Nearly 2000 Patients Join Global EMBARQ-CSU Trials

Completion of enrollment in 2 large phase 3 trials of barzolvolimab marks a notable milestone in the development of new therapies for chronic spontaneous urticaria (CSU).¹ Celldex announced that 1939 patients have been randomly assigned across the global EMBARQ-CSU1 (NCT06445023) and EMBARQ-CSU2 (NCT06455202) studies, making this the largest phase 3 program conducted to date in antihistamine-refractory CSU, including a substantial cohort of patients with prior exposure or inadequate response to advanced therapies, such as omalizumab.^2,3

Unmet Need in Antihistamine-Refractory CSU

CSU remains a challenging condition for clinicians despite the availability of guideline-directed therapies. Characterized by spontaneous wheals, intense pruritus, and episodic angioedema without an identifiable trigger, the disease often persists for years. Although second-generation H1 antihistamines are first-line therapy, many patients remain symptomatic despite dose escalation. Omalizumab and, more recently, other biologics have improved outcomes for some individuals, but complete disease control remains elusive for a significant proportion of patients.

The burden of CSU extends beyond cutaneous symptoms. Patients frequently report sleep disruption, work impairment, social withdrawal, and psychological distress. Angioedema, often involving the lips, eyelids, or extremities, can be particularly distressing and unpredictable. Epidemiologic data have also suggested an association between CSU and increased long-term mortality, underscoring that this is not merely a cosmetic condition but a systemic inflammatory disorder with measurable health consequences.

With this in mind, rapid enrollment—completed 6 months ahead of initial projections—may reflect both persistent unmet need and interest in a therapy with a distinct mechanism of action.

Targeting Mast Cells Through KIT Inhibition

Barzolvolimab is a humanized monoclonal antibody designed to bind with high specificity to a unique epitope of the KIT receptor. KIT is highly expressed on mast cells and plays a central role in their development, survival, and activation. By inhibiting KIT signaling, barzolvolimab aims to reduce mast cell numbers and function, thereby addressing a widely recognized root driver of CSU pathophysiology.

This approach differs from currently approved biologics that primarily target downstream mediators, such as IgE. For clinicians, the conceptual appeal lies in intervening at the level of the effector cell itself rather than modulating upstream immune signals.

Barzolvolimab is also being studied in other mast cell–mediated or mast cell–associated conditions, including cold urticaria, symptomatic dermatographism, prurigo nodularis, and atopic dermatitis, reflecting broader interest in KIT-directed strategies.

Phase 2 Signal: Depth and Durability of Response

The phase 3 program builds on results from a randomized, placebo-controlled phase 2 study in CSU. In that study, up to 51% of treated patients achieved a complete response—defined as a weekly Urticaria Activity Score (UAS7) of 0, indicating no itch and no hives—by week 12. With continued therapy, the proportion of complete responders increased to as high as 71% by week 52.

Notably, responses appeared durable in a subset of patients even after treatment discontinuation. Up to 41% maintained a complete response 7 months after their last dose. Improvements were also reported in angioedema activity (Angioedema Activity Score over 7 days = 0 in up to 65% at week 12 and 77% at week 52) and in dermatology-specific quality-of-life measures, with a substantial proportion achieving Dermatology Life Quality Index scores of 0 or 1.

Although cross-trial comparisons should be approached cautiously, these rates of complete response and sustained remission are of clear interest to clinicians accustomed to incremental improvements rather than symptom-free disease.

Phase 3 Design and Key End Points

EMBARQ-CSU1 and EMBARQ-CSU2 are randomized, double-blind, placebo-controlled, parallel-group trials conducted across 43 countries and more than 500 sites. Patients with CSU inadequately controlled on H1 antihistamines were randomly assigned evenly to 1 of 3 arms:

• Barzolvolimab 150 mg every 4 weeks (after a 300-mg loading dose)
• Barzolvolimab 300 mg every 8 weeks (after a 450-mg loading dose)
• Placebo

At week 24, patients initially assigned to placebo are again randomly assigned to active treatment. The primary end point is the change in UAS7 at week 12. The trials are powered to detect clinically meaningful differences vs placebo, both in the overall population and in the subpopulation refractory to omalizumab.

The primary analysis will occur after all participants complete the 24-week placebo-controlled period. A global long-term extension study is ongoing, allowing continued observation of safety and durability.

Looking Ahead

If phase 3 results confirm the magnitude and durability of response observed in phase 2, barzolvolimab could represent a significant shift in the therapeutic landscape of CSU, particularly for patients with persistent symptoms despite existing biologics. For clinicians, key considerations will include safety profile, onset of action, durability of therapy, and positioning relative to established agents.

Top-line results are anticipated later this year. Until then, the scale and design of the EMBARQ-CSU program signal both the maturity of mast cell–targeted approaches and the continuing need for therapies capable of delivering complete and sustained disease control in CSU.

References

1. Celldex completes enrollment in global phase 3 studies (EMBARQ-CSU1 and EMBARQ-CSU2) of barzolvolimab in chronic spontaneous urticaria. News release. Celldex. February 25, 2026. Accessed February 25, 2026. https://www.globenewswire.com/news-release/2026/02/25/3244485/24180/en/Celldex-Completes-Enrollment-in-Global-Phase-3-Studies-EMBARQ-CSU1-and-EMBARQ-CSU2-of-Barzolvolimab-in-Chronic-Spontaneous-Urticaria.html
2. Celldex presents additional positive data demonstrating barzolvolimab’s ability to drive rapid, profound and durable complete urticaria control in phase 2 chronic spontaneous urticaria (CSU) study. News release. Celldex. November 6, 2025. Accessed February 25, 2026. https://ir.celldex.com/news-releases/news-release-details/celldex-presents-additional-positive-data-demonstrating
3. Celldex Therapeutics initiates global phase 3 program for barzolvolimab in patients with chronic spontaneous urticaria. News release. Celldex. July 16, 2024. Accessed February 25, 2026. https://ir.celldex.com/news-releases/news-release-details/celldex-therapeutics-initiates-global-phase-3-program