised status, and major health conditions.

Selected studies were compared across three areas: (A) study characteristics and demographic information (e.g., number of participants, age, gender distribution, ethnic diversity, and dropout rates); (B) CSU outcome measures (e.g., Urticaria Activity Score over 7 days, UAS7); and (C) frequency of serious adverse events.

Data were normalized for the placebo effect, while statistical differences were as reported by the original authors. Studies NCT03137069 and NCT04180488 involved two cohorts with similar dosage protocols, respectively fenebrutinib 200 mg BID and dupilumab 300 mg SC Q2W. Combined p values were calculated using Fisher's combined probability test, and the survival function of the chi-squared distribution was computed using the chi2.sf function of the scipy Python library.⁷ In studies with multiple dosages, we selected the most effective regimen, resulting in the most significant decrease of UAS7 scores from baseline to endpoint normalized to placebo (Normalized ΔUAS7 = [(UAS7_{End of study} – UAS7_Baseline)]_Treatment – [(UAS7_{End of study} – UAS7_Baseline)]_Placebo).

Given the randomized controlled design and registration in global clinical trial registries, we considered the internal validity established. In contrast, the external validity was assessed based on demographic/non-demographic variables representing populations across studies. Out of 6 selected studies, 5 provided sufficient information on clinical trial methods and results for a validity assessment (Figure 1B, Table 1). Although preliminary reports on trial results were accessible,^{8, 9} the complete methodology for rilzabrutinib/NCT05107115 was unpublished at the time, thus limiting our analysis. Across the studies, the average dropout rate was highest in benralizumab/NCT04612725 (32.9%) and lowest in dupilumab/NCT04180488 (0%). Participant numbers ranged from 134 to 311, with a mean age of 42.8–46.4 years and a female majority (68.7%–77.6%). Racial composition varied significantly, with non-white participants ranging from 17.7% to 37.7%. The studies maintained uniform characteristics across placebo and treatment groups, ensuring acceptable validity. However, potential biases could arise from slight differences in dropout rates, gender and racial composition across cohorts, especially in the fenebrutinib/NCT03137069 and dupilumab/NCT04180488 trials.

For instance, the placebo group included a higher percentage of female participants (84.6% Cohort 1, 73.9% Cohort 2) compared to the 200 mg BID-treated arms of the fenebrutinib trial (78.6% Cohort 1, 69.6% Cohort 2) and in placebo (73.5% Group A, 75.9% Group B) versus dupilumab 300 mg Q2W (58.6% Group A, 68.5% Group B). Similarly, drop-out rates differed notably between the fenebrutinib 200 mg BID-treated cohorts (21.4% Cohort 1 vs. 8.7% Cohort 2). These discrepancies may have also contributed to the more significant UAS7 reduction observed in the respective treated arms.

When evaluating efficacy, four medications produced statistically significant improvement in CSU symptoms. Remibrutinib administered 25 mg BID proved most effective, with ΔUAS7 equal to −12.34 (p < 0.0001), while fenebrutinib (200 mg BID), rilzabrutinib (400 mg TID) and dupilumab (300 mg Q2W) ranged from −7.72 to −6.75 (Figure 1C). Fenebrutinib also displayed the highest rate of well-controlled CSU (30.6% UAS7 ≤6). On average, BTK inhibitor-based treatments offered a 19% greater improvement in ΔUAS7 compared to dupilumab and 55% compared to all cytokine blockers combined. However, anti-cytokine treatments reported less severe adverse events (0%–4%) than BTK inhibitors (4.65%–5.36%, Figure 1D). Overall, remibrutinib and dupilumab emerged as the best options per each drug category, with the highest efficacy and relatively lower frequency of adverse events.

In conclusion, our analysis of phase 2 RCTs on BTK inhibitors for CSU treatment demonstrated higher efficacy in symptom control, although results from ongoing phase 3 RCTs are still warranted. Except for dupilumab, none of the analyzed studies addressed treatment response by CSU subtype (i.e., type I vs. type IIb autoimmune CSU) or stratified by anti-IgE treatment response. Hence, it remains unclear whether underperforming treatments, like anti-TSLP and IL-5 receptor antibodies, may offer superior outcomes in specific patient groups and/or associated comorbidities.¹⁰

Anastasia Diamanti and Silvia Bulfone-Paus conceptualized the study. Anastasia Diamanti performed the database search and statistical analyses. Anastasia Diamanti and Chiara Tontini created the figure and table. Anastasia Diamanti, Chiara Tontini and Silvia Bulfone-Paus wrote and revised the manuscript.

The authors declare no conflicts of interest.