Efficacy and Safety of Tezepelumab in Eosinophilic Esophagitis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

The primary objective of this study is to evaluate the effect of **tezepelumab** on the histologic response and symptom improvement in adult and adolescent participants with symptomatic and histologically active eosinophilic esophagitis (EoE). This is clinically relevant as EoE is a chronic inflammatory disorder characterized by esophageal dysfunction and eosinophilic infiltration, which can significantly impact patients' quality of life. Understanding the efficacy of tezepelumab in modifying these histological and symptomatic parameters could lead to improved therapeutic strategies for managing EoE.

Secondary objectives include:

• Evaluating the effect of tezepelumab on the centrally-read EoE EREFS and EoE-HSS.
• Assessing the long-term effect of tezepelumab on histologic response, symptom improvement, and centrally-read EoE EREFS.
• Evaluating the effect of tezepelumab on peak eosinophil count and EoE symptoms in adolescents.
• Assessing the pharmacokinetics (PK) and immunogenicity of tezepelumab.

The clinical trial involves a total of **149 participants** diagnosed with **eosinophilic esophagitis (EoE)**, a rare, chronic inflammatory disorder. The study population includes both male and female subjects, ranging in age from 12 to 80 years. Participants were selected based on their symptomatic and histologically active EoE, confirmed through esophageal biopsy. All participants are required to maintain a stable diet for at least 8 weeks prior to and during the study, without initiating or reintroducing elimination diets. They may continue any background medication for EoE, such as proton pump inhibitors (PPI) or swallowed topical corticosteroids (STC), provided these have been stable for at least 8 weeks before the trial. Additionally, those on leukotriene inhibitors or steroid treatments for asthma or allergies must have a stable dose for at least 4 weeks prior to the trial. The trial includes a vulnerable population, ensuring careful consideration of ethical standards in the study design.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 3 study to evaluate the efficacy and safety of **tezepelumab** in patients with **eosinophilic esophagitis** (EoE). The trial aims to assess the histologic response and symptom improvement in adult and adolescent participants with symptomatic and histologically active EoE. The study will involve the administration of **Tezspire 210 mg solution for injection** in a pre-filled syringe via **subcutaneous injection**. Participants will be randomly assigned to receive either the active treatment or a placebo, ensuring the study's double-blind nature.

The trial is expected to commence recruitment on March 25, 2024, and is estimated to conclude by January 8, 2027. The total duration of the trial for each participant is approximately 76 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participants' response to the treatment, and an end-of-study visit to assess the final outcomes. The primary endpoints include the histologic response of peak esophageal eosinophil count and changes in the Dysphagia Symptom Questionnaire (DSQ) score at Week 24. Secondary endpoints will be evaluated at both Week 24 and Week 52, including changes in EoE Endoscopic Reference Score (EREFS) and EoE Histologic Scoring System (HSS) scores, among others.

Participants are expected to remain involved in the study for the entire duration unless specific conditions necessitate early termination. These conditions may include adverse reactions to the treatment, non-compliance with the study protocol, or withdrawal of consent. The trial will adhere to strict eligibility criteria, including age, weight, and a confirmed diagnosis of EoE, to ensure the safety and reliability of the results. The study will not involve any pediatric formulations, and participants must maintain a stable diet and medication regimen throughout the trial period.

The clinical trial involves the administration of **Tezspire**, a 210 mg solution for injection in a pre-filled syringe, developed by AstraZeneca AB. The active substance in this experimental medication is **tezepelumab**, a protein-based therapeutic agent. The pharmaceutical form is a solution for injection, specifically designed for subcutaneous administration. Participants will receive the medication via subcutaneous injection, with the dosing schedule and frequency determined by the study protocol. The maximum treatment period for this trial is 76 weeks. The pre-filled syringe is accessorized, although it does not possess a CE mark. Compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group, where participants will receive a placebo treatment, referred to as Tezepelumab-placebo. The placebo is designed to match the experimental medication in appearance and administration method, ensuring the study remains double-blind. The placebo does not contain any active substance and serves as a comparator to evaluate the efficacy and safety of Tezspire. The administration route and frequency for the placebo group will mirror that of the experimental group, maintaining consistency across the trial arms. Participant compliance with the placebo regimen will be similarly monitored to ensure the integrity of the study results.

The efficacy of Tezepelumab in the treatment of **Eosinophilic Esophagitis (EoE)** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the histologic response, measured by the peak esophageal eosinophil count per high-power field (HPF) of ≤ 6 across all available esophageal levels at Week 24, and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score at Week 24. Secondary endpoints will evaluate changes from baseline in the EoE Endoscopic Reference Score (EREFS) and EoE Histologic Scoring System (EoE-HSS) grade and stage scores at Weeks 24 and 52. Additional secondary endpoints include histologic response at Week 52, endoscopic response, and remission at Week 52, as well as changes in peak esophageal eosinophil count and Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) Module at Weeks 24 and 52 for adolescents. Serum trough concentrations and anti-drug antibody levels will be measured at Weeks 0, 4, 12, 24, and 52.