A Trial Evaluating EP-104IAR in Adults With Eosinophilic Esophagitis

Study Overview
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Brief Summary
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An open-label, dose-escalation study to explore the safety, tolerability and pharmacokinetics of EP-104IAR in adults with eosinophilic esophagitis (EoE). Endoscopic and histologic assessments will also be evaluated to understand the local effects of EP-104IAR on eosinophilic EoE disease activity. The study will evaluate up to 8 doses of EP-104IAR (4 mg to 40 mg) in cohorts of 3 to 6 participants per cohort. If all planned cohorts are evaluated, or cohorts need to be repeated, up to 24 participants could be enrolled. The study involves 7 site visits spread over approximately 32 weeks. All participants will receive active study drug (EP-104IAR), The study drug will be administered by qualified personnel during an esophagogastroduodenoscopy (EGD) procedure at the Baseline/Dosing visit. Safety will be assessed throughout the study. Blood and urine samples will be collected at site visits for laboratory assessments and to measure plasma levels of EP-104IAR. Participants will complete questionnaires to assess symptoms of dysphagia and odynophagia and will undergo 3 EGDs with esophageal biopsies at the Baseline/Dosing Visit, and at 4 and 12 weeks post dose.

Official Title
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A Phase 1b, Open Label Trial Evaluating the Safety, Pharmacokinetics, and Efficacy of EP-104IAR in Adults With Eosinophilic Esophagitis (EoE)

Conditions
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Eosinophilic Esophagitis

Intervention / Treatment
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* Drug: EP-104IAR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptomatic EoE; For women of childbearing potential, a negative pregnancy test and willing to use a highly effective method of birth control until end of study; Willing and able to adhere to study-related procedures and visit schedule; Willing and able to provide informed consent. Exclusion Criteria: Concomitant esophageal disease, relevant GI disease, or any condition, history, or laboratory abnormality that might interfere with the study; Oral or esophageal mucosal infection of any type (bacterial, viral, or fungal); Oropharyngeal or dental conditions that prevents normal eating; Severe esophageal motility disorders other than EoE; Contraindication to or factors that substantially increase risks associated with EGD or biopsy, or narrowing of the esophagus that precludes EGD with a standard 9-10 mm endoscope, stricture requiring dilation within 8 weeks prior to Screening, or the need for dilation prior to EGD at Baseline; Any condition for which the use of corticosteroids is contraindicated (Participants with well controlled non-insulin dependent diabetes are permitted); Active or quiescent systemic fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Or recent use of IV or oral antibiotics; Hypersensitivity, or intolerance to corticosteroids, or to any of the ingredients in the investigational medicinal product; Recent use of disallowed medications, or unwillingness to not use disallowed medications during the study; Recent initiation of a elimination or elemental diet (dietary therapy must remain stable throughout the study); Morning serum cortisol level ≤ 5 μg/dL (138 nmol/L); Clinically significant abnormal laboratory values; Recent or currently planned participation in another interventional trial ; Previous participation in this study and had received study treatment; Females who are pregnant, breastfeeding, or planning to become pregnant during the study; Malignancies or history of malignancy within prior 5 years, except for treated or excised non-metastatic BCC, SCC of the skin, or cervical carcinoma in situ; History of alcohol or drug abuse; Any other reason, that, in the Investigator's opinion, unfavorably alters participant risk, confounds results, or prevents the participant from complying with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EP-104IAR 4 mg<br>4 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 8 mg<br>8 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 12 mg<br>12 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 16 mg<br>16 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 10 mg<br>4 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 20 mg<br>8 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 30 mg<br>12 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|
| Experimental: EP-104IAR 40 mg<br>16 submucosal injections of EP-104IAR administered during an EGD procedure at the Baseline/Dosing visit. | Drug: EP-104IAR<br>* Long-acting fluticasone propionate for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (TEAEs) | TEAEs will be summarized by dose/cohort | 12 weeks | 
| Severity of treatment emergent adverse events (TEAEs) | TEAEs will be summarized by dose/cohort and severity (mild, moderate, severe). | 12 weeks | 
| Change from baseline in morning serum cortisol levels | Cortisol will be will be summarized by dose/cohort and over time and compared to pre-dose values. A prolonged and clinically significant reduction in cortisol may indicate adrenal insufficiency. | 12 weeks | 
| Plasma concentrations of fluticasone propionate | Plasma concentrations of fluticasone propionate over time will be used to calculate PK parameters for each dose/cohort. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak eosinophil count (PEC) | Biopsy specimens will be used to evaluate peak eosinophil counts (PEC). A higher number of eosinophils indicates more severe histological disease. | 4 weeks | 
| Peak eosinophil count (PEC) | Biopsy specimens will be used to evaluate peak eosinophil counts (PEC). A higher number of eosinophils indicates more severe histological disease. | 12 weeks | 
| Change from baseline in the Straumann Dysphagia Index (SDI) score | The SDI is a patient-reported outcome measure of dysphagia with a 7-day recall period. The SDI assesses the frequency and intensity of dysphagia on two separate 5-point and 6-point scales. Total SDI scores are calculated by adding the two sub-scores (range, 0-9), with a higher total score indicating more severe dysphagia. | 2 weeks | 
| Change from baseline in the Straumann Dysphagia Index (SDI) score | The SDI is a patient-reported outcome measure of dysphagia with a 7-day recall period. The SDI assesses the frequency and intensity of dysphagia on two separate 5-point and 6-point scales. Total SDI scores are calculated by adding the two sub-scores (range, 0-9), with a higher total score indicating more severe dysphagia. | 4 weeks | 
| Change from baseline in the Straumann Dysphagia Index (SDI) score | The SDI is a patient-reported outcome measure of dysphagia with a 7-day recall period. The SDI assesses the frequency and intensity of dysphagia on two separate 5-point and 6-point scales. Total SDI scores are calculated by adding the two sub-scores (range, 0-9), with a higher total score indicating more severe dysphagia. | 8 weeks | 
| Change from baseline in the Straumann Dysphagia Index (SDI) score | The SDI is a patient-reported outcome measure of dysphagia with a 7-day recall period. The SDI assesses the frequency and intensity of dysphagia on two separate 5-point and 6-point scales. Total SDI scores are calculated by adding the two sub-scores (range, 0-9), with a higher total score indicating more severe dysphagia. | 12 weeks | 
| Change from baseline in dysphagia measured on an 11 point Likert scale | The participant will assess the severity of their dysphagia symptoms (troubles to swallow) over the previous 7-days using an 11-point Likert scale where 0 = no trouble and 10 = most severe trouble swallowing. | 4 weeks | 
| Change from baseline in dysphagia measured on an 11 point Likert scale | The participant will assess the severity of their dysphagia symptoms (troubles to swallow) over the previous 7-days using an 11-point Likert scale where 0 = no trouble and 10 = most severe trouble swallowing. | 8 weeks | 
| Change from baseline in dysphagia measured on an 11 point Likert scale | The participant will assess the severity of their dysphagia symptoms (troubles to swallow) over the previous 7-days using an 11-point Likert scale where 0 = no trouble and 10 = most severe trouble swallowing. | 12 weeks | 
| Change from baseline in odynophagia measured on an 11 point Likert scale | The participant will assess the severity of their pain during swallowing over the previous 7 days using an 11 point Likert scale where 0 = no pain and 10 = most severe pain during swallowing. | 4 weeks | 
| Change from baseline in odynophagia measured on an 11 point Likert scale | The participant will assess the severity of their pain during swallowing over the previous 7 days using an 11 point Likert scale where 0 = no pain and 10 = most severe pain during swallowing. | 8 weeks | 
| Change from baseline in odynophagia measured on an 11 point Likert scale | The participant will assess the severity of their pain during swallowing over the previous 7 days using an 11 point Likert scale where 0 = no pain and 10 = most severe pain during swallowing. | 12 weeks | 
| Change from baseline in the EoE Endoscopic Reference Score (EREFS) | Endoscopic Reference Score (EREFS) scoring system is used to determine the severity of 5 endoscopic findings: edema, rings, exudates, furrows, and strictures. The total EREFS is calculated by summing the grades of the 5 individual endoscopic items (range, 0 to 9), with higher scores indicating more severe endoscopic disease. | 4 weeks | 
| Change from baseline in the EoE Endoscopic Reference Score (EREFS) | Endoscopic Reference Score (EREFS) scoring system is used to determine the severity of 5 endoscopic findings: edema, rings, exudates, furrows, and strictures. The total EREFS is calculated by summing the grades of the 5 individual endoscopic items (range, 0 to 9), with higher scores indicating more severe endoscopic disease. | 12 weeks | 
| Change from baseline in EoE Histology Scoring System (EoEHSS) score | The EoEHSS scores the stage and grade of 8 histologic items: eosinophil inflammation, basal zone hyperplasia, dilated intercellular spaces, eosinophil abscesses, surface layering, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis), on separate 4-point Likert scales. A composite EoEHSS grade and stage scores are calculated by summing the individual grade and stage items and dividing by the maximum score for evaluated items (range, 0-1). A lower score indicates improvement. | 4 weeks | 
| Change from baseline in EoE Histology Scoring System (EoEHSS) score | The EoEHSS scores the stage and grade of 8 histologic items: eosinophil inflammation, basal zone hyperplasia, dilated intercellular spaces, eosinophil abscesses, surface layering, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis), on separate 4-point Likert scales. A composite EoEHSS grade and stage scores are calculated by summing the individual grade and stage items and dividing by the maximum score for evaluated items (range, 0-1). A lower score indicates improvement. | 12 weeks |