Fall Clinical Talk Highlights KIT Inhibition's Promise for Chronic Spontaneous Urticaria

Emerging evidence supports KIT inhibition as a novel therapeutic approach, Naiem Issa, MD, PhD, FAAD, said in a talk at the 2026 Fall Clinical Dermatology Conference.

Targeting the KIT signaling pathway may offer a new treatment strategy for patients with chronic spontaneous urticaria (CSU), including those who have failed previous biologic therapy, according to Dr. Issa, who reviewed emerging mast cell biology clinical evidence during his presentation, "DermDash: What's in Your KIT for Chronic Spontaneous Urticaria."

Issa emphasized that understanding mast cell biology is essential to appreciating the potential of emerging therapies such as barzolvolimab, an investigational monoclonal antibody targeting KIT, also known as CD117. The approach differs from existing treatments by targeting a pathway essential to mast cell survival and proliferation rather than simply blocking inflammatory mediators released during activation.

"KIT is a major survival and functional pathway, and its targeted blockade can profoundly reduce tissue mast cells," Dr. Issa said.

Understanding the Role of Mast Cells in CSU

Dr. Issa began by emphasizing that CSU may be underrecognized, particularly when patients experience symptoms beyond the skin. Although urticaria is commonly associated with wheals, itching, and angioedema, mast cells are also present in extracutaneous tissues, including the gastrointestinal tract and joints. Consequently, patients may experience abdominal discomfort, nausea, joint pain, and other symptoms that are not immediately attributed to mast cell activation.

Dr. Issa encouraged clinicians to consider these manifestations when reviewing symptoms in patients with suspected CSU. He then outlined two principal autoimmune mechanisms implicated in CSU. Type I autoallergic CSU involves IgE autoantibodies, whereas type IIb autoimmune CSU involves IgG autoantibodies directed against IgE or its high-affinity receptor. Both pathways can ultimately result in mast cell activation and degranulation.

Traditional treatment strategies intervene at different points in this process, Dr. Issa added. Antihistamines block the effects of histamine, mast cell stabilizers attempt to prevent degranulation, and Bruton tyrosine kinase (BTK) inhibitors interfere with intracellular signaling involved in mast cell activation. Other targeted therapies, including omalizumab and dupilumab, act on upstream immunologic pathways. However, KIT inhibition introduces a different strategy by interfering with the survival of the mast cell itself.

KIT Signaling as a Therapeutic Target

KIT is a receptor tyrosine kinase highly expressed on mast cells, Dr. Issa noted. Binding of its ligand, stem cell factor (SCF), supports mast cell survival, growth, migration, and activation. At higher levels of stimulation, SCF-KIT signaling can also promote degranulation and enhance IgE-mediated mast cell activation. Blocking KIT therefore offers the potential to reduce both mast cell activity and the number of mast cells available to initiate inflammatory responses.

Dr. Issa highlighted barzolvolimab, an anti-KIT monoclonal antibody being investigated for CSU. Early phase 1b findings demonstrated reductions in serum tryptase, a marker associated with mast cell burden, alongside improvements in urticaria activity and disease control measures beginning as early as the first week of treatment.

Phase 2 Findings Demonstrate Substantial Disease Control

Dr. Issa reviewed results from a phase 2 study evaluating several barzolvolimab dosing regimens in patients with moderate-to-severe CSU inadequately controlled with H1-antihistamines. The primary efficacy assessment occurred at week 12, with investigators evaluating changes in the 7-day Urticaria Activity Score (UAS7), a patient-reported measure incorporating itch severity and hive activity over 7 days.

A UAS7 score of 6 or lower represents well-controlled disease, whereas a score of zero indicates complete absence of reported hives and itching during the assessment period. At week 12, more than 50% of patients receiving barzolvolimab 150 mg every 4 weeks or 300 mg every 8 weeks achieved a UAS7 score of 6 or lower. Approximately 30% to 50% of patients receiving these regimens achieved complete response, defined as UAS7 = 0.

"With nearly half of these patients achieving that deep endpoint within the first 12 weeks, this is a very deep response," Dr. Issa said. He noted that the response appeared dose-dependent, with efficacy beginning to plateau at the 150-mg every-4-weeks and 300-mg every-8-weeks regimens.

Benefits extended to patients with previous exposure to omalizumab, including those whose disease had been refractory to the anti-IgE therapy. At the more effective barzolvolimab doses, mean reductions in UAS7 at week 12 were approximately 24 points among omalizumab-naive patients, 21 to 24 points among omalizumab-experienced patients, and 25 to 29 points in the smaller omalizumab-refractory subgroup. Dr. Issa suggested these findings support targeting KIT independently of upstream activation pathways.

"The biology makes sense clinically," he said.

Improvements Extend to Angioedema

The phase 2 findings also demonstrated improvements in angioedema, an important manifestation of CSU that can substantially affect quality of life. Across all three evaluated barzolvolimab dose groups, improvements in the 7-day Angioedema Activity Score (AAS7) were significantly greater than placebo through week 12. Separation from placebo was evident as early as week 1, with benefits sustained throughout the primary assessment period.

Tryptase concentrations decreased across the barzolvolimab treatment groups, and greater reductions were correlated with greater improvements in UAS7. The association provided additional evidence supporting the proposed mechanism of action, although further investigation is needed to establish how serum tryptase measurements might inform treatment decisions.

Safety Considerations Include Hair Pigmentation Changes and Neutropenia

KIT is expressed in several cell types beyond mast cells, including melanocytes and hematopoietic stem and progenitor cells, helping explain the hair pigmentation changes and reductions in neutrophil counts observed during clinical development, Dr. Issa noted. In the phase 2 study, treatment-emergent adverse events were reported in 56.4% of patients receiving barzolvolimab compared with 27.5% receiving placebo.

Hair color changes occurred in 9.0% of barzolvolimab-treated patients overall, including 9.6% receiving 150 mg every 4 weeks and 17.6% receiving 300 mg every 8 weeks. Dr. Issa described hair hypopigmentation as a distinctive adverse effect of KIT inhibition and said clinicians would need to discuss this possibility with patients if the therapy receives regulatory approval. He referenced additional data presented at Fall Clinical indicating that more than 90% of affected patients experienced restoration of original hair color within 24 weeks after discontinuation.

Neutropenia or decreased neutrophil counts occurred in 7.7% of barzolvolimab-treated patients compared with none in the placebo group. These events were generally mild to moderate and were not associated with infections in the phase 2 study. Seven barzolvolimab recipients (4.5%) discontinued study treatment because of treatment-emergent adverse events.

Phase 3 Results Signal Continued Development

Dr. Issa noted that topline phase 3 results had been announced in late September 2026, shortly before the conference. He described them as encouraging and consistent with substantial responses observed in earlier trials. He characterized reported UAS7 responses as potentially best-in-class.

For dermatologists managing difficult-to-control CSU, the emerging evidence suggests KIT inhibition could eventually provide an additional option, particularly when existing therapies fail to achieve adequate disease control. The results also demonstrate how advances in understanding mast cell survival and signaling can translate into new therapeutic strategies for inflammatory disease.

"Targeting it with anti-KIT therapeutics, especially now barzo, is giving us a new viable option for CSU patients with deep urticaria activity score responses and complete responses, as well as for angioedema," Dr. Issa concluded.