Introduction
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by inflammation, an influx of eosinophils and esophageal remodeling. Therapy for EoE includes proton-pump inhibitors, swallowed topical corticosteroids, dupilumab, and dietary elimination, but these are not always effective and have potential side effects.
EP-104GI is a long-acting fluticasone propionate (FP) injectable suspension being developed as a first-in-class treatment for EoE. EP-104GI consists of coated FP crystals that release at a pre-defined rate via diffusion at the injection site. Steady-state diffusion reduces peak concentrations while prolonging the therapeutic window.
RESOLVE (NCT05608681) is a Phase 1b/2a, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, feasibility, pharmacokinetics, and efficacy of EP-104GI in adults with symptomatic and histologically confirmed active eosinophilic esophagitis.
Aims & Methods
In this study, EP-104GI is injected at multiple sites in alternating quadrants at 2 cm intervals in the esophagus. Dose escalations increase the dose per injection site and/or number of sites, with the 6th cohort receiving 4 mg at 16 sites (64 mg total dose). After a single administration of EP-104GI, participants are followed for 24 weeks (cohorts 1-4) or 52 weeks (cohorts 5+). Safety assessments include adverse events and laboratory tests. Efficacy assessments include histological endpoints and patient-reported symptom outcomes, including the Straumann Dysphagia Index (SDI) and EoE Histologic Scoring System (EoEHSS). Esophageal biopsies are collected at baseline, Weeks 4, 12, and 36.
Results
Previously reported data from cohorts 3-5 (total doses 20-48 mg) showed symptom (SDI) reductions at Week 12 for 8/9 patients, the majority maintained to Week 24. Mean peak eosinophil count declined for 7/9 participants at Week 12, including one patient who achieved <6 eosinophils/hpf at all sites assessed, representing complete histological remission.
In Cohort 6, all three participants experienced a significant reduction in peak eosinophil count compared to baseline, ranging from 59 to 91% by Week 12. Symptoms (SDI) decreased for all 3 participants to Week 12, with a peak reduction of up to 6 points (0-9 scale). Histology scores have shown a progressively greater decrease from baseline with increasing EP-104GI dose. In Cohort 6 at Week 12, mean EoEHSS stage reduction was 66% or 0.40 points (composite score of 0-1) and mean EoEHSS grade reduction was 65% or 0.38 points (Table 1).
Plasma FP levels increased with dose and in Cohort 6 were stable at <25 pg/mL after the initial peak. Treatment-emergent adverse events were mild to moderate, most unlikely related to EP-104GI. Serum glucose and cortisol were stable post-dose with no adverse events such as candidiasis or adrenal suppression.
Table 1: Change from Baseline in EoEHSS, SDI, PEC, and mean plasma FP after a single dose of EP-104GI
| | Cohort 3 (n=3)
2.5 mg × 8 sites
Total 20 mg | Cohort 4 (n=3)
2.5 mg × 12 sites
Total 30 mg | Cohort 5 (n=3)
4 mg × 12 sites
Total 48 mg | Cohort 6 (n=3)
4 mg × 16 sites
Total 64 mg |
| Mean change from baseline (CFB) in composite EoEHSS grade / stage at Week 12 | -7% / -15% | -37% / -39% | -54% / -54% | -65% / -66% |
| Mean CFB in Straumann Dysphagia Index at Week 12 / Week 24 | -28% / -17% | -45% / -55% | -41% / -82% | -47% / TBD |
| Mean CFB in PEC at Week 12 from 16 biopsy sites | -13% | 1% | -32% | -79% |
| Percentage of biopsy sites in remission (PEC ≤6) at Week 12 | 19% | 29% | 38% | 62% |
| Mean plasma concentration of FP at 2 hours post-dose (pg/mL) | 37.2 | 35.5 | 39.6 | 91.7 |
Conclusion
These data support that local delivery of FP via EP-104GI has been feasible and safe in the ongoing study. Higher doses yield improved patient responses such as histological remission, enhanced patient-reported symptom scores, and favorable histology results, without the occurrence of corticosteroids-related side effects.
Disclosure
AM, JH, MMK, CD, VP: Employees of Eupraxia Pharmaceuticals. HHK, GH: Nothing to declare. WA: Speaker, advisory board member, and a clinical investigator for Abbvie, Amgen, Avir Pharma, Eli-Lilly, Eupraxia, Janssen, JAMP Pharma, Merck, Pfizer, Roche, Sandoz, Sanofi, Takeda. GH: TBD. ESD: Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Sanfoi, Shire/Takeda, Uniquity; Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apogee, 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, Third Harmonic Bio, Upstream Bio Educational grant: Allakos, Aqilion, Holoclara, Invea. AJB: Research funding: 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.
