A Phase 1b/2 study to explore the safety, efficacy and pharmacokinetics of EP-104GI in adults with eosinophilic esophagitis (EoE). Endoscopic and histologic assessments will also be evaluated to understand the local effects of EP-104GI on eosinophilic EoE disease activity. Approximately 27 to 33 participants will be enrolled in dose escalation: 3-6 participants per dose cohort. The number of participants enrolled in escalation will depend on the number of dose escalation cohorts evaluated, and dose cohorts needing to be expanded. An additional 10-24 participants will be enrolled in 1 or 2 cohorts of 10-12 participants each at tolerable dose regimen(s) selected based on the accumulated clinical data to identify the recommended phase 2 dose(s) (RP2D). In the Phase 2 randomized dose optimization portion of the study, approximately 120 subjects will be randomized to Dose A (120 mg total dose), Dose B (160 mg total dose), or matching vehicle control, with an overall assignment ratio of 1:1:1. The total number of participants in both portions of the study will be approximately 160. The study involves 8-10 site visits spread over approximately 52 weeks. Participants in an extended PK sub study will have up to 4 additional visits, to a maximum of 108 weeks post-dose. The participants will either receive the active study drug (EP-104GI) or matching vehicle control. Matching vehicle control will be used only in randomized dose optimization portion of the study. Participants randomized to receive vehicle control may receive EP-104GI (Dose A or Dose B) following the completion of Week 24 providing they meet eligibility criteria for crossover to EP-104GI. Participants randomized to receive EP-104GI on Day 0 will not receive EP-104GI or vehicle control at Week 24. The study drug or matching vehicle control 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-104GI. Participants will complete questionnaires to assess symptoms of dysphagia and odynophagia and will undergo 3-5 EGDs with esophageal biopsies at the Baseline, Week 4 (dose escalation phase only), Week 12, Week 24 (randomized dose optimization phase only), Week 26, and Week 52 (randomized dose optimization phase only).

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.

Criteria for crossover to EP 104GI from vehicle control (randomized dose optimization portion):

1. Has completed the randomized dose optimization portion of the trial to Week 24, inclusive
2. Without safety concerns for receiving EP 104GI ie, does not meet exclusion criteria or have other safety issue

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, including carboxymethyl cellulose, and polysorbate 80, or to the ingredients in Synacthen / cosyntropin (used in the ACTH stimulation test);
• 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.