Emerging IgE and non-IgE targeted therapies for chronic urticaria

Abstract

Chronic urticaria (CU) affects a significant percent of the global population and carries a higher burden of unmet medical need. Current standard-of-care includes antihistamines and omalizumab, but omalizumab is not effective in all patients and has not been shown to induce long-term disease remission. This review examines the diverse therapeutic pipeline spanning IgE-based and non-IgE based mast cell targeting strategies, including recent clinical data. The therapeutic landscape has expanded rapidly with multiple mechanisms under investigation. IgE-targeted approaches include omalizumab biosimilars, with CT-P39 having received FDA approval. Dupilumab received FDA approval for antihistamine refractory chronic spontaneous urticaria (CSU) supporting the targeting of type-2 cytokines, IL-4 and IL-13, in this disease. Bruton’s tyrosine kinase (BTK) inhibitors show promise, with remibrutinib receiving FDA approval and demonstrating significant reductions in UAS7 in Phase 3 trials. c-Kit (c-Kit or KIT) inhibition with barzolvolimab shows robust efficacy with sustained effects post-treatment. Finally, JAK inhibitors, MRGPRX2 antagonists and other novel mechanisms are advancing through clinical trials. Although 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), these studies have informed many of the other positive studies. In summary, over the last year, we have seen the CU pipeline mature with multiple Phase 3 programs and new approvals representing diverse mechanisms of action. Nevertheless, significant therapeutic gaps persist for omalizumab-refractory disease and chronic inducible urticaria. In this review, we will provide an overview of recently completed and ongoing clinical studies investigating emerging IgE and non-IgE therapeutic options for chronic urticaria.

Introduction

Chronic urticaria (CU), either spontaneous (CSU) or inducible (CIndU), refers to urticaria that persists on most days for more than 6 weeks. CU is a common disease across the world with an overall adjusted lifetime prevalence of 1.4% and point prevalence of 0.7%.^1,2 Women are affected twice as frequently as men, and CSU tends to be more common in older adult patients compared to CIndU.^3,4 CSU and CIndU are not mutually exclusive. Up to 35% of patients with CSU also have CIndU, reporting a comorbid physical or inducible trigger of their symptoms.⁵ CIndU subtypes are divided based on presence of physical triggers—including symptomatic dermatographism, delayed-pressure urticaria/angioedema, heat contact urticaria, cold urticaria, solar urticaria, vibratory urticaria and aquagenic urticaria—or inducible triggers such as cholinergic urticaria.

Beyond urticaria, angioedema is a common feature. Approximately 40–59% of CSU patients can present with concurrent angioedema and up to 10% of patients present with isolated angioedema.^6–8 In terms of prognosis, a retrospective assessment of outpatients with spontaneous urticaria in Japan revealed that 101 out of 912 patients (~11%) presenting with acute urticaria at 10 allergy/derm clinics progressed to chronic spontaneous urticaria, with day 14 of disease serving as a key timepoint for predicting resolution versus chronicity.⁹ Finally, patients with systemic complaints have longer disease duration, elevated tryptase levels, and require more frequent emergency department visits and oral corticosteroid treatment, underscoring the unmet clinical burden and treatment challenges associated with CSU.¹⁰

Current treatment guidelines begin with avoidance of cofactors (such as NSAIDs) and known triggers in patients with CIndU.¹¹ The first line of treatment consists of non-sedating, second generation antihistamines. Approximately 20–40% of patients achieve symptom control with a single daily oral antihistamine (OAH). Increasing the OAH dose (up to four times a day) raises the response rate to approximately 50–60%.^12,13 While up-dosing may not be tolerated by all patients (e.g. somnolence), a systematic review and meta-analysis of seven studies using multiple doses of second-generation antihistamines for CSU showed no significant difference in adverse events between single-dose and high-dose treatment groups.¹⁴ Leukotriene receptor antagonists (LRTAs), such as montelukast, have been investigated as add-on therapy to antihistamines. A recent meta-analysis of 34 randomized controlled trials concluded that the addition of LRTAs to H1-antihistamines provides modest reduction in urticaria activity with moderate certainty.¹⁵ For patients that fail to respond to maximized OAH therapy, the next step involves anti-IgE therapy with omalizumab. Based on evidence from randomized controlled trials, omalizumab demonstrates efficacy in approximately 50–60% of patients who are refractory to antihistamines, with omalizumab up-dosing yielding benefits in some non-responders.^16–18 Notably, the pivotal ASTERIA I and II trials for omalizumab enrolled patients on approved (standard daily) doses of H1-antihistamines, whereas the GLACIAL trial enrolled patients who remained symptomatic despite up-dosing to 4-times the approved dose.¹⁷ Omalizumab demonstrated consistent efficacy regardless of background therapy.

Therefore, omalizumab is not effective in all patients and has not been shown to induce long-term disease remission.¹⁹ Several baseline characteristics have been proposed as predictors of poor response to antihistamines and/or omalizumab. Antihistamine non-responders tend to have higher urticaria activity scores (UAS), C-reactive protein (CRP), D-dimer, basopenia and eosinopenia.^20–22 Predictors of poor therapeutic responses to omalizumab at baseline include basopenia, low IgE, low basophil IgE receptors and high biomarkers of serum activity (elevated CD203c expression by basophils exposed to CSU serum, positive autologous serum skin test or increased histamine releasing activity).^23–29 In one of the largest retrospective assessments of omalizumab response, Le et al. reanalyzed Phase 3 ASTERIA I, II and GLACIAL omalizumab clinical trial data and demonstrate reduced omalizumab response when multiple negative baseline biopredictors were present. Specifically, they found that the combination of low IgE, positive CU index and low blood basophil numbers at baseline were associated with poor treatment response.³⁰ While multiple baseline characteristics have been associated with omalizumab-treatment response in individual studies, a systematic appraisal of these predictors is necessary to validate their predictive value.

According to the 2022 EAACI guidelines, the next step in treatment beyond omalizumab involves cyclosporine alone or in combination with omalizumab, with careful monitoring of renal function and blood pressure.¹¹ However, it should be noted that guidelines vary in their recommendations. A recent systematic review and network meta-analysis demonstrated that while cyclosporin may be among the most effective for improving urticaria (UAS7 mean differences: cyclosporine −10.18 [−14.92 to −5.43]), compared with standard-dose omalizumab (300 mg monthly; −8.37 [−10.28 to −6.46]) and low-dose omalizumab (<300mg or administered less frequently than monthly; −5.25 [−7.83 to −2.68]), cyclosporin may also be among the most harmful in increasing the adverse events.³¹ Therefore, for the approximately 40% of patients who continue to have persistent hives despite treatment with omalizumab, there is a significant unmet medical need for safer and more effective treatments that can achieve long-term disease remission or cure. Additionally, an important evidence gap persists in CSU management regarding whether early treatment with targeted therapies leads to more rapid control and improved long-term outcomes. In this review, we will provide an overview of the diverse array of treatments currently under investigation for CSU, reflecting the maturity and highly competitive nature of this therapeutic area (Figure 1).

Figure 1. Targeted pathway and receptors in chronic urticaria.

IgE-based mast cell targeting

Novel anti-IgE agents

Ligelizumab is a second generation anti-IgE antibody with 40-fold to 50-fold greater affinity for free IgE and a 9-fold increased suppression of free IgE compared to omalizumab.³² Two multicenter phase 3 studies, PEARL1 and PEARL2, as well as an extension study demonstrated the superiority of ligelizumab over placebo with a 19–20 point reduction in UAS7 scores from baseline.³³ However, further development of this molecule was terminated due to lack of demonstrated clinical superiority when compared to omalizumab.³³ Despite this, the ligelizumab studies reinforce the safety of IgE-targeted approaches in humans, supporting ongoing investigation of numerous omalizumab biosimilars. Additionally, these data with ligelizumab provide further evidence for the use of IgE-reducing therapies in patients presenting with angioedema in addition to urticaria.³³ Several omalizumab biosimilars and novel anti-IgE drugs are approved or in development including CT-P39, UB-221, LP-003, TEV-45779, ADL-018, CMAB007, JYB1904 and SYN008. Among these, the omalizumab biosimilars, CT-P39, TEV-45779, ADL-018 and CMAB007, have advanced to Phase 3 trials. Notably, CT-P39 demonstrated equivalent efficacy with reference omalizumab and received FDA approval in March 2025 with release planned for Fall 2026, while ADL-018 has reported positive topline results at the time of this review.³⁴ A novel anti-IgE agent called JYB1904 differs from omalizumab through the removal of two isomerization hotspots in the complementarity-determining regions of omalizumab and replacement of several murine amino acids with human amino acids.³⁵ LP-003 reportedly binds to IgE with higher affinity and also prevents IgE binding to both FcεRI and FcεRII (CD23) receptors.³⁶ UB-221 represents the most mechanistically unique approach, binding to a mixed protein-carbohydrate epitope spanning the Cε2-Cε3 domains and permitting binding to CD23-IgE complexes.³⁷ In summary, the safety profile of IgE-targeted approaches have been well characterized through extensive clinical trial experience with omalizumab in asthma (approved since 2003) and urticaria (approved since 2014), with the most common adverse events in urticaria trials including headache, arthralgia, and injection site reactions.³⁸

Bruton’s Tyrosine Kinase (BTK) inhibitors

Bruton’s tyrosine kinase (BTK) plays a critical role in the downstream signaling cascade of the high affinity IgE receptor (FcεRI), making it an attractive therapeutic target for CSU. BTK inhibitors (BTKi) have been demonstrated to reduce mast cell and basophil release of inflammatory mediators while protecting against IgE-mediated anaphylaxis in humans.^39–41 This mechanism also addresses the pathophysiologic drivers of CSU. However, BTK is also expressed in B cells, where it is essential for B cell development and function, as well as in macrophages and platelets. Early generation BTK inhibitors (BTKi), developed for autoimmune disease and B cell lymphomas, such as chronic lymphocytic leukemia (CLL), have been associated with adverse events during chronic use. Adverse events following chronic use have included increased infection risk, atrial fibrillation, bleeding complications, hypertension, arthralgia and diarrhea.⁴¹ These off-target effects are thought to come from poor kinase selectivity, particularly with first-generation covalent inhibitors like ibrutinib. Next-generation BTKi employ different binding strategies to improve selectivity and safety profiles: remibrutinib achieves selectivity through irreversible covalent binding to BTK locked in an inactive conformation; rilzabrutinib uses reversible covalent binding to the active site, allowing for potential enzyme activity recovery between doses; while fenebrutinib employs reversible non-covalent binding to the inactive confirmation, requires sustained drug exposure for efficacy.⁴² The combination of binding mechanism (covalent vs. non-covalent) and conformational targeting (active vs. inactive BTK) creates distinct pharmacologic profiles that seem to translate into different clinical outcomes. Resistance to covalent BTKi has been described in patients on treatment for CLL due to sequence variations in BTK or PLCG2 kinase domains, and it remains to be seen if loss of control over time is expected in CSU due to compensatory activation of alternate pathways.

Remibrutinib, an oral covalent irreversible BTKi, is the most advanced in development for CSU, with recently completed Phase 3 trials (REMIX-1 and REMIX-2) in 470 and 455 patients, respectively, followed by FDA approval in September 2025. In both studies, remibrutinib 25 mg twice a day led to a rapid reduction in UAS7 by week 2 compared to placebo, and this reduction was sustained at week 12 of therapy (−20.0±0.7 vs. −13.8±1.0 [P<0.001] in REMIX-1 and −19.4±0.7 vs. −11.7±0.9 [P<0.001] in REMIX-2).⁴³ Safety was further assessed in the preceding Phase 2b extension study of remibrutinib 100 mg twice a day for 52 weeks, which showed comparable safety to the Phase 2b dose-finding study with the top three treatment-emergent adverse events including infections (30.9%), skin and subcutaneous tissue disorders (26.8%) and gastrointestinal disorders (16.5%).⁴⁴ Loss of control or resistance was not observed. Because BTK plays a role in B-cell signaling, questions have been raised about potential effects on B cell numbers, immunoglobulin production and vaccine responses. Phase 3 data from REMIX-1 and REMIX-2 provide reassurance, showing no meaningful changes in total immunoglobulin levels and comparable infection rates between remibrutinib 25mg BID and placebo arms at week 52.⁴⁵ To more directly address vaccine responses, a randomized, double-blind, placebo-controlled parallel-group study in healthy volunteers evaluated the effect of remibrutinib on immune response to influenza and 23-valent pneumococcal polysaccharide vaccines. Participants were randomized to three arms: (1) placebo therapy BID for 6 weeks, (2) continuous remibrutinib 100mg BID (placebo for 1 week, active drug for 5 weeks), and (3) interrupted remibrutinib 100mg BID (dosed 1 week, held for 3 weeks, then resumed for 2 weeks).⁴⁶ In all arms, vaccines were administered at day 15. Assessment of vaccine response was as follows: (1) influenza, a ≥4-fold increase in hemagglutinin antibody titers at day 43 (28 days after vaccination) compared with baseline and (2) PPSV23, a ≥2-fold increase in immunoglobulin G titers at day 43 (28 days after vaccination) compared with baseline for at least 50% serotypes (≥12 of 23). The proportion of patients achieving a protective hemagglutinin antibody titer ≥1:40 was similar in placebo and interrupted remibrutinib arms. While these primary endpoints were met in the interrupted remibrutinib group, concomitant remibrutinib treatment was associated with attenuated responses to one of four influenza antigens and reduced PPSV23 responses compared to placebo.⁴⁶ It should be noted that these studies evaluated the response to inactivated vaccines only. Given a lack of data on live vaccine responses and general concerns regarding reactivation risk with immunosuppressive agents, patients on remibrutinib are advised to avoid live or live-attenuated vaccines. The overall incidence of adverse events was similar across all groups, with no deaths or serious adverse events. In the pooled safety summary (N=606 remibrutinib, N=306 placebo), evaluated during the 24-week placebo-controlled period, the mean age was approximately 41–46 years with all patients at least 18 years of age. The study population had CSU with a mean duration 4.6–6.9 years, and approximately 50% of patients presented with concurrent angioedema at baseline. About one-third of patients had previous exposure to omalizumab. The overall incidence of adverse events was similar between remibrutinib (64.9%) and placebo (64.7%), with most being mild or moderate in severity. Infections were the most common adverse event and occurred at similar rates between groups (202 (33%) remibrutinib vs. 104 (34%) placebo), with serious infections being uncommon and no opportunistic infections reported. Serious adverse events were observed in 20 (3.3%) patients in the remibrutinib group and 7 (2.3%) in the placebo group and were considered unrelated to the trial regimen.⁴³ Ongoing trials for remibrutinib include extension studies to evaluate safety as well as adolescent, CIndU and dupilumab head-to-head studies.

Rilzabrutinib, an oral covalent reversible BTKi, has received fast track designation from the FDA for immune thrombocytopenia as well as orphan drug designation for other diseases. In the 52-week Phase 2 RILECSU trial, rilzabrutinib 1200mg/d demonstrated a significant reduction in UAS7 (−16.89 vs −10.14 [P = .02]) and ISS7 (−9.21 vs −5.77 [P = .02]) at week 12 compared to placebo. ⁴⁷ Significant reductions in symptom were seen as early as week 1, supporting the observations that BTKi have a rapid onset of action in CSU. Fenebrutinib, an oral non-covalent reversible BTKi, met its primary endpoint in a Phase 2 trial with dose-dependent improvement in UAS7 at week 8.⁴⁸ Further long-term safety and efficacy studies were terminated due to reversible liver transaminitis. Several other BTKi are in development including TAS5315 (completed Phase 2), HWH486 (recruiting Phase 2), and HS-10561 (Phase 1/2). BGB-16673, a novel BTK degrader, represents a new approach to BTK inhibition now in Phase 1 trials. Lastly, spleen tyrosine kinase (Syk) is also downstream of FcεRI signaling. Syk inhibition with the agent GSK2646264, a topical cream, completed Phase 1 studies in urticaria without clear benefits with no follow up studies reported.⁴⁹

Non-IgE based mast cell targeting

Cytokine pathway targeting

Dupilumab (anti-IL4Rα) was approved in April 2025 in the U.S. for the treatment of CSU in adults and adolescents (12 year and older) who remain symptomatic despite antihistamine treatment.⁵⁰ The LIBERTY-CSU CUPID A study evaluated omalizumab-naïve patients and demonstrated significant differences in UAS7 (−20.5 vs. −12.0 [P = 0.0003]), ISS7 (−10.2 vs. −6.0 [P=0.0005]) and HSS7 (−10.3 vs. −5.9 [P=0.0003]) compared to placebo at week 24 and further confirmed in CUPID C.⁵¹ The Phase 3 CUPID B study evaluated omalizumab-refractory patients (defined by inadequate response following a 3-month trial of omalizumab therapy) and was stopped due to futility at interim analysis. In CUPID A and B, patients were required to be symptomatic despite ongoing H1-antihistmaine therapy at approved or higher doses (up to 4-fold), with 47.9% (CUPID A) and 63.5% (CUPID B) using above-standard antihistamine doses at baseline.⁵⁰ In CIndU patients, a Phase 3 study evaluating the efficacy of dupilumab for cold urticaria did not meet its primary endpoint (NCT04681729).

Several other biologics targeting different components of the type 2 pathway have shown limited success in CSU. Mepolizumab (anti-IL-5) is under investigation in a Phase 1 trial (NCT03494881) that has recently completed. In a separate open-label single-arm, exploratory study, mepolizumab 200mg every 2 weeks was given to 10 CSU patients over 10 weeks and only 3 patients achieved ≥ 95% reduction in baseline UAS7.⁵² Benralizumab (anti-IL5Rα), which depletes both blood and tissue eosinophils, did not achieve a statistically significant reduction in ISS7 at week 12 compared to placebo in the Phase 2b ARROYO trial.⁵³ Notably, benralizumab has been shown in patients with severe asthma to markedly reduce in circulating basophils.⁵⁴ Therefore, the results of ARROYO suggest that therapeutic depletion of IL-5Rα-expressing basophils may not be sufficient to control CSU. This highlights the complexity of CSU pathophysiology and suggest that basophils may serve as better biomarkers rather than primary therapeutic targets. Similarly, tezepelumab (anti-TSLP) failed to meet its primary endpoint (UAS7 reduction) at week 16 in the Phase 2b INCEPTION study, which compared two tezepelumab doses (210mg and 280mg every 4 weeks) against both omalizumab as an active comparator and placebo. Notably, tezepelumab showed a small, sustained treatment effect during the off-treatment period, when omalizumab-treated patients had returned to baseline.⁵⁵

c-Kit inhibition

Barzolvolimab (CDX-0159), a subcutaneous monoclonal anti-c-Kit antibody, has two Phase 3 EMBARQ studies ongoing (NCT06445023 and NCT06455202) with a primary endpoint assessed at week 12. In Phase 2, doses of 75mg every 4 weeks, 150mg every 4 weeks, and 300mg every 8 weeks were evaluated in antihistamine refractory CSU. Significant decreases in UAS7 (150mg: −23.02 vs. −10.47 [P < 0.0001], 300mg: −23.87 vs. −10.47 [P < 0.0001]) were reported at week 12 compared to placebo.⁵⁶ Treatment with barzolvolimab for 52 weeks in another Phase 2 study noted rapid improvement in UAS7 at week 1 that was sustained and robust regardless of prior omalizumab exposure.⁵⁷ Importantly, these improvements in UAS7, as well as quality of life, persisted 28 weeks after the last dose was given.⁵⁸ Treatment emergent adverse events found in over 10% of treated patients included skin hypopigmentation (13%), shifts in hair color (with longer term exposure) (9–26%), neutropenia (without further decline or association with infections) (8–22%), urticaria (9%) and nasopharyngitis (11–22%).^59,60 Given that c-Kit signaling play a role in mouse spermatogenesis and preclinical studies in monkeys treated with barzolvolimab demonstrated a significant decrease in sperm count that recovered within 12 months, further investigation of fertility effects is warranted.⁶¹ Prior to these larger trials in CSU, an open-label trial was performed with a single IV dose of barzolvolimab (3mg/kg) in 21 antihistamine-refractory CIndU patients which led to reductions in skin mast cells (without changes in epidermal melanocytes), circulating tryptase and improvement in quality of life; interestingly, plasma stem cell factor (SCF) rapidly increased.⁶² BLU-808, an oral wild-type c-Kit inhibitor, has demonstrated ability to decrease mast cell degranulation in vivo and in vitro and a Phase 2 study in CIndU and CSU is currently ongoing.⁶³ Development of THB001, another oral wild-type KIT inhibitor, was halted due to asymptomatic liver transaminitis following the first dose in two patients during its Phase 1b study. Briquilimab, a subcutaneous monoclonal targeting c-Kit, which has an ongoing BEACON Phase 1b/2 trial in CSU and CIndU. Positive data was reported in a press release showing reductions in UAS7 at week 12 for the 120 mg and 180 mg every 8-week dosing (120mg: −27.2 vs. −9.2, 180mg: −13.2 vs. −9.2] versus placebo).⁶⁴ However, results from two cohorts were confounded by a drug product lot issue affecting 10 of 13 patients, which resulted in lower than expected drops in mean tryptase and no impact on UAS7 scores. The company is enrolling additional patients with corrected drug product, with further data expected in 2025.⁶⁵ As a class, c-Kit-targeted biologics appear to have a rapid and sustained effect on chronic urticaria symptoms and have the potential to be an important new treatment option pending additional long term safety and efficacy data.

JAK inhibitors

Several janus kinase (JAK) inhibitors are under investigation for CSU, capitalizing on their ability to disrupt cytokine-driven inflammation and oral availability. JAK inhibitors block intracellular signaling downstream of multiple cytokine receptors that may participate in CSU pathophysiology. Specifically, JAK1 mediates signaling for IL-4, IL-6, IL-10, type I and II interferons, and others, while TYK2 is essential for IL-10, IL-12, IL-23 and type I interferon signaling.⁵² Through multi-cytokine pathway disruption, JAK inhibitors may provide a broad anti-inflammatory effect making them particularly attractive for CSU which exhibits significant disease heterogeneity. TLL-018 is an oral JAK1/TYK2 inhibitor (10mg BID and 30mg BID) which has completed a Phase 1b study in 41 antihistamine refractory CSU patients. Improvement in UAS7 and ISS7 was reported at week 4 and week 12 compared to placebo.⁶⁶ Safety data from the use of TLL-018 in other diseases is available, and the ongoing Phase 3 study of TLL-018 in CSU will provide further information. Studies with povorcitinib, an oral selective JAK1 inhibitor, and ritlecitinib, an oral JAK3/TEC kinase inhibitor, are active and recruiting, respectively, for CSU. Povorcitinib, in an exploratory analysis of the Phase 2 study (NCT05936567), demonstrated improvement in hives severity score and itch severity score with the 45mg and 75mg daily doses versus placebo at week 12 as well as up to 50% of patients with complete control.⁶⁷

MRGPRX2 antagonists

Mas-related G protein-coupled receptor X2 (MRGPRX2) receptors are selectively expressed on mast cells and mediate degranulation in response to various triggers including medications, neuropeptides, etc. MRGPRX2 receptors represent a promising target in CSU patients especially in those whose symptoms are driven by non-IgE-mediated mast cell activation. EP262, an oral small molecule MRGPRX2 antagonist, completed a Phase 1b trial in CIndU. In addition, EP262 was being evaluated for CSU in CALM-CSU a Phase 2 study. However, development of EP262 was terminated due to concerns with preclinical in vivo animal toxicology findings. EVO756, an oral MRGPRX2 antagonist, has completed a Phase 2a in CIndU with positive topline data reported in May 2025 and has an ongoing Phase 2b trial for CSU.

Sialic Acid Binding Immunoglobulin-like Lectin (Siglec) targeting

Siglecs are a family of inhibitory receptors that recognized sialic acid-containing glycans. Siglec-6 is selectively expressed by mast cells, while Siglec-8 is expressed by eosinophils and mast cells.⁶⁸ Lirentelimab (AK002), an intravenous humanized anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells, failed to show significant reduction in UAS7 versus placebo in a Phase 2b study in CSU and CIndU, despite promising initial Phase 2a data.⁶⁹ AK006, an intravenous humanized anti-Siglec-6 antibody that depletes mast cells, was found in pre-clinical studies to have a broader and more potent mast cell inhibition than lirentelimab. However, in a Phase 1b study including CSU patients with or without prior exposure to omalizumab, no statistically significant decrease in UAS7 was observed compared to placebo. In summary, indirect inhibition of mast cell activation as an approach has not demonstrated clinical activity in CSU, whereas approaches involving mast cell depletion and direct inhibition of mast cell activation have yielded promising results.

Other Agents:

The complement system, another non-IgE pathway for mast cell activation, is under investigation with the development of INF904, an oral complement 5a receptor 1 (C5aR1) inhibitor. A phase 2a open label study in patients with CSU or hidradenitis suppurativa is recruiting to evaluate safety. Tryptase inhibitors such as MTPS9579A inhibit the activity of the mast cell mediator directly, and the phase 2 study of MTPS9579A in antihistamine refractory CSU was withdrawn. Table 1 summarizes the agents under development with active or recently completed trial for chronic urticaria.

Table 1.

Novel Agents Under Investigation for the Management of Chronic Spontaneous Urticaria

Approach	Agent	Molecule	Route	Mechanism of action	Clinical Trial Identifier
IgE-targeting	TEV-45779	anti-IgE	Subcutaneous	Omalizumab biosimilar	NCT04976192
	ADL-018	anti-IgE	Subcutaneous		NCT06929052
	CMAB007	anti-IgE	Subcutaneous		NCT06365879
	JYB1904	anti-IgE	Subcutaneous	Improved stability and half life	NCT06509334
	LP-003	anti-IgE	Subcutaneous	Improved IgE binding and increased half life	NCT06228560
	Remibrutinib	BTK inhibitor	Oral	Bruton's tyrosine kinase inhibition in mast cell and B cell signaling	NCT05513001, NCT05170724, NCT05976243, NCT06865651, NCT05677451, NCT06042478, NCT06868212
	TAS5315	BTK inhibitor	Oral		NCT05335499
	HWH486	BTK inhibitors	Oral		NCT06295302
	BGB-16673	BTK degrader	Oral		NCT07005713
Non-IgE targeting	Mepolizumab	anti-IL-5	Subcutaneous	Blocks IL-5	NCT03494881
	Barzolvolimab	c-Kit inhibitor	Subcutaneous	Inhibits binding of SCF to c-Kit	NCT06445023, NCT06455202
	BLU-808	c-Kit inhibitor	Oral	Blocks wild type c-Kit tyrosine kinase activity	NCT06931405
	Briquilimab	c-Kit inhibitor	Subcutaneous	Inhibits binding of SCF to c-Kit	NCT06162728, NCT06353971, NCT06736262
	TLL-018	JAK inhibitors	Oral	JAK1/TYK2 inhibition	NCT05373355, NCT06396026
	Povorcitinib	JAK inhibitors	Oral	JAK1 inhibition	NCT05936567
	Ritlecitinib	JAK inhibitors	Oral	JAK3/TEC inhibition	NCT06795373
	EVO756	MRGPRX2 inhibitors	Oral	Mas-related G protein-coupled receptor X2 antagonism	NCT06603220, NCT06873516
	INF904	C5aR inhibitors	Oral	Blocking the binding of C5a to C5aR	NCT06555328

Conclusions

The therapeutic landscape for CSU and CIndU is rapidly expanding, driven by significant unmet medical need and evolving understanding of urticaria pathophysiology. The heterogeneous nature of CSU is evident from incomplete responses to standard-of-care antihistamines and omalizumab. While dupilumab and remibrutinib provide new options for patients, the robust clinical pipeline highlights persistent therapeutic gaps for omalizumab-refractory CSU and CIndU. The pipeline has matured significantly with multiple Phase 2/3 programs spanning diverse mechanisms that include mast cell depletion, mast cell silencing and inhibition of cytokine signaling. Along with this rapid growth of drug development, the clinical methodology appears to be more standardized around comprehensive outcome assessment with UAS7, ISS7 and HSS7 as well as quality of life measures. Translating these advances into improved patient outcomes will require the development of reliable biomarkers for treatment selection, comprehensive safety evaluation, and an improved understanding of pathway interactions to guide optimal therapeutic combinations.

Key Messages:

• Significant treatment gaps exist in chronic urticaria for patients that are refractory to standard-of-care antihistamines and omalizumab.

• New treatment options are advancing through clinical trials with recent FDA approvals for dupilumab, an omalizumab biosimilar, and remibrutinib.

• Mast cell targeting through novel mechanisms such as Bruton’s tyrosine kinase (BTK) and c-Kit/SCF inhibitors have demonstrated robust efficacy, rapid onset and sustained effects in the case of barzolvolimab (anti-c-Kit).

• Future therapeutic success requires the continued development of reliable biomarkers for treatment selection and response prediction, comprehensive long-term safety profiles, and strategic therapeutic combinations to address disease heterogeneity.

Abbreviations:

BTK

Bruton’s tyrosine kinase

CIndU

chronic inducible urticaria

CLL

chronic lymphocytic leukemia

CRP

C-reactive protein

CSU

chronic spontaneous urticaria

CU

chronic urticaria

FcεRI

high affinity IgE receptor

HSS

Hives Severity Score

ISS

Itch Severity Score

JAK

Janus kinase

LRTA

Leukotriene receptor antagonists

MRGPRX2

Mas-related G protein-coupled receptor X2

OAH

oral antihistamines

SCF

stem cell factor

Siglec

sialic acid binding immunoglobulin-like lectin

Syk

spleen tyrosine kinase

TSLP

thymic stromal lymphopoietin

Tyk2

tyrosine kinase 2

UAS

Urticaria Activity Score