New Frontiers in Eosinophilic Esophagitis Treatment: The Rise of Advanced Therapies

Vol. 31, Issue 1 (March 2026)

David T. Dulaney, MD
Associate Professor of Medicine and Gastroenterology
Fellowship Program Director
Brooke Army Medical Center
San Antonio, TX, USA

 

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus mediated by a type 2 inflammatory response to allergens. EoE causes eosinophilic infiltration of the esophagus leading to fibrostenotic complications and symptoms of esophageal dysfunction.¹ Global incidence and prevalence of EoE continues to rise over time.² It is estimated that the projected global incidence and prevalence rates will be 12.67/100,000 and 110.82/100,000 by 2037 with increases throughout regions in which EoE was previously unknown. In particular, Asia has experienced increasing incidence and prevalence of the disease.³

Diagnosis is made with endoscopic sampling of the esophagus in those with symptoms of esophageal dysfunction. Current guidelines reiterate the diagnostic criteria of the AGREE consortium of >15 eosinophils per high powered field on biopsy in a patient with symptoms of esophageal dysfunction and/or high clinical suspicion for EoE.⁴ Endoscopy can be used to assess the esophageal disease activity of EoE to include rings, linear furrowing, strictures, edema (noted by decreased vascularity), and exudates. These are included on the Endoscopic Reference Score (EREFS). Further findings during endoscopy include fragile esophageal mucosa, commonly referred to as “crepe paper esophagus” and firm mucosa on biopsy (i.e the “tug” sign).⁵

EoE leads to a complex interaction of type 2 inflammation of the esophageal mucosa in response to environmental allergy triggers. This continued inflammation leads to worsening barrier dysfunction of the esophageal epithelium, which, in turn, further propagates more inflammation.⁶ In response to these environmental triggers, epithelial cells of the esophagus release thymic stromal lymphopoietin (TSLP), which activates type 2 lymphoid cells in the esophagus. Overall, the type 2 inflammatory response of the esophagus is ultimately driven by type 2 helper T cells. These cells produce pro-inflammatory cytokines such as interleukin (IL) -4, IL-5, and IL-13, which further activate the inflammatory response in the esophageal mucosa. IL-4 and IL-13 are key central mediators of this response. They share overlapping signaling receptors such as IL-4Rα, a receptor that is expressed on various lymphocyte types to include eosinophils. Their action on this receptor increases the release of IL-4, IL-5, and IL-13. Furthermore, IL-4 and IL-13 upregulate the expression and release of key chemokines such as eotaxin and periostin. These chemokines promote chemotaxis of eosinophils to the esophageal mucosa to further propagate inflammation and contribute to eventual fibrosis of the esophagus.⁷ The pro-inflammatory cytokines of IL-4, IL-5, and IL-13 are key targets for advanced therapies in the treatment of EoE.

Treatments

Multiple treatments exist for EoE that are not advanced therapies. Many of these, due to their ease of administration, are considered first-line therapies among multiple societal guidelines around the world. These include proton pump inhibitors (PPIs), swallowed topical corticosteroids, and dietary elimination therapy.3 Recent guidelines from the American College of Gastroenterology suggest that these should be considered first-line anti-inflammatory treatments to resolve eosinophilic inflammation of the esophagus. The decision of which anti-inflammatory treatment to initiate upon diagnosis hinges on shared decision making with the patient and their provider. The mainstay of treatment for fibrostenotic disease remains esophageal dilation therapy.⁵

Proton Pump Inhibitors (PPIs)

PPI therapies are believed to have multiple mechanisms to treat EoE, including restoration of the mucosal barrier via reduction of acidic refluxate and inhibition of eotaxin driven recruitment of eosinophils. However, there remains a paucity of studies regarding their efficacy. Two randomized controlled trials have been performed on PPI therapy but only in comparison to swallowed topical
corticosteroids.³ These demonstrated both histologic and symptomatic efficacy of PPIs for treatment of EoE.⁵ Overall, when considering their efficacy among these studies and observational studies, the unweighted histologic response rate is 42%.⁸

Topical Corticosteroids

Historically, swallowed topical corticosteroids were the first medical treatments used for EoE. Earlier guidelines recommended the use of swallowed fluticasone delivered by inhaler. However, there are now commercially available oral budesonide solutions and budesonide orodispersible tablets in the United States and Europe, respectively. Recent phase 3 trials of these formulations demonstrated a 62-95% histologic response rate.^{5, 8}

Dietary Therapy

Elimination diets can also be considered as a first-line therapy for treatment of inflammation secondary to EoE in properly counseled patients. Elimination diets require the elimination of common allergen triggers from the diet with assessments of histologic response. The six most common allergens (in order of likelihood to cause inflammatory response in the esophagus) are: milk (dairy), wheat, soy, egg, nuts/peanuts, and fish/shellfish. The empiric six food elimination diet (SFED) excludes each of these foods from the diet for 6-8 weeks. This is followed by a 6-8 week reintroduction period of each of these groups in order of least likely to cause inflammation. Each reintroduction is followed by an endoscopy with tissue sampling to assess for histologic disease activity.⁵ Given this onerous task of identifying food triggers, alternative diets to include four-food (FFED) and one food (OFED) (dairy) elimination diets have been proposed. Pooled histologic remission rates for the SFED, FFED, and OFED are 61.3%, 49.4%, and 51.4%.9 Elemental formula diets have been studied in pediatric and adult populations, which have an over 90% response rate. However, due to poor palatability, non-adherence is common and percutaneous gastrostomy tube placement may be necessary. Furthermore, this dietary strategy has significant developmental complications for pediatric patients as well as psychosocial implications for both adult and pediatric patients.⁸

Advanced Therapies

Based on the efficacy of the aforementioned treatments for EoE, it is clear that there are significant gaps in treatment for symptom improvement and to fully induce and maintain histologic remission. Multiple advanced therapies (i.e. biologics and small molecules) have been studies for the treatment of EoE. For the purposes of this review, only those which have demonstrated both symptomatic and histologic efficacy will be discussed. Biologics such as omalizumab, mepolizumab, reslizumab, benralizumab, and lirentelimab have been studied but failed to meet either symptomatic, histologic, or both efficacy end points.³

Dupilumab

Dupilumab is the only biologic therapy that is currently approved for use for EoE in the United States and Europe. It is approved for the treatment of patients aged ≥ 1-year-old weighing ≥ 15 kg.3 It is a monoclonal antibody agent that blocks the IL-4Rα, thus, blocking the actions of both IL-4 and IL-13 as described above. It was assessed in two studies of patients aged 12 years and up and 1-11 years.^{10, 11} The study in adults and adolescents enrolled patients with >15 eosinophils per high power field on endoscopic sampling as well as Dysphagia Symptom Questionnaire (DSQ) scores of ≥ 10. Patients were enrolled into Part A or Part B of the study for a 24-week treatment period. Part A enrolled randomized patients to 300 mg dupilumab weekly or placebo arm. Part B enrolled patients into 300 mg weekly dupilumab, 300 mg every 2 week dupilumab, or placebo arms. Patients from Parts A and B who were in remission at 24 weeks were enrolled into Part C to receive 300 mg dupilumab weekly.10 At 24 weeks of treatment in Part A, 25/42 (60%) patients receiving weekly dupilumab were in histologic remission, which was defined as <6 eosinophils per high powered field, compared to 2/39 (5%) receiving placebo. Similarly, in Part B, 47/80 (59%) of patients on weekly dupilumab, 49/81 (60%) of patients on every 2 week dupilumab, and 5/79 (6%) of those receiving placebo were in histologic remission. Part C demonstrated sustained histologic remission at week 52 for those who had received weekly dupilumab in Part A, and those who initially received placebo showed increases in histologic remission (18/30, 60%).¹⁰ However, when comparing reductions in DSQ scores, only those who received weekly dupilumab demonstrated a significant reduction.¹⁰ Therefore, the recommended dosage for patients aged 12 years and older weighing at least 40 kg is 300 mg weekly.

Data in the pediatric studies of patients aged 1 to 11 years demonstrated similar results. Patients were randomized to groups with low dose or high dose dupilumab as well as two placebo groups. At the conclusion of 16 weeks of treatment, 68% of patients in the high dose groups and 58% of patients in the low dose group achieved histologic remission defined by <6 eosinophils per high power field, whereas only 3% of patients in the placebo groups did so.¹¹ Pediatric dosing is weight dependent, with those 15-30 kg receiving 200 mg of dupilumab every other week and those weighing 30-40 kg receiving 300 mg of dupilumab every other week.

Cendakimab

Cendakimab is a biologic medication that has been recently studied for treatment of EoE. It binds directly to IL-13 to prevent its interaction with IL-13 receptors. In a recent phase 3 trial, cendakimab was studied in the treatment of EoE for patients aged 12-75. Coprimary endpoints were assessed that included histologic response defined at <6 eosinophils per high power field and change from baseline dysphagia days. At 24 weeks, the patients receiving weekly treatments with cendakimab showed a significant reduction in baseline dysphagia days compared to placebo (-6.1 [0.3] vs -4.2 [0.4] days). Furthermore, 28.6% of patients receiving cendakimab demonstrated histologic response compared to 2.2% of patients receiving placebo. Both of these outcomes were statistically significant findings.¹² At present, cendakimab is not commercially available for treatment of patients with EoE.

Etrasimod

Etrasimod is an oral, once-daily dosed, selective sphingosine-1 phosphate receptor modulator that has been approved for treatment of ulcerative colitis. A phase 2 study was recently published trialing its use for eosinophilic esophagitis. Patients were randomized to 2 mg daily etrasimod, 1 mg daily etrasimod, and placebo groups. The primary end point was percent change in peak eosinophil counts from baseline. At week 16, the median percentage changes in peak eosinophil count was -58.4% for etrasimod 2 mg, -39.4% for etrasimod 1 mg, and -21.5% for placebo group. Only the median change peak eosinophil count for the etrasimod 2 mg group was statistically significant compared to placebo.¹³ Further study is required to determine the effectiveness of etrasimod in the treatment of EoE.

Conclusion

In summary, EoE is a chronic inflammatory condition of the esophagus caused by type 2 inflammation in response to allergens in the esophageal mucosa. Per recent societal guideline updates, the mainstays of initial treatments for inflammatory disease activity remain proton pump inhibitors, swallowed topical corticosteroids, and elimination diets.^{3, 5-6, 8} However, these have variable histologic response rates as well as poor adherence in the case of elimination diets. Biologic therapies have been studied for their use in EoE. At present, dupilumab is the only approved biologic therapy available in the United States and Europe.³ However, both cendakimab and etrasimod have been studied with positive findings in their recently published trials.^12-13 Further study is required to determine their role in the treatment paradigm of EoE.

References

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