Remibrutinib Sustains 52-Week CIndU Control But Quantitative Proof Still Withheld

Novartis' Rhapsido Shows Sustained Efficacy in Chronic Inducible Urticaria

Novartis announced 52-week results from the Phase III RemIND program for Rhapsido (remibrutinib) in chronic inducible urticaria (CIndU). The data demonstrated early and sustained efficacy through Week 52 across the three most prevalent CIndU subtypes: symptomatic dermographism (SD), cold urticaria (ColdU), and cholinergic urticaria (CholU). Patients initially on Rhapsido maintained symptom improvements, and those who switched from placebo at Week 24 achieved similar response rates by Week 52. The safety profile was consistent with previous studies, reinforcing Rhapsido's clinical profile for CIndU and supporting future regulatory submissions.

• The RemIND study demonstrated that Rhapsido 25 mg twice daily provided early and sustained efficacy over 52 weeks in patients with chronic inducible urticaria (CIndU). Clinically meaningful responses were observed across symptomatic dermographism (SD), cold urticaria (ColdU), and cholinergic urticaria (CholU), with complete or partial response rates at Week 52 reaching 46.8% for SD, 83.3% for ColdU, and 58.2% for CholU in patients initially randomized to Rhapsido.
• Patients initially randomized to placebo who switched to Rhapsido at Week 24 achieved comparable complete or partial response rates by Week 52 to those who received Rhapsido from the start. Specifically, response rates were 47.7% for SD, 88.9% for ColdU, and 69.8% for CholU in the switched cohort, indicating that Rhapsido can provide effective and sustained relief even when treatment is initiated later.
• Rhapsido maintained a safety profile consistent with prior studies and established experience in chronic spontaneous urticaria (CSU) throughout the 52-week period. These comprehensive Phase III data, generated from the largest clinical program in CIndU to date, further strengthen Rhapsido's clinical profile and will support additional regulatory submissions globally, building on its existing approvals for CSU and SD.

The Burden of CIndU and Current Treatment Gaps

Current treatment of chronic inducible urticaria is constrained by limited evidence-based options and heterogeneous, often incomplete responses. Second-generation H1-antihistamines remain first-line therapy, yet many patients show insufficient response even with up-dosing, while omalizumab is frequently used off-label in antihistamine-refractory cases despite scarce prospective data.

• Poor antihistamine response and limited evidence for advanced therapy: Treatment of delayed pressure urticaria is disappointing owing to the lack of response to antihistamines, even when up-dosing. There is an absence of randomized clinical trials and the low number of patients included in studies mean that there is little scientific evidence for the validity of omalizumab in delayed pressure urticaria, with scarce prospective delayed pressure urticaria-specific data with objective provocation testing.

• Diagnostic and monitoring limitations of provocation testing: There are limited high-quality data available to support the diagnostic utility of office challenges for physical urticaria/angioedema syndromes, and studies of sufficient methodologic quality to calculate positive/negative likelihood ratios for recommended diagnostic challenges could not be identified. Of 76 subjects with a positive history of a physical urticaria, 38% (n = 29) were challenge negative to the presenting diagnosis, there is a low sensitivity associated with methacholine intradermal challenge for confirming a diagnosis of cholinergic urticaria, and even minimal cold exposure during diagnostic testing can induce anaphylaxis in susceptible patients.

• Heterogeneity and lack of predictive tools: Type I autoallergic and type IIb autoimmune mechanisms represent major endotypes, but many patients show overlapping or mixed features, contributing to heterogeneous clinical courses and variable treatment responses. Important unmet needs remain, including reliable biomarkers for endotyping, evidence-based selection among emerging therapies, better data in children and other special populations, standardized definitions of remission and relapse and disease-modifying strategies.

• Access barriers and incomplete response rates: The most significant barriers to omalizumab prescription were cost (63%) and restricted formulary (24%). Only 22% of respondents reported 80-100% of chronic spontaneous urticaria patients were complete responders to omalizumab, indicating the need for novel therapies.

Rhapsido's 52-Week Efficacy and Safety in CIndU

Recent studies in chronic inducible urticaria (CIndU) have evaluated dupilumab and omalizumab across cold urticaria, delayed pressure urticaria, and combined physical urticaria phenotypes. Efficacy varied by subtype, with rapid control in delayed pressure urticaria and no statistically significant benefit in cold urticaria.

• LIBERTY-CINDU CUrIADS (ClinicalTrial.gov identifier NCT04681729) evaluated dupilumab, 300 mg, every 2 weeks versus placebo over a 24-week treatment period in 82 adult patients with ColdU who remain symptomatic despite the use of antihistamines. There were no statistically significant differences between the dupilumab and placebo recipients in terms of primary or secondary end points, including proportion with negative ice cube provocation test result at week 24, change from baseline in Peak Pruritus Numeric Rating Scale score at the provocation site, and Dermatology Life Quality Index. The proportion with treatment-emergent adverse events was lower with dupilumab than with placebo (53.5% vs 69.2%).

• Standardized pressure provocation as an objective clinical marker of omalizumab response in delayed pressure urticaria: an open-label, real-life, prospective cohort evaluated omalizumab 300 mg subcutaneously every 4 weeks in 42 patients with dermographometer-confirmed DPU refractory to licensed or high-dose second-generation H1-antihistamines. After the first omalizumab dose, 41/42 patients (97.6%) achieved complete symptom control within 96 hours (median 24 hours); 57.1% responded within 24 hours and 83.3% within 48 hours, with one patient achieving only partial control. No serious adverse events or need for rescue systemic corticosteroids were observed.

• Differential Effects of Dupilumab in a Patient With Localized Heat Urticaria, Delayed Solar Urticaria, and Symptomatic Dermographism reported dupilumab subsequently administered 12 times after antihistamines were ineffective and omalizumab improved only the symptomatic dermographism, with no effect on the heat or solar urticaria. Repeated provocation testing during treatment showed resolution of symptomatic dermographism, whereas localized heat urticaria persisted and delayed solar urticaria showed no meaningful improvement. The Urticaria Control Test score also did not improve.

• PECU: A multicenter study on pediatric patients with cold-induced urticaria included 203 pediatric patients with ColdU across 30 centers in Türkiye with median 3.5-year follow-up, where most patients (82.2%) received second-generation H1-antihistamines. In refractory cases, omalizumab achieved >90% symptom control in 12 refractory cases, and ColdA occurred in 17.2%.

The Evolving Treatment Landscape for CIndU

Second-generation H1-antihistamines remain the first-line therapy for chronic inducible urticaria (CIndU), with up-dosing recommended in insufficient responders. In a retrospective analysis of 423 patients, treatment response rates in CIndU were 51.6%, 51.5%, and 86.5% with standard-dose second-generation H1-antihistamines (sgAHs), updosed/combined sgAH, and omalizumab, respectively, and overall antihistamine response was higher in CIndU than CSU plus CIndU (78.3% vs. 62%, p = 0.002). A meta-analysis reported that cold urticaria was managed by H1-antihistamines in 95.67% (95% CI, 92.47% to 97.54%) of patients and omalizumab in 5.95% (95% CI, 2.55% to 13.27%) of patients, while a separate meta-analysis of five studies with 355 CSU patients and 103 CIndU patients found no significant difference in the efficacy of omalizumab in the treatment of CSU and CIndU (OR -0.83, 95% CI [0.84, 2.21], P > 0.05). In delayed pressure urticaria refractory to 2 or more second-generation H1-antihistamines in an up-dosing regimen, all 14 patients responded superfast to omalizumab 300 mg every 4 weeks, with mean Urticaria Control Test levels of 3.07 (±2.40) before treatment reaching 15.28/16 (±1.72) after the first dose.

The landscape has expanded with mast cell-targeted strategies under investigation. In an open-label trial in patients with antihistamine refractory cold urticaria (ColdU) or symptomatic dermographism (SD) receiving one IV dose of barzolvolimab (3 mg/kg) with 12-week follow-up, treatment resulted in significant depletion of skin mast cells, decreased tryptase (

Not all emerging approaches have translated to CIndU efficacy. In LIBERTY-CINDU CUrIADS (ClinicalTrial.gov identifier NCT04681729), a phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter trial in which patients aged 12 years or older who had ColdU received dupilumab, 300 mg, or placebo every 2 weeks for 24 weeks, there were no statistically significant differences between the dupilumab and placebo recipients in terms of primary or secondary end points. In total, 82 adult patients were enrolled, the primary end point was the proportion of patients with a negative ice cube provocation test result at week 24, and the proportion with treatment-emergent adverse events was lower with dupilumab than with placebo (53.5% vs 69.2%). Some programs have been discontinued due to safety concerns or lack of efficacy such as fenebrutinib (BTK inhibitor), THB001 (c-Kit inhibitor), EP262 (MRGPRX2 antagonist), tezepelumab (anti-TSLP), as well as lirentelimab and AK006 (Siglec-targeting agents), and significant therapeutic gaps persist for omalizumab-refractory disease and chronic inducible urticaria.