P0390 - Efficacy and Safety of IRL201104, a Novel Peptide Immunomodulator, in a Phase 2a, Double-Blind, Placebo-Controlled Multi-Center Study in Patients With Active Eosinophilic Esophagitis

Sunday, October 22, 2023

3:30 PM – 7:00 PM PT

Location: Exhibit Hall

Has Audio

Presenting Author(s)

ED

Evan S. Dellon, MD, MPH

University of North Carolina School of Medicine
Chapel Hill, North Carolina

Award: Presidential Poster Award

Evan S. Dellon, MD, MPH¹, Michael D. Kulis, PhD¹, Jorge De Alba, BSc, PhD², Lara Ravanetti, BSc, PhD², Philip Tong, ³, Nancy T. Vinh, ³, Roly Foulkes, BSc, PhD², Jones W. Bryan, PhD³
¹University of North Carolina School of Medicine, Chapel Hill, NC; ²Revolo Biotherapeutics, London, England, United Kingdom; ³Revolo Biotherapeutics, New Orleans, LA

Introduction: Novel treatments are needed for eosinophilic esophagitis (EoE). IRL201104 is a novel immunomodulatory peptide derived from mTB Chaperonin 60.1 with a short half-life (~10-15mins) but long-lasting pharmacodynamic effect across multiple inflammatory cell types in preclinical models. The aim of this Phase 2a trial (NCT05084963) was to evaluate the safety, efficacy, and effect on biomarkers of IRL201104 in EoE patients.

Methods: This randomized double-blind placebo controlled study enrolled 36 adults with active EoE (1:1:1 randomization to 8mg, 4mg, or placebo). Patients had to have at least 2 episodes of dysphagia per week and a screening biopsy with ≥15 eos/hpf in at least 2 of 3 esophageal regions. Enrolled patients were administered 3 intravenous doses of IRL201104 or placebo weekly over 2 weeks with repeat esophageal biopsy at 4 weeks. Primary outcome was change from baseline in peak intraepithelial count at week 4. Biopsies were collected for histology, flow cytometry and transcriptomics and blood for PBMC immunophenotyping.

Results: There were no serious adverse events (SAEs), discontinuations from AEs, or safety signals in this study (Table 1). Most frequent AEs were constipation, nausea, headace, and fatigue. Most AEs were mild or moderate, with no severe related AEs. Esophageal biopsies demonstrated a dose-dependent reduction in peak intraepithelial eosinophil counts in patients on IRL201104 compared to placebo [Fig 1A/B]. Flow cytometry confirmed the reduction in tissue eosinophil counts [Fig 1C] and demonstrated significant reduction in tissue CD8+ lymphocytes in the 8mg group [Fig 1D], as well as a marked increase in regulatory T cells (Tregs) in the same group [Fig 1E]. Interestingly, there was also a significant increase in regulatory B cells (Bregs) in peripheral blood from patients in the 8mg group [Figure 1F]. Additionally, there were associated improvements in expression of genes related to EoE pathogenesis.

Discussion: IRL201104 was well tolerated and showed a dose-dependent reduction in tissue peak eosinophil counts. IRL201104 also impacted genes associated with EoE pathogenesis and several upstream markers of inflammation, including Tregs and Bregs. The effect on Tregs, critical for downregulating inflammatory responses, as well as the novel finding of an effect on Bregs, with a growing role in immune tolerance, supports further research of IRL201104 as a treatment for EoE.

Figure: Figure 1. Histology: (A) Eosinophils per High-Powered Field: numerical change from baseline. Statistical comparison V4 vs screen group carried out in raw absolute data using Student’s paired t-test for each individual group (*P<0.05); n=8(placebo); 11(4mg); 13(8mg; (B) Eosinophils per High-Powered Field: % change from baseline; Biopsy Flow Cytometry: (C) Eosinophils:% change from baseline; (D) CD8+ lymphocytes (% total CD3+):% change from baseline ; (E) Treg lymphocytes: % change from baseline. Statistical comparison V4 vs screen group carried out in raw absolute data using Student’s unpaired t-test for each individual group (*P<0.05; **P<0.01); n=9(placebo); 8(4mg); 8(8mg); Blood Flow Cytometry:(F) B regs: % change from baseline. Statistical comparison V4 vs screen group carried out in raw absolute data using Student’s unpaired t-test for each individual group (**P<0.01); n=7(placebo); 11(4mg); 12(8mg).

Category	IRL201104 4 mg N=11 n(%)	IRL201104 8 mg N=13 n(%)	Placebo N=12 n(%)	Overall N=36 n(%)
Number of participants who had a TEAE	6 (54.5)	7 (53.8)	7 (58.3)	20 (55.6)
Number of participants who had a serious TEAE	0	0	0	0
Number of participants who had a treatment related TEAE	3 (27.3)	0	5 (41.7)	8 (22.2)
Number of participants who had a treatment related serious TEAE	0	0	0	0
Number of participants who had a TEAE leading to study discontinuation	0	0	0	0

Table: Overview of Adverse Events (Safety Analysis Set).
Abbreviations: AE = adverse event; AESI = adverse event of special interest; IP = investigational product; IV = intravenous; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event; TEAE = treatment-emergent adverse event. N = The total number of participants in each treatment group under the stated population. n = Number of participants with non-missing data within the specific category. Percentages were based on N. ‘Treatment-emergent’ was defined as starting or worsening after the first dose of IP. Adverse events were coded using MedDRA Version 24.0.

Disclosures:

Evan Dellon: Abbott – Consultant. Abbvie – Consultant. Adare/Ellodi – Consultant, Grant/Research Support. Aimmune – Consultant. Akesobio – Consultant. Alfasigma – Consultant. ALK – Consultant. Allakos – Consultant, Grant/Research Support. Amgen – Consultant. Aqilion – Consultant. Arena/Pfizer – Consultant, Grant/Research Support. Aslan – Consultant. AstraZeneca – Consultant, Grant/Research Support. Avir – Consultant. Banner Pharmaceuticals – Grant/Research Support. Biorasi – Consultant. Calypso – Consultant. Celgene/Receptos/BMS – Consultant, Grant/Research Support. Celldex – Consultant. Eli Lilly – Consultant. EsoCap – Consultant. Eupraxia – Consultant. Ferring – Consultant. Gossamer Bio – Consultant. GSK – Consultant, Grant/Research Support. Holoclara – Consultant, Grant/Research Support. Invea – Consultant, Grant/Research Support. Knightpoint – Consultant. Landos – Consultant. LucidDx – Consultant. Meritage – Grant/Research Support. Miraca – Grant/Research Support. Morphic – Consultant. Nexstone Immunology – Consultant. Nutricia – Consultant, Grant/Research Support. Parexel/Calyx – Consultant. Phathom – Consultant. Regeneron Pharmaceuticals Inc. – Consultant, Grant/Research Support. Revolo Biotherapeutics – Consultant, Grant/Research Support. Robarts/Alimentiv – Consultant. Salix – Consultant. Sanofi – Consultant. Shire/Takeda – Consultant, Grant/Research Support. Target RWE – Consultant. Upstream Bio – Consultant.

Michael Kulis: Revolo Biotherapeutics – Grant/Research Support.

Jorge De Alba: Revolo Biotherapeutics – Employee, Stock Options.

Lara Ravanetti: Revolo Biotherapeutics – Employee, Stock Options.

Philip Tong: Revolo Biotherapeutics – Employee, Stock Options.

Nancy Vinh: Revolo Biotherapeutics – Employee, Stock Options.

Roly Foulkes: Revolo Biotherapeutics – Employee, Stock Options.

Jones Bryan: Revolo Biotherapeutics – Employee, Stock Options.

Evan S. Dellon, MD, MPH¹, Michael D. Kulis, PhD¹, Jorge De Alba, BSc, PhD², Lara Ravanetti, BSc, PhD², Philip Tong, ³, Nancy T. Vinh, ³, Roly Foulkes, BSc, PhD², Jones W. Bryan, PhD³. P0390 - Efficacy and Safety of IRL201104, a Novel Peptide Immunomodulator, in a Phase 2a, Double-Blind, Placebo-Controlled Multi-Center Study in Patients With Active Eosinophilic Esophagitis, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.