A Study to Investigate the Efficacy and Tolerability of ESO-101 in Patients With Eosinophilic Esophagitis

A Randomized, Placebo-controlled, Double-blind Trial Evaluating the Efficacy, Tolerability and Safety of ESO-101 in Adult Patients With Active Eosinophilic Esophagitis

This is a randomized, placebo-controlled, double-blind trial to evaluate the efficacy, tolerability, and safety of ESO-101 in adult patients with active eosinophilic esophagitis (EoE). Patients will be screened at 2 visits (Visit 1 and Visit 2) during which their eligibility will be assessed based on endoscopy-independent criteria (Visit 1) and based on the histologic assessment of esophageal biopsy samples taken during the screening endoscopy (Visit 2). Eligible patients will be randomized 2:1 to once-daily treatment with ESO-101 or placebo and treated for 28 days starting on Day 0. Further clinic visits will be performed at Day 14 (Visit 4) and Day 28 (Visit 5, end of treatment) to assess the efficacy, tolerability, and safety. In addition, a safety follow-up call will be scheduled 2 weeks after the end of treatment (Day 42, Visit 6).

Inclusion Criteria:

1. Adult patients aged 18-70 years;

2. Confirmed clinicopathological diagnosis of EoE (eosinophilic esophagitis);

3. Active and symptomatic EoE, defined as:

   1. peak eosinophil count ≥15 eosinophils/high-powered field (hpf) at 2 levels of the esophagus at the screening endoscopy (Visit 2) as measured in a total of 6 hpfs derived from 6 biopsies, 2 each from the proximal, mid, and distal segment of the esophagus;
   2. either a dysphagia or odynophagia severity sore of ≥4 on a 11-point numeric rating scale for ≥1 day during the 7 days before Screening (Visit 1);

4. Written informed consent;

5. Willingness and ability to comply with the protocol for the duration of the trial;

6. Negative pregnancy test at Screening (Visit 1) and Day 0 (Visit 3) in women of childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy);

7. Women of childbearing potential must be willing to use (for a least 3 monthly cycles before the screening endoscopy [Visit 2] and until 4 weeks after the last intake of IMP) a highly effective method of contraception or birth control (failure rate less than 1% per year when used consistently and correctly). Reliable methods for this trial are:

   1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal);
   2. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable);
   3. intrauterine device or intrauterine hormone-releasing system;
   4. bilateral tubal occlusion;
   5. a vasectomized sexual partner;
   6. sexual abstinence (only accepted as true abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal] is not an acceptable method of contraception).

Exclusion Criteria:

1. Women who are pregnant, lactating, possibly pregnant or planning a pregnancy during the trial period;
2. Current or past (within the last 3 months) alcohol or drug abuse;
3. Initiation of a diet-modifying food restriction within 4 weeks before the screening endoscopy (Visit 2) until EOT (end of treatment);
4. Use of systemic corticosteroids or biologic immunomodulators within 3 months before the screening endoscopy (Visit 2) until the EOT;
5. History of non-response to treatment of EoE with topical corticosteroid drugs (defined as no improvement of clinical symptoms of EoE after a minimum of 4 weeks corticosteroid therapy used at appropriate doses according to the investigator's judgment) or requirement of cessation of corticosteroid therapy for EoE treatment due to oral candidiasis or systemic corticosteroid side effects;
6. Use of corticosteroids for treatment of EoE within 4 weeks before the screening endoscopy (Visit 2) until the EOT;
7. Use of inhalable (pulmonary or nasal) corticosteroids within 4 weeks before the screening endoscopy (Visit 2) until the EOT;
8. Asthma requiring corticosteroid therapy in the seasonal allergy period according to the investigator's judgment based on anamnesis until the EOT;
9. Change in proton pump inhibitor (PPI) dosing regimen within 4 weeks before the screening endoscopy (Visit 2) until the EOT;
10. Use of systemic leukotriene receptor antagonists, immunosuppressant therapy, or chronic oral or systemic anticoagulants (such as coumarin derivates, novel oral and subcutaneous anticoagulants) within 2 weeks before Screening (Visit 1) until the EOT;
11. Unable to swallow a test tablet of about the size of the IMP capsule used in the trial;
12. History of diabetes mellitus;
13. Other severe comorbid condition, concurrent medication, or other issue that renders the patient unsuitable to participate in the trial in the judgment of the investigator, including but not limited to: comorbid condition with an estimated life expectancy of ≤12 months, dialysis, severe pulmonary (requiring home oxygen, uncontrolled chronic obstructive pulmonary disease Gold III/IV) or cardiovascular conditions (heart failure New York Heart Association III and IV, uncontrolled hypertension systolic blood pressure by repeated measurement >180mmHg);
14. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) or treatment with anticancer therapy (chemotherapy, immunotherapy, radiotherapy, hormone therapy for cancer treatment, targeted therapy or gene therapy) within 12 months before Screening (Visit 1) until the EOT;
15. Known intolerability or hypersensitivity to mometasone furoate or any of the IMP excipients (e.g. bovine gelatin, polyvinyl alcohol, polyvinyl acetate, glycerol, sorbitol);
16. Systemic autoimmune disorders or any condition requiring immunosuppression (e.g. methotrexate, cyclosporine, interferon alpha, tumor necrosis factor alpha inhibitors, antibodies to immunoglobulin E) within 3 months before Screening (Visit 1);
17. Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the trial or presence of any condition that impacts compliance with the trial procedures;
18. Use of any investigational or non-registered product (medicinal product or medical device) within 4 weeks before the screening endoscopy (Visit 2) until the EOT;
19. Employee at the trial center, spouse, partner or child of investigators or sub-investigators or employee of the sponsor.
20. History of or active eosinophilic gastroenteritis and colitis, inflammatory bowel disease, celiac disease, oral or esophageal mucosal infection of any kind, and esophageal varices;
21. Gastroesophageal reflux disease with Los Angeles Grade B or higher, or erosive esophagitis Grade 2 or above;
22. Presence of Barrett's esophagus with a maximum length of ≥3 cm with intestinal metaplasia or dysplasia, peptic stricture, achalasia, significant hiatal hernia >3 cm, esophageal scleroderma, or diagnosis of Lichen planus;
23. Emergency endoscopy for bolus impaction within 2 weeks before Screening (Visit 1);
24. Any mouth or dental condition that prevents normal eating;
25. History of (dilation within the previous 8 weeks) or current severe endoscopic structural abnormality in esophagus (e.g. high-grade stenosis where an 8-10 mm endoscope cannot pass without dilatation at the screening endoscopy [Visit 2]);
26. Diagnosed liver cirrhosis or portal hypertension;
27. History of upper gastrointestinal bleeding within 8 weeks before Screening (Visit 1);
28. Known allergy to β-lactoglobulin (cow milk protein).