CROSSING Wins Histology Decisively but Symptom Margin Leaves EoE Filing Exposed

TEZSPIRE Achieves Sustained Histologic and Symptom Remission in EoE

Amgen and AstraZeneca announced full Phase 3 CROSSING trial results for TEZSPIRE (tezepelumab-ekko) in adolescent and adult patients with symptomatic and uncontrolled eosinophilic esophagitis (EoE). The trial demonstrated statistically significant and clinically meaningful improvements across co-primary and key secondary endpoints, sustained through 52 weeks. At week 24, histologic remission was achieved in 64.8% (210 mg dose) and 68.9% (420 mg dose) of patients versus 3.5% for placebo (p<0.001). Dysphagia symptoms, measured by the Dysphagia Symptom Questionnaire (DSQ) score, reduced by 18.8 points (210 mg; p=0.049) and 22.0 points (420 mg; p<0.001) from baseline compared to 14.7 points for placebo. These benefits were maintained at week 52, including total endoscopic remission in 34.4% (210 mg) and 29.5% (420 mg) of patients versus 4.1% for placebo (p<0.001).

• The Phase 3 CROSSING trial demonstrated that TEZSPIRE achieved significant histologic remission in patients with eosinophilic esophagitis. At week 24, 64.8% of patients on the 210 mg dose and 68.9% on the 420 mg dose achieved histologic remission (peak eosinophil count ≤6 per high power field), compared to only 3.5% on placebo (p<0.001). These high rates of remission were durably sustained through week 52, indicating long-term control of the underlying esophageal inflammation.
• TEZSPIRE treatment led to clinically meaningful and sustained improvements in dysphagia symptoms and endoscopic features. Patients experienced significant reductions in Dysphagia Symptom Questionnaire (DSQ) scores, with average reductions of 22.1 points (210 mg) and 24.0 points (420 mg) from baseline at week 52, versus 13.2 points for placebo (both p<0.001). Additionally, 34.4% (210 mg) and 29.5% (420 mg) of patients achieved total endoscopic remission (EREFS=0) at week 52, compared to 4.1% for placebo (p<0.001).
• The safety profile of TEZSPIRE in the CROSSING trial was consistent with its approved indications, with the most frequently reported adverse events being upper respiratory infection (nasopharyngitis), headache, and diarrhea. The trial design allowed patients to continue stable background medications for EoE, such as proton pump inhibitors and swallowed topical corticosteroids, highlighting TEZSPIRE's potential as an effective add-on therapy without introducing new safety concerns.

The Unmet Need in Eosinophilic Esophagitis Treatment

Current pharmacologic and dietary therapies can induce clinical and histologic remission in eosinophilic esophagitis, but there is no universal approach to treatment. Disease activity commonly recurs when successful treatments are stopped, and long-term maintenance is limited by safety, adherence, and gaps in evidence.

• Rapid recurrence after treatment cessation and need for chronic maintenance: Clinical, endoscopic, and histological features usually recur when successful treatments are stopped. Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year with overall median time to symptom recurrence of 244 days, 78% of patients had histologic relapse at symptom recurrence, 45% had symptom relapse at six month follow-up, and the majority of patients experienced a recurrence of symptoms upon the discontinuation of fluticasone. In untreated patients, persistent esophageal eosinophilic inflammation may progress to fibrostenosis over time, giving place to strictures and narrow-caliber esophagi.

• Safety and tolerability of corticosteroids and biologics: With prednisone, 40% suffered adverse effects and three withdrew early from treatment with severe adverse effects (hyperphagia, weight gain, cushingoid features). With fluticasone, 15% developed esophageal candidiasis, and one recipient of fluticasone developed oral candidiasis. Budesonide showed infections more frequent with budesonide (RR: 2.14; 95% CI: 1.20-3.80; P = 0.009) with most infections localized (e.g., oropharyngeal candidiasis), and transient cortisol suppression occurred in sensitivity analyses (SMD: -0.41; 95% CI: -0.66 to 0.16; P = 0.001). For dupilumab for EoE-tx, there were 1459 observations with 103 (7.1%) serious reactions and 44 (3.0%) serious outcomes including 3 deaths, driven largely by increased injection-site and gastrointestinal reactions.

• Burden and adherence limits of dietary therapy: Six-food elimination diet can be challenging and affect patients' quality of life, with patient willingness to undergo repeated endoscopies and biopsies and variable results of allergy testing. In long-term maintenance, 57% (24/42) of maintenance stage patients were ACTIVE users, FORMER users rated effectiveness lower (5.45 ± 3.96, 10 max. versus 8.29 ± 2.76, p = .02), 100% of FORMER users agreed social situations create challenges compared to 67% of ACTIVE users, and anxiety related to SFED was higher among FORMER users (64%) compared to ACTIVE users (21%, p < .01).

• Dilation provides no anti-inflammatory effect and fibrosis persists: Dilation provides at least temporary symptom relief but has no effect on the underlying esophageal inflammation, and dilation alone does not improve the inflammatory process, hence a combination with dietary or medical intervention is required. Budesonide showed fibrosis scores with no significant improvement (P = 0.48), and persistent symptoms in fibrostenotic disease highlight the need for adjunct therapies.

• Limited and heterogeneous evidence base for long-term and comparative outcomes: As only three relevant RCTs were identified, we have limited capacity to compare the benefits and harms of medical interventions currently used for treating EE. Available literature consists of small studies with diverse methods and population characteristics with moderate to substantial heterogeneity observed for most outcomes, and data evaluating long-term efficacy and safety is limited. Unanswered questions include adequate definition for sustained remission, best strategies for maintenance drugs and diets, durability of remission beyond one year, comparative effectiveness relative to other therapies, long-term effectiveness for preventing esophageal fibrosis/stricture, and cost-effectiveness analysis.

Decoding the Positive Phase 3 CROSSING Trial for TEZSPIRE

Recent Eosinophilic esophagitis trials have evaluated topical corticosteroids, dietary elimination, and interventional designs using histologic, endoscopic, and patient-reported endpoints. Designs range from double-blind placebo-controlled studies to double-dummy and open-label diet comparisons, with treatment durations of 6 to 36 weeks. The Dysphagia Symptom Questionnaire, peak eosinophil count thresholds, and endoscopic severity scores feature consistently across primary and secondary endpoints.

TEZSPIRE's TSLP Inhibition: Broad Potential Beyond EoE

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A New Frontier in EoE: TSLP Blockade Delivers Sustained Remission

The recent announcement of full Phase 3 CROSSING trial results for TEZSPIRE (tezepelumab-ekko) in eosinophilic esophagitis (EoE) marks a pivotal moment for patients grappling with this chronic, immune-mediated esophageal disorder. EoE, characterized by debilitating dysphagia, food impaction, and progressive tissue remodeling, has long presented a challenge for clinicians, with many patients experiencing inadequate responses to conventional therapies like proton pump inhibitors, topical corticosteroids, and elimination diets.

Tezepelumab's mechanism of action, targeting thymic stromal lymphopoietin (TSLP), offers a novel approach by inhibiting an upstream epithelial cytokine known to drive type 2 inflammation and contribute to tissue remodeling. This upstream blockade differentiates it from other biologics, such as dupilumab, which target downstream cytokines like IL-4 and IL-13. The trial's success, demonstrating statistically significant and clinically meaningful improvements in both histologic remission and dysphagia symptoms, sustained over 52 weeks, underscores the potential for a new, effective therapeutic pathway. For patients with severe fibrostenotic disease or those refractory to existing treatments, this upstream targeting could be particularly impactful, offering a chance for more comprehensive disease control.

However, the competitive landscape for EoE is evolving. Dupilumab is already an established, FDA-approved biologic with a growing body of real-world evidence supporting its long-term efficacy and safety across diverse patient populations, including those with comorbidities. Tezepelumab will need to clearly articulate its unique value proposition, perhaps by focusing on its distinct mechanism and potential benefits in specific patient subgroups or those who have failed other type 2 biologics. Furthermore, while 52-week data are encouraging, EoE is a lifelong condition. Robust long-term data on tezepelumab's ability to prevent esophageal remodeling and stricture formation will be crucial for widespread adoption and payer acceptance. The inherent heterogeneity of type 2 gene expression in EoE patients also highlights the need for better patient selection tools or biomarkers to ensure that TSLP inhibition is directed to those most likely to benefit, paving the way for more personalized medicine approaches in EoE management.