The Next Generation of Chronic Spontaneous Urticaria Treatments: Targets, Approvals, and Pipeline Momentum

After years of limited therapeutic progress, chronic spontaneous urticaria is entering a period of rapid innovation. In the United States alone, CSU affects an estimated 1.7 million patients, many of whom remain symptomatic despite standard treatment. Antihistamines remain first-line therapy, yet more than half of patients continue to experience symptoms even at increased doses, highlighting a substantial unmet need.

In late 2025, this landscape shifted meaningfully with the FDA approval of Novartis’ Rhapsido, marking the first oral, targeted BTK inhibitor approved for CSU. Alongside this milestone, additional BTK inhibitors, cytokine-pathway inhibitors, and mast cell–targeting antibodies are advancing through the clinic, signaling a structurally different era for CSU management.

Next-Generation CSU Therapies: Clinical Landscape

The table below summarizes key emerging and approved therapies for CSU, including their molecular targets, regulatory status, and notable clinical updates, based on publicly disclosed trial data and FDA actions in the US market.

Note: Phase and approval status reflect the US regulatory context and may differ by region.

Rhapsido and the Rise of Oral BTK Inhibition

Rhapsido represents a fundamental shift in CSU treatment. As the first FDA-approved targeted BTK inhibitor for the disease, it offers oral dosing, rapid onset of action within approximately two weeks, and no requirement for routine laboratory monitoring. This profile contrasts sharply with prior injection-based therapies that provided incomplete symptom control for many patients.

Its approval establishes BTK inhibition as a validated therapeutic mechanism in CSU, opening the door for additional agents in this class.

Sanofi’s BTK Strategy Beyond CSU

Rilzabrutinib has demonstrated rapid and meaningful improvements in itch severity and urticaria activity scores in antihistamine-refractory CSU patients in the Phase 2 RILECSU trial. While the current status of its CSU development program has not been publicly updated, Sanofi continues to deploy this molecule across a range of immune-mediated diseases, suggesting broader strategic value beyond urticaria.

Dupixent Expands the Type 2 Inflammation Franchise

The FDA approval of Dupixent for CSU in April 2025 added an eighth indication to an already established biologic franchise. By blocking IL-4 and IL-13 signaling, Dupixent addresses the type 2 inflammatory pathways underlying CSU. Its approval provides a strong option for patients with overlapping type 2 comorbidities such as asthma or atopic dermatitis.

Together, Dupixent and Rhapsido represent complementary approaches rather than direct substitutes. Dupixent brings extensive long-term biologic experience across inflammatory diseases, while Rhapsido offers a pill-based option aimed at rapid symptom control in antihistamine-refractory patients.

Mast Cell Depletion as a Differentiated Strategy

Celldex’s Barzolvolimab takes a mechanistically distinct approach by directly targeting and depleting mast cells rather than suppressing their activation. In Phase 2 CSU trials, the therapy achieved complete response in 71 percent of patients, raising the possibility of durable disease control. The program has now advanced into Phase 3, with additional studies underway in other pruritic and inflammatory conditions.

Takeaway

The CSU treatment landscape is undergoing its most significant transformation in decades. With the approval of Rhapsido, the expansion of Dupixent, and the advancement of novel mechanisms such as KIT-targeting antibodies, clinicians may soon have a broader set of tools tailored to distinct patient profiles. Rather than a single dominant therapy, CSU management is evolving toward mechanism-based selection, balancing speed of onset, convenience, durability of response, and comorbid disease burden.