Recent clinical trials have revealed promising advances in the treatment of chronic spontaneous urticaria (CSU), with several novel therapies demonstrating complete response rates exceeding 30% in patients who have failed standard treatments.
CSU is a mast cell-mediated skin condition characterized by unpredictable itchy hives, angioedema, or both, persisting for more than six weeks. The condition significantly impacts quality of life for approximately 40% of patients, with over 80% experiencing symptoms for more than a year. Current first-line and second-line treatments achieve complete disease control in only a small percentage of patients, highlighting the urgent need for more effective therapies.
Remibrutinib Shows Rapid and Sustained Efficacy
Remibrutinib, a novel, highly selective, oral Bruton tyrosine kinase (BTK) inhibitor, has demonstrated superior efficacy compared to placebo in patients with CSU in the phase 3 REMIX-1 and REMIX-2 trials. These identical, multicenter, randomized, double-blind, placebo-controlled studies assessed the efficacy and safety of remibrutinib in patients who remained symptomatic despite treatment with second-generation H1-antihistamines.
The trials, which included 912 patients (606 receiving remibrutinib and 306 receiving placebo), showed that remibrutinib rapidly improved urticaria control as measured by the weekly Urticaria Control Test (UCT7). By week 2, the mean change from baseline in UCT7 was significantly higher with remibrutinib compared to placebo (REMIX-1: 5.74 vs 1.95; REMIX-2: 5.57 vs 2.27), with improvements sustained through week 52.
"The REMIX-1/-2 studies demonstrated improved urticaria control with add-on remibrutinib as early as week 2, with improvements remaining through week 52," noted study investigators. By week 24, a significantly higher percentage of patients achieved well-controlled urticaria (UCT ≥12) with remibrutinib versus placebo (REMIX-1: 63.1% vs 41.6%; REMIX-2: 64.8% vs 40.2%).
Importantly, a pooled safety analysis from both trials showed that remibrutinib treatment did not cause clinically meaningful changes in mean blood cell counts, consistent with the favorable clinical safety profile observed in the phase 3 studies. Complete response rates during phase 3 trials ranged from 28% to 32%.
Dupilumab Targets Key Inflammatory Pathways
Dupilumab, a monoclonal antibody that blocks IL-4 receptor α (IL-4Rα) and inhibits signaling of both IL-4 and IL-13, has also shown promising results in CSU treatment. These cytokines substantially contribute to CSU pathogenesis through type 2 inflammation and activated Th2 cells.
In phase 3 clinical trials, 30% to 31% of patients with CSU showed complete response to dupilumab treatment. The therapy demonstrated a safety profile similar to placebo, with the most common adverse event being injection site reactions (12%).
Barzolvolimab: Targeting Mast Cell Development
Another promising therapy, barzolvolimab, takes a different approach by targeting the tyrosine kinase receptor KIT and its ligand, stem cell factor (SCF), which are critical for mast cell development and function. Barzolvolimab is a humanized IgG1k monoclonal antibody that binds to KIT with high affinity, inhibiting SCF binding.
In phase 2 trials, barzolvolimab was well-tolerated and demonstrated complete response rates of 38% to 51% at week 12. The most common adverse events included changes in hair color (14%), neutropenia/decreased neutrophil count (9%), and skin hypopigmentation (1%).
Long-Term Safety of Omalizumab Confirmed
While new therapies emerge, research continues to support the long-term safety and efficacy of established biologics like omalizumab, a recombinant humanized monoclonal antibody against immunoglobulin E (IgE). The FDA has approved omalizumab for patients with severe allergic asthma, severe CSU, and chronic rhinosinusitis with nasal polyps.
A study conducted at a tertiary clinic administered omalizumab to adult patients with asthma (IgE levels, 30-700 IU/L) and adolescent patients (IgE levels, 30-1300 IU/L), as well as to patients with severe CSU who did not respond to conventional H1-antihistamines at 3 to 4 times the suggested dose or who depended on oral steroids.
Researchers administered more than 2.5 million omalizumab injections over the past two decades without any reported anaphylaxis or serum sickness requiring medical intervention, demonstrating "a high level of safety and efficacy with virtually no risk of anaphylaxis or serum sickness."
Personalized Treatment Approaches
The rapid development of the CSU treatment pipeline includes omalizumab biosimilars entering the market and novel small molecules and biologics becoming available in the next 1 to 2 years. The FDA recently approved omalizumab-igec (Omlyclo; Celltrion), the first respiratory biosimilar in the US with interchangeability status.
Researchers emphasize that endotyping patients with CSU and identifying specific biomarkers will help enable tailored treatments in the context of precision medicine. Patients with autoimmune CSU, who make up between 8% and 69% of all CSU patients, are typically nonresponders to first- and second-line treatments and are characterized by high disease activity, autoimmune comorbidities, low total IgE levels, and poor response to antihistamines and omalizumab.
"Future studies with long-term follow-up will show whether any of the novel treatments, e.g., BTK inhibitors and dupilumab, possess disease-modifying properties and will be game-changers in CSU management," study authors concluded.
The emerging therapies offer hope for patients with difficult-to-treat CSU, potentially providing complete disease control and improved quality of life for those who have not responded to conventional treatments.
