Study background and disease burden
Eosinophilic oesophagitis (EoE) is a chronic, immune-mediated inflammatory disease characterized by eosinophil-predominant inflammation of the oesophagus, leading to symptoms such as dysphagia and food impaction. The condition currently presents substantial unmet medical needs due to limited effective therapies and frequent reliance on off-label treatments like proton pump inhibitors (PPIs), topical corticosteroids, and esophageal dilation. Novel therapeutic agents targeting the underlying immune pathways are urgently needed to improve long-term disease control and patient quality of life.
Etrasimod is an oral, once-daily, selective modulator of sphingosine 1-phosphate (S1P) receptors 1, 4, and 5. By modulating lymphocyte trafficking and immunologic activity, etrasimod has shown efficacy in other immune-mediated inflammatory diseases. Given the immunopathology of EoE, the selective targeting of the S1P pathway represents a promising therapeutic approach.
Study design
The VOYAGE study was a multicenter, double-blind, randomized, placebo-controlled phase 2 clinical trial conducted across 64 sites in Australia, Belgium, Spain, Switzerland, and the USA. Enrollment included adults aged 18 to 65 years with a prior diagnosis of EoE and histologically active disease at baseline.
Participants were randomized in a 3:3:2 ratio to receive oral etrasimod 2 mg, etrasimod 1 mg, or placebo once daily for 24 weeks (placebo-controlled period). Key stratification factors included history of oesophageal dilation and concurrent PPI use. Following this period, participants either continued their assigned dose or, if initially on placebo, were randomized 1:1 to etrasimod 2 mg or 1 mg for an additional 28-week extension phase.
The primary endpoint was the median percentage change from baseline in oesophageal peak eosinophil count (PEC) at week 16. Safety and tolerability were assessed through week 52.
Key findings
Between December 15, 2020, and May 27, 2022, 108 patients were randomized: 41 to etrasimod 2 mg, 39 to etrasimod 1 mg, and 28 to placebo. The cohort was balanced in terms of sex distribution. The full analysis set and safety populations included all patients receiving at least one dose of study medication.
At week 16, patients receiving etrasimod 2 mg exhibited a significant median reduction in PEC of -58.4% (interquartile range [IQR] -86.2 to -26.3) compared to a -21.5% change (IQR -57.2 to 55.4) in the placebo group (p=0.010). The 1 mg dose group showed a non-significant median reduction of -39.4% (IQR -71.1 to 79.0; p=0.29 vs placebo). Notably, 79% of patients completed the double-blind period and entered the extension phase, where histological improvements with continued etrasimod treatment were sustained over 52 weeks.
Regarding safety, gastrointestinal adverse events were the most frequently reported treatment-emergent events across all groups but were generally mild or moderate in severity. Bradycardia occurred in a minority of patients (5% in etrasimod 2 mg, 4% placebo) and was mild to moderate without leading to discontinuations. Importantly, no serious adverse events or deaths related to the study medication were reported.
Endoscopic findings corroborated histologic improvements, and symptom relief was particularly noted in patients who had not undergone oesophageal dilation.
Expert Commentary
The VOYAGE trial provides compelling evidence that S1P receptor modulation via etrasimod effectively reduces eosinophilic inflammation in EoE. The dose-related efficacy observed at 2 mg emphasizes the importance of adequate receptor engagement. The sustained histological and endoscopic improvements over one year suggest disease modification potential beyond symptomatic control.
Considering that current treatments often have incomplete efficacy or significant safety concerns, etrasimod introduces a novel mechanism that directly targets immune pathophysiology. While the trial’s relatively modest sample size and certain subgroup analyses warrant further evaluation in larger phase 3 studies, the results align well with the biological rationale and preclinical data related to S1P signaling modulation.
This trial sets a precedent for S1P receptor modulators in EoE therapeutic development and may prompt updates to guidelines pending confirmatory data.
Conclusion
Etrasimod represents a promising new oral therapeutic option for adults with eosinophilic oesophagitis, demonstrating significant and sustained reductions in oesophageal eosinophilic inflammation, endoscopic improvement, and favorable safety over 52 weeks. The VOYAGE phase 2 trial marks a critical step in validating the S1P pathway as a viable treatment target for EoE, addressing an important unmet need in this immune-mediated disease. Future phase 3 studies are warranted to confirm these findings and to explore long-term clinical outcomes and symptom control further.
References
1. Dellon ES, Collins MH, Bredenoord AJ, Philpott H, Biedermann L, Dulcine M, Nguyen-Cleary T, Su C, Yu J, Tan H, Cataldi F, Wu J, Wang W, Clax P, Woolcott JC, Hirano I. Etrasimod as a treatment for eosinophilic oesophagitis (VOYAGE): a double-blind, placebo-controlled, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2025 Jul;10(7):622-633. doi: 10.1016/S2468-1253(25)00062-7.
