Efficacy and Safety Evaluation of Barzolvolimab in Adults with Active Eosinophilic Esophagitis: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of barzolvolimab, compared to placebo, in reducing esophageal intraepithelial infiltration of **mast cells** as assessed by peak esophageal intraepithelial mast cell (PMC) count in patients with **Eosinophilic Esophagitis** (EoE). This is clinically relevant as mast cell infiltration is a key pathological feature of EoE, contributing to inflammation and esophageal dysfunction.

Secondary objectives include:

• Evaluating the efficacy of barzolvolimab, compared to placebo, in reducing symptoms of **dysphagia** as assessed by the dysphagia symptom questionnaire (DSQ) in EoE patients.
• Assessing the efficacy of barzolvolimab, compared to placebo, in reducing esophageal intraepithelial infiltration of **eosinophils** as measured by peak esophageal intraepithelial eosinophil (PEC) count in EoE patients.
• Evaluating the safety profile of barzolvolimab in EoE patients.

The clinical trial involves a total of **52 participants** diagnosed with **Eosinophilic Esophagitis** (EoE). The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on specific criteria, including a documented diagnosis of EoE confirmed by endoscopy and a history of esophageal intraepithelial eosinophilic infiltration. All participants must have been symptomatic, experiencing dysphagia with solid foods, and must have maintained a stable diet including solid foods for at least two months prior to the screening visit. The trial includes individuals who have had an inadequate response to or are intolerant of standard EoE treatments. The study population is considered vulnerable, and the selection process ensures that participants have provided informed consent. The trial aims to evaluate the efficacy of barzolvolimab in reducing esophageal intraepithelial infiltration of mast cells compared to a placebo.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **barzolvolimab** in adults with active **eosinophilic esophagitis**. The primary objective is to assess the reduction in esophageal intraepithelial infiltration of mast cells, as measured by the peak esophageal intraepithelial mast cell count. The trial is expected to commence recruitment on December 5, 2023, and conclude by December 5, 2025, with a total duration of approximately 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of eosinophilic esophagitis, and symptomatic history. The trial will include follow-up visits at regular intervals to monitor the participants' response to the treatment and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints, including changes in dysphagia symptom questionnaire scores and the incidence of treatment-emergent adverse events.

The expected length of participant involvement is approximately 12 weeks, with the primary endpoint being the absolute change from baseline to Week 12 in the peak mast cell count per high power field. Conditions that may lead to early termination from the study include significant adverse reactions, non-compliance with study protocols, or withdrawal of consent by the participant. The study will utilize a placebo matching the investigational product, ensuring the integrity of the double-blind design. Participants will receive the investigational product or placebo via **subcutaneous injection**. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent prior to enrollment.

The clinical trial involves the administration of **Barzolvolimab**, a humanized immunoglobulin G1 kappa (IgG1k) **monoclonal antibody**. This experimental medication is provided as a **concentrate for solution for infusion**. The active substance, Barzolvolimab, is a protein-based therapeutic agent developed by Celldex Therapeutics, Inc. The maximum daily dose is 300 mg, with a total maximum dose of 2100 mg over a treatment period of 24 weeks. The route of administration is via **subcutaneous injection**. Participant compliance with the dosing schedule will be monitored throughout the study.

A **placebo** matching CDX-0159 is also utilized in this study. It is designed to mimic the solution for injection form of Barzolvolimab, ensuring the double-blind nature of the trial. The placebo does not contain any active substance and serves as a control to evaluate the efficacy and safety of the experimental treatment.

Additionally, **Epinephrine** is included as an auxiliary treatment. It is provided as a solution for injection under the product name FASTJEKT, with a concentration of 300 micrograms per dose. The maximum daily and total dose is 600 micrograms, administered via subcutaneous injection. This chemical agent is used as a standard emergency treatment for allergic reactions, ensuring participant safety during the trial. The administration of epinephrine is not part of the experimental treatment but is available as a precautionary measure.

The efficacy of **barzolvolimab** in the treatment of active eosinophilic esophagitis (EoE) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the absolute change from baseline to Week 12 in the peak esophageal intraepithelial mast cell (PMC) count per high power field (hpf). Secondary endpoints include absolute changes from baseline to Week 12 in the Dysphagia Symptom Questionnaire (DSQ) scores, absolute change in PMC/hpf among patients with baseline PMC ≥ 12/hpf, absolute change in peak esophageal intraepithelial eosinophil count (PEC)/hpf, percent change from baseline to Week 12 in PMC/hpf, and the incidence of treatment-emergent adverse events (TEAEs).

Measurements will be collected at specified timepoints, with the primary and secondary efficacy parameters being evaluated at baseline and Week 12. The assessment of PMC and PEC will be conducted using histological analysis of esophageal biopsies, while DSQ scores will be obtained through patient-reported outcomes. The analysis will focus on the comparison of changes from baseline to Week 12 between the barzolvolimab and placebo groups, providing insights into the drug's efficacy in reducing esophageal intraepithelial infiltration of mast cells and improving symptoms in EoE patients.