Introduction
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by inflammation, influx of eosinophils and esophageal remodeling. Therapy for EoE includes swallowed/topical corticosteroids, dupilumab, proton pump inhibitors, and dietary elimination; but these are not always effective.
EP-104GI is an extended-release fluticasone propionate (FP) intra-esophageal injection being developed as a novel treatment for EoE. It consists of polymer-coated FP crystals that release drug locally via diffusion at a pre-defined rate to reduce peak concentrations and prolong the therapeutic window. Preclinical work in pigs has demonstrated that EP-104GI remains at injection sites for at least 6 weeks (duration of the study), with FP spreading 2-4 cm into the surrounding tissue.
Aims & Methods
RESOLVE (NCT05608681) is a Phase 1b, multicenter, open-label, 3+3 design dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of EP-104GI in patients with EoE. The starting dose of EP-104GI consisted of 1 mg injected at each of 4 sites in 4 quadrants over 2 circumferential areas in the esophagus (4 mg total dose). Dose escalations increase the dose per site and/or number of sites; the second and third cohorts received 1 mg and 2.5 mg respectively at each of 8 sites; the fourth cohort received 2.5 mg at 12 sites (8, 20, and 30 mg total doses). After a single administration of EP-104GI in these cohorts, participants are assessed for up to 24 weeks. Additional cohorts are planned to evaluate greater dose per injection site and/or increased number of injections with a longer duration of follow-up.
Assessments include Peak Eosinophil Count (PEC) from esophageal biopsies at 16 sites, patient-reported symptom outcomes including the Straumann Dysphagia Index (SDI) and Likert scales for dysphagia and odynophagia, and plasma concentrations of FP. Adverse events (AEs) and laboratory tests including serum glucose and cortisol are assessed.
Results
Cohort 1-3 safety observations include mild-moderate AEs; the majority not related to EP-104GI. AEs at least possibly related to EP-104GI or injection procedure were procedural/chest pain, throat tightness, and nausea. Glucose levels post-dose have remained stable. Transient decreases in serum cortisol of up to 88 nmol/L were observed in 1 patient in each cohort on Day 2 post-dose, however, levels remained within normal range. There have been no symptoms of adrenal insufficiency.
Response data from Cohorts 1 and 2 (Table 1) demonstrate a decrease from baseline in symptom scores at Weeks 12 and 24. Reduction in mean PEC has been observed in all patients in Cohort 2, with a trend indicating that increasing the total dose of EP-104GI results in a more consistent reduction in PEC at the 16 biopsy sites assessed.
Table 1: Patient-reported symptom outcomes, peak eosinophil count (PEC), and plasma fluticasone propionate (FP) after a single dose of EP-104GI
| Cohort 1 (1 mg × 4 sites, total 4 mg)
| Cohort 2 (1 mg × 8 sites, total 8 mg)
|
|---|
Mean change from baseline (CFB) in Straumann Dysphagia Index (0-9) at Weeks 12 and 24
| -4.0, -4.0
| -2.7, -3.3
|
Mean CFB in Dysphagia (0-10) at Weeks 12 and 24
| -4.0, -5.0
| -4.3, -4.0
|
Mean CFB in Odynophagia (0-10) at Weeks 12 and 24
| -2.0, -3.0
| -5.7, -4.3
|
Mean CFB in PEC at Weeks 4 and 12 (cells/hpf from 16 sites)
| No reduction observed
| -26%, -44%
|
Mean plasma concentration of FP at 2 hours post-dose (pg/mL)
| 4.3
| 11.2
|
Conclusion
A novel diffusion-based localized delivery of FP via EP-104GI injection into the esophagus is feasible and safe in patients with EoE in this initial escalating dose cohort study. Initial efficacy data show improvement in symptom outcomes and histological findings which may increase with dose. These findings support the potential for extended intervals of at least 6 months between injections. Recruitment is ongoing.
Disclosure
JH, AM, MMK, CD, AL, VP and MW: employees of Eupraxia Pharmaceuticals
ED: Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio Educational grant: Allakos, Aqilion, Holoclara, Invea
HHK: advisory board and speaker's bureau for Sanofi.
AJB: received research funding from Nutricia, Thelial, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Reckitt and AstraZeneca
NG: nothing to declare
