The primary objective of this study is to assess the efficacy of vonoprazan 20 mg once daily (QD) compared to placebo QD in the number of participants with a peak eosinophilic histologic response <15 eosinophils per high-power field (eos/hpf) after 12 weeks of therapy.

Inclusion Criteria:

• The participant is ≥18 years of age at the time of informed consent signing.
• In the opinion of the investigator or subinvestigators, the participant is capable of understanding and complying with protocol requirements, including completion and compliance with the electronic diary. The diary must be completed on at least 11 of the last 14 days in the 2 weeks prior to Visit 2 (Day -1).
• The participant signs and dates a written informed consent form (ICF) and any required privacy authorization prior to the initiation of any study procedures.
• The participant has a peak eosinophil count of at least 15 eos/hpf [X 400] from at least 2 of the 3 esophageal levels on screening endoscopy as measured in at least 6 biopsies, at least 2 each from the proximal, mid, and distal segments of the esophagus based on central reading.
• The participant has 4 or more days with dysphagia episodes documented via electronic diary in the 2 weeks prior to Visit 2 (Day -1).
• The participant must remain on a stable diet for at least 6 weeks prior to the Screening Period and is expected to remain on a stable diet during the course of the study; stable diet is defined as not initiating new elimination diets or reintroducing previously eliminated foods.
• A female participant of childbearing potential who is or may be sexually active with a non-sterilized male partner agrees to routinely use adequate contraception from the signing of informed consent until 4 weeks after the last dose of study drug.

Exclusion Criteria:

• The participant is on a pure liquid diet.

• The participant has documented erosive esophagitis at the screening endoscopy.

• The participant has other known causes of esophageal eosinophilia or either of the following conditions: hypereosinophilic syndrome, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome).

• The participant has a documented diagnosis of eosinophilic gastritis, duodenitis, jejunitis, ileitis, proctitis, or colitis.

• The participant has endoscopic Barrett's esophagus (>1 cm of columnar-lined esophagus) or dysplastic changes in the esophagus.

• The participant has a history of achalasia, Crohn's disease, ulcerative colitis, or celiac disease.

• The participant has a known active Helicobacter pylori infection.

• The participant has any other clinically significant structural conditions affecting the esophagus, including: esophageal varices, viral or fungal infection, and history of radiation therapy, radiofrequency ablation, endoscopic mucosal resection, cryotherapy to the esophagus, caustic or physiochemical trauma (including sclerotherapy or esophageal variceal band ligation), or esophageal surgery.

• The participant has a history of surgery or non-EoE endoscopic intervention, such as gastric bypass, fundoplication, gastric sleeve, or a history of gastric or duodenal surgery (except endoscopic removal of benign polyps).

• The participant has gastric ulcer(s) or duodenal ulcer(s) within 4 weeks before the first dose of study drug.

• The participant has had clinically significant upper or lower gastrointestinal bleeding within 4 weeks prior to the Screening Period.

• The participant has esophageal stricture(s) unable to be passed with an 8 to 10 mm endoscope, clinically requires dilation, or has a history of dilation within the 3 months prior to the Screening Period.

• Use of prescription or non-prescription PPIs or PCABs within 2 months prior to the Screening Period.

• Use of swallowed topical corticosteroid or budesonide oral suspension for EoE within 2 months prior to the Screening Period.

• Use of systemic corticosteroid for any condition within 3 months prior to the Screening Period.

• Use of inhaled or nasal glucocorticoids within 3 months prior to the Screening Period, except stable dose for at least 3 months prior to the Screening Period for any condition (should not be changed during the study).

• Use of dupilumab within 3 months prior to the Screening Period.

• The participant has received any investigational compound within 30 days or any investigational biologic within 3 months prior to the start of the Screening Period (including those in post-marketing studies) or vonoprazan in a clinical trial at any time. A participant who has been screen failed from another clinical study and who has not been dosed may be considered for enrollment in this study.

• The participant has used immunomodulatory therapy within 3 months prior to the Screening Period or anticipates using immunomodulatory therapy during the study (except for any ongoing regimen of allergy therapy).

• The participant is a study site employee, an immediate family member, is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling), or who may have consented under duress.

• The participant has a history of hypersensitivity or allergies to vonoprazan (including the formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, ascorbic acid, fumaric acid, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 8000, titanium oxide, or red ferric oxide). Skin testing may be performed according to local standard practice to confirm hypersensitivity.

• The participant has a history of alcohol abuse, illegal drug use, drug addiction or regularly consumes alcohol within the 12 months prior to the Screening Period (based on self-report). Participants must have a negative urine drug screen for non-prescribed medications at screening. Participants taking prescription drugs will be allowed. Occasional, recreational use of cannabis is allowed. However, participants with a cannabis use disorder (eg, frequent use, functional-social impairment, withdrawal symptoms) per the opinion of the investigator should be excluded.

• The participant is taking any excluded medications or treatments listed in the protocol.

• If female, the participant is pregnant, lactating, or intending to become pregnant before, during, or within 4 weeks after participating in this study, or intending to donate ova during such time period.

• The participant has a history or clinical manifestations of significant central nervous system, cardiovascular, pulmonary, metabolic, other gastrointestinal, urological, endocrine, or hematological disease that, in the opinion of the investigator, would confound the study results or compromise participant safety.

• The participant has a history of malignancy (including MALToma) or has been treated for malignancy within 5 years prior to the start of the Screening Period (Visit 1). The participant may be included in the study if he/she has recovered from cutaneous basal cell carcinoma or cervical carcinoma in situ.

• The participant has acquired immunodeficiency syndrome or human immunodeficiency virus infection, or tests positive for the hepatitis B surface antigen, hepatitis C virus (HCV) antibody, or HCV-ribonucleic acid (RNA). However, participants who test positive for HCV antibody but negative for HCV-RNA are permitted to participate.

• The participant has Zollinger-Ellison syndrome or other gastric acid hypersecretory conditions.

• The participant requires hospitalization or has surgery scheduled during the course of the study or has undergone major surgical procedures within 30 days prior to the Screening Period.

• The participant has moderate to severe hepatic impairment (Child-Pugh Class B and Child-Pugh Class C).

• The participant has severe renal impairment (estimated glomerular filtration rate <30 mL/min).

• The participant has any of the following abnormal laboratory test values at the start of the Screening Period:

  1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper limit of normal (ULN) or total bilirubin >2 × ULN (except participants with Gilbert Syndrome).
  2. Creatinine levels: >2 mg/dL (>177 μmol/L)

• The participant is refractory to prior PPI therapy as judged by the investigator.