Efficacy and Safety APT-1011 in Adult Subjects With Eosinophilic Esophagitis (EoE) (FLUTE-2)

Fluticasone Propionate Oral Dispersible Tablet Formulation in Eosinophilic Esophagitis: A Two-Part, Randomized, Double-blind, Placebo-Controlled Study of APT-1011 With an Open-label Extension, in Adult Subjects With Eosinophilic Esophagitis

This is a 2-part randomized, double-blind, placebo-controlled study followed by an open-label extension (OLE) of APT-1011 in adults with EoE.

Part A will evaluate the efficacy and safety of APT-1011 3 mg administered hora somni (HS; at bedtime) for the induction of response to treatment (histologic and symptomatic) over 12 weeks.

Part B will evaluate histological relapse-free status in patients re-randomized to continue APT-1011 or placebo (active treatment withdrawal) until Week 52.

Part C, the OLE, will continue until regulatory approval of APT-1011 or Sponsor termination of the study.

This is a 2-part randomized, double-blind, placebo-controlled study followed by an OLE of APT-1011 in adults with EoE.

Part A will evaluate the efficacy and safety of APT-1011 3 mg administered HS for the induction of response to treatment (histologic and symptomatic) over 12 weeks.

At Week 14, subjects will move into Part B. Subjects with histological response to APT-1011, defined as ≤6 peak eos/HPF, will be re-randomized to continue APT-1011 or receive placebo (active treatment withdrawal). APT-1011 histological non-responders will continue APT-1011, and placebo histological non-responders will receive APT-1011 3 mg HS. Placebo histological responders will continue placebo. The double-blind will be sustained throughout Part B. Histological responder status will be determined at the time of esophagogastroduodenoscopy (EGD) in Part B (at or prior to Week 52, depending on unscheduled EGDs performed when the Investigator deems the subject's symptoms necessitate EGD) and is defined as ≤6 peak eos/HPF.

At Week 52, subjects may enter Part C, an open-label single-arm extension phase, and continue study drug uninterrupted. Part C will terminate upon regulatory approval of APT-1011 or Sponsor termination of the study.

Inclusion Criteria:

1. Male or female ≥18 years of age at the time of informed consent or assent

2. Each subject must read, understand, and provide consent on the ICF for this study and be willing and able to adhere to study-related treatment regimens, procedures, and visit schedule

3. Diagnosis or presumptive diagnosis of EoE that is confirmed during the Screening period by histology that demonstrates ≥15 peak eos/HPF. In order to ensure that a diagnosis can be made, at least 6 biopsies should be taken including both proximal and distal specimens (at least 3 each). Mid-esophageal biopsies are not required (optional). HPF will be defined as a standard area of 235 square microns in a microscope with 40x lens (0.3 mm^2) and 22 mm ocular.

   1. Esophagogastroduodenoscopies and biopsies are to be obtained during the Screening period
   2. Biopsies will be read by a central pathologist
   3. Esophagogastroduodenoscopies and biopsies performed outside the study will not be accepted to meet eligibility criteria
   4. Optional biopsies may be taken and processed locally for local use, if specified in the local ICF. If serious pathology is unexpectedly encountered biopsies of such lesions must be processed locally

4. Have a subject-reported history of ≥6 episodes of dysphagia in the 14 days prior to baseline

5. Completion of the daily diary on at least 11 out of the 14 days during the 2-week Baseline Symptom Assessment

Exclusion Criteria:

1. Have known contraindication, hypersensitivity, or intolerance to corticosteroids
2. Have a contraindication to, or factors that substantially increase the risk of, EGD procedure or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope
3. Have history of an esophageal stricture requiring dilatation within the 12 weeks prior to Screening
4. Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the Investigator's judgment might interfere with study procedures or the ability of the subject to adhere to and complete the study or increase the safety risk to the subject such as uncontrolled diabetes or hypertension
5. History or presence of oral or esophageal mucosal infection whilst using inhaled or nasal corticosteroids
6. Have any mouth or dental condition that prevents normal eating (excluding braces)
7. Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease; hiatus hernia longer than 3 cm, Barrett's esophagus, and achalasia)
8. Use of systemic (oral or parenteral) corticosteroids within 60 days before Screening, use of swallowed corticosteroids within 30 days before Screening
9. Initiation of either inhaled or nasal corticosteroids or high-potency dermal topical corticosteroids within 30 days before Screening
10. Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks before Screening
11. Use of potent cytochrome P450 (CYP) 3A4 inhibitors (eg, ritonavir and ketoconazole) in the 12 weeks before Screening
12. Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF)
13. Morning (07:00 to 09:00, or as close to that window as possible) serum cortisol level ≤5 μg/dL (138 nmol/L) that is not responsive to adrenocorticotropic hormone (ACTH) stimulation: defined as a serum cortisol level <16 μg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test using 250 μg cosyntropin (i.e., an abnormal result on the ACTH stimulation test)
14. Use of biologic immunomodulators in the 24 weeks before Screening (allergy desensitization injection or oral therapy is allowed as long as the course of therapy is not altered during the study period)
15. Subjects who have initiated, discontinued, or changed dosage regimen of histamine H2 receptor antagonists, antacids or antihistamines for any condition such as gastro-esophageal reflux disease within 4 weeks before qualifying endoscopy during Screening. If already receiving these drugs, the dosage must remain constant throughout the study
16. Subjects who have changed dosage regimen of PPIs within 8 weeks before qualifying endoscopy. If already receiving PPIs, the dosage must remain constant throughout the study
17. Infection with hepatitis B, hepatitis C, or human immunodeficiency virus
18. Have gastrointestinal bleeding or documented active peptic ulcer within 4 weeks prior to Screening or entering a new study period
19. Have chronic infection such as prior or active tuberculosis, active chicken pox or measles or absence of prior measles, mumps and rubella vaccine. Subjects with tuberculosis exposure or who live in, or travel to, high endemic areas should be assessed locally for tuberculosis before consideration for the study
20. Immunosuppression or immunodeficiency disorder
21. Have a history or presence of Crohn's disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including eosinophilic gastroenteritis
22. Have current drug abuse in the opinion of the Investigator.
23. Have current alcohol abuse in the opinion of the Investigator.
24. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study
25. Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the End of Study visit
26. Have received an investigational product, as part of a clinical trial within 30 days (or 5 half-lives, whichever is longest) of Screening. Subjects who are currently participating in observational studies or enrolled in patient registries are allowed in this study
27. Have participated in a prior study with investigational product APT-1011