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.