VOYAGE trial

The **VOYAGE trial** was a **phase 2 clinical study** designed to evaluate the efficacy, safety, and tolerability of **etrasimod**, an investigational oral therapy, in adults with **eosinophilic esophagitis (EoE)**. Below is a detailed summary of the trial:

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### **Background and Clinical Need**

• **Eosinophilic Esophagitis (EoE)** is a chronic allergic inflammatory disease of the esophagus characterized by symptoms such as **dysphagia** (difficulty swallowing), **food impaction**, and **reduced quality of life**.
• Current standard treatments (e.g., swallowed corticosteroids, proton pump inhibitors, and biologic therapies like dupilumab) have limitations, including **partial efficacy**, **long-term safety concerns**, and the lack of **approved oral small-molecule therapies**.
• **Etrasimod** is a promising candidate for EoE treatment due to its mechanism of action as a **selective sphingosine 1-phosphate (S1P1,4,5) receptor modulator**, which reduces **lymphocyte trafficking** and inflammation. It has previously shown efficacy in other immune-mediated diseases, such as **ulcerative colitis**.

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### **Trial Design**

• **Type**: Randomized, double-blind, placebo-controlled phase 2 study.
• **Duration**: Conducted between 2020–2022.
• **Locations**: 64 sites across five countries.
• **Participants**: 108 adults aged 18–65 years with **histologically active EoE** (≥15 eosinophils per high-power field [eos/hpf] and ≥2 dysphagia episodes per week).
• **Groups**:
• **41 patients** received etrasimod 2 mg.
• **39 patients** received etrasimod 1 mg.
• **28 patients** received placebo.

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### **Baseline Characteristics**

• Patients had a **mean disease duration** of 4–5 years.
• Many had prior therapies: ~60% had used corticosteroids, ~40% used proton pump inhibitors (PPI).
• High disease activity was noted:
• **Mean Dysphagia Symptom Questionnaire (DSQ)** score: ~33.
• **Peak eosinophil count (PEC)**: ~110 eos/hpf.
• **Endoscopic Reference Score (EREFS)**: ~3.7.

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### **Primary Endpoint**

• **Week 16:** Reduction in **peak eosinophil count (PEC)**:
• **Etrasimod 2 mg**: –58.4% reduction (**p=0.010 vs placebo**).
• **Etrasimod 1 mg**: –39.4% reduction (**p=0.29 vs placebo**).
• **Placebo**: –21.5% reduction.
• The 2 mg dose demonstrated **significant efficacy** in reducing eosinophilia compared to placebo.

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### **Key Efficacy Outcomes**

1. **Histologic Remission**:

• **Week 16**: 22% of patients on **etrasimod 2 mg** achieved histologic remission (**PEC <15 eos/hpf**), compared to **0% on placebo**.
• **Week 24**: Remission rates increased to **32%** for the 2 mg group.

2. **Deeper Remission**:

• **Week 16**: 22% of patients on **etrasimod 2 mg** achieved deeper remission (**PEC ≤6 eos/hpf**), compared to **0% on placebo**.

3. **Symptom Improvement**:

• **Dysphagia Symptom Questionnaire (DSQ)**: Significant improvement at **week 24** in non-dilated patients on **etrasimod 2 mg** (–21.6 vs –9.6 placebo, **p=0.031**).
• **Patient Global Impression of Severity (PGI-S)**: Improved significantly with **2 mg** at week 24 (**p=0.012**).

4. **Endoscopic Improvement**:

• **EREFS score**: Improved with **etrasimod 2 mg** at week 16 (–1.0, **p=0.014**) and sustained at week 24 (–0.9, **p=0.030**).

5. **Histology Scores**:

• Both doses of etrasimod led to significant improvements in **Histologic Scoring System (HSS)** grade and stage at week 24 (**p<0.0001**) and sustained benefits through **week 52**.

6. **Durability**:

• Improvements in eosinophilia, histology, and endoscopy were maintained during the **28-week extension phase**, demonstrating **long-term efficacy**.

7. **Rescue Therapy**:

• Fewer patients required rescue therapy on **etrasimod** (10%) compared to placebo (18%), indicating better disease control.

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### **Mechanism of Action**

• **Peripheral lymphocyte counts** decreased dose-dependently:
• **60% reduction** with etrasimod 2 mg.
• **37% reduction** with etrasimod 1 mg (**p<0.0001**).
• This is consistent with etrasimod's immune-modulating mechanism of reducing **lymphocyte trafficking**.

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### **Safety Profile**

1. **Adverse Events (AEs)**:

• Treatment-emergent adverse events (TEAEs) occurred in:
• **71%** (etrasimod 2 mg).
• **69%** (etrasimod 1 mg).
• **75%** (placebo).
• Most AEs were **mild-to-moderate**, with gastrointestinal events being the most frequent.

2. **Common AEs**:

• Nausea, food impaction, and COVID-19 were reported.
• No deaths, macular edema, or serious safety signals were observed.

3. **Cardiac Safety**:

• Mild bradycardia occurred in two patients on **etrasimod 2 mg** and one on placebo, all resolving without intervention.
• This supports a **manageable cardiac risk** profile.

4. **Comparative Tolerability**:

• GI-related adverse events were more frequent in **placebo (50%)** than in etrasimod groups (27–33%), indicating **good tolerability** of the drug.

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### **Clinical Implications**

The **VOYAGE trial** demonstrated that **etrasimod 2 mg** provides significant **histologic, endoscopic, and symptomatic improvements** in adults with EoE. These findings establish proof of concept for **oral S1P receptor modulation** as a promising new therapeutic class for EoE. The drug also showed a **favorable safety profile** and long-term durability, making it a potential alternative to existing treatments for this challenging condition.