Tezepelumab Clears Phase 3 Bar in EoE, But Payer Differentiation Case Remains Unbuilt

TEZSPIRE Achieves Positive Phase 3 Results in Eosinophilic Esophagitis

Amgen and AstraZeneca announced positive top-line results from the Phase 3 CROSSING trial of TEZSPIRE® (tezepelumab-ekko) in patients with eosinophilic esophagitis (EoE). The trial demonstrated statistically significant and clinically meaningful improvements across both co-primary and all key secondary endpoints at week 24, which were sustained through week 52. The co-primary endpoints included histologic remission and the frequency and severity of dysphagia. TEZSPIRE's safety profile was consistent with its approved indications. This success in EoE, a chronic epithelial-driven inflammatory disorder affecting over 470,000 people in the U.S., supports the broad potential of TEZSPIRE.

• TEZSPIRE achieved statistically significant and clinically meaningful improvements in both co-primary endpoints of the CROSSING trial: histologic remission and the frequency and severity of dysphagia. These positive effects were observed at week 24 and were sustained through week 52, indicating a durable benefit for patients struggling with the underlying inflammation and debilitating swallowing difficulties characteristic of eosinophilic esophagitis.
• The positive results in eosinophilic esophagitis mark TEZSPIRE's efficacy in a third epithelial-driven inflammatory condition, reinforcing its broad therapeutic potential. This expands upon its existing approvals for severe asthma and chronic rhinosinusitis with nasal polyps. The drug's mechanism of action, targeting thymic stromal lymphopoietin (TSLP), positions it as a foundational treatment for various inflammatory diseases driven by epithelial dysfunction.
• The Phase 3 CROSSING trial was a randomized, double-blind, placebo-controlled study involving 368 adults and adolescents (aged 12-80 years) with symptomatic and histologically active EoE who were on maintenance therapy. Patients received TEZSPIRE subcutaneously every four weeks at one of two doses. This trial design provides robust evidence for TEZSPIRE as a potential new, convenient, and effective treatment option for a patient population with significant unmet needs.

Addressing the Unmet Needs in Eosinophilic Esophagitis

Despite meaningful advances in the therapeutic landscape for eosinophilic esophagitis (EoE), several critical gaps persist across pharmacologic, dietary, and endoscopic treatment modalities. These limitations underscore the complexity of managing a chronic, relapsing disease with heterogeneous triggers and manifestations.

• Absence of approved pharmacologic therapies (until recently) and long-term safety data: No U.S. Food and Drug Administration-approved therapies existed for EoE for an extended period, requiring patients to be treated with medications such as inhalers or aqueous nebulizer solutions not originally formulated for this indication. While topical corticosteroids (fluticasone, budesonide) are effective and represent first-line therapy, no data on topical corticosteroid long-term safety in EoE are available. Transient cortisol suppression has been observed with budesonide, and long-term adrenal monitoring is warranted. The most common adverse effects — oropharyngeal candidiasis and Candida esophagitis — are generally manageable but require ongoing vigilance.

• Failure to reverse fibrosis and address fibrostenotic disease: Budesonide does not reverse fibrosis, as fibrosis scores showed no significant improvement (P = 0.48) in meta-analytic data. Esophageal strictures develop as a consequence of long-lasting esophageal eosinophilia, with patient age and diagnostic delay as well-established risk factors. Persistent symptoms in fibrostenotic disease highlight the need for adjunct therapies, and esophageal dilation — while effective for symptomatic relief — has no effect on the underlying eosinophil inflammation, necessitating repeated procedures to maintain remission.

• Complexity and burden of dietary elimination therapy: Dietary restriction therapies require a team approach involving a dietitian and an allergist, are more challenging to implement, and often require extensive allergy testing and multiple endoscopies. They are not effective when environmental allergens trigger EoE. Multiple factors — including demographics, nutritional status, social and financial support, and patient acceptance of multiple endoscopies — must be considered, and ongoing multi-disciplinary support during initiation and maintenance phases is crucial.

• Lack of comparative studies and optimized dosing regimens: No comparative studies of topical corticosteroids versus dietary restrictions exist. Research is needed to establish the lowest most effective and safe dose of topical corticosteroids, the extent of adherence needed when eliminating foods, and less-invasive ways to monitor histologic disease activity. Future research should also optimize dosing regimens and evaluate combination strategies to maximize patient benefit while maintaining disease remission.

• Gaps in real-world follow-up and monitoring for emerging biologics: For dupilumab — the first FDA-approved treatment for EoE — endoscopic assessment was lacking in 25.9% of real-world patients, limiting the ability to confirm histologic remission. Future research should focus on predictors of response, durability of remission beyond one year, and comparative effectiveness relative to other therapies.

Positive Phase 3 Results for TEZSPIRE in EoE

Recent clinical investigations in eosinophilic esophagitis (EoE) have evaluated a range of interventions — from swallowed topical corticosteroids to biologic agents — across both induction and maintenance settings. The studies below represent a cross-section of recent evidence, capturing histological, symptomatic, and safety endpoints.

TEZSPIRE's Broad Potential in Epithelial-Driven Inflammation

Beyond eosinophilic oesophagitis, tezepelumab (tezepelumab-ekko; TEZSPIRE™) is being developed across several additional indications, each reflecting its upstream mechanism of blocking thymic stromal lymphopoietin (TSLP), an epithelial cytokine central to type 2 and broader airway inflammation. The indications under active clinical development include chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), and chronic spontaneous urticaria. In the context of CRSwNP specifically, tezepelumab is currently in a phase III clinical trial, building on earlier evidence that tezepelumab treatment showed benefits on sino-nasal and asthma outcomes in CRSwNP and aspirin-exacerbated respiratory disease (AERD).

The intervention model for the asthma programme — which forms the backbone of tezepelumab's clinical development — is a randomised, double-blind, placebo-controlled, parallel-group design, as exemplified by the phase 2 CASCADE study. In CASCADE, tezepelumab 210 mg is administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma, with the primary endpoint being change from baseline to week 28 in airway submucosal inflammatory cells from bronchoscopic biopsies. The phase 3 NAVIGATOR trial similarly employed subcutaneous administration every 4 weeks over a 52-week period in patients with uncontrolled, severe asthma receiving medium- or high-dose inhaled glucocorticoids.

The knowledge base does not have sufficient information on this aspect regarding the specific intervention models for the COPD and chronic spontaneous urticaria trials.

TEZSPIRE's EoE Success Validates TSLP, Reshapes Treatment Landscape

The recent announcement of positive Phase 3 CROSSING trial results for TEZSPIRE in eosinophilic esophagitis (EoE) marks a pivotal moment for patients grappling with this chronic, debilitating condition. EoE, characterized by significant inflammation and esophageal remodeling, often leads to severe dysphagia and a diminished quality of life. For many, existing treatments like proton pump inhibitors, topical corticosteroids, and even other biologics targeting eosinophils, prove insufficient, leaving a substantial unmet need.

TEZSPIRE's success across both histologic remission and symptom improvement, sustained over a year, underscores the critical role of thymic stromal lymphopoietin (TSLP) in driving the inflammatory cascade in EoE. This outcome not only offers a new, targeted therapeutic option for a disease affecting hundreds of thousands but also profoundly validates the TSLP pathway as a broad therapeutic target across various type 2 inflammatory conditions. This strategic expansion beyond severe asthma positions TEZSPIRE as a versatile biologic, enhancing its market footprint and potentially setting a new standard of care for EoE, particularly for those with refractory disease.

However, as with any significant therapeutic advance, important considerations remain. While the 52-week data are encouraging, the chronic nature of EoE necessitates continued investigation into long-term efficacy and safety, especially concerning the progression of esophageal remodeling and fibrosis. Furthermore, the diverse patient population in EoE, including those who have failed multiple prior treatments, suggests that variability in patient response will be an ongoing area of focus. Understanding which patient subgroups derive the most benefit, and whether predictive biomarkers, similar to those explored in severe asthma with PAI-1 gene polymorphism, could guide treatment selection, will be crucial. The evolving competitive landscape for EoE treatments will also require careful navigation, with patient access and reimbursement playing a significant role in widespread adoption.