Introduction

Eosinophilic esophagitis (EoE) is a chronic and progressive Type 2 inflammatory disease with a significant unmet need for effective and safe long-term targeted therapy. Cendakimab (CEN) is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) thereby blocking interaction with its receptors, IL-13Rα1 and IL-13Rα2. CEN is currently under clinical development for the treatment of EoE. Here, we present the results of 2 phase 1, randomized, single-center, single-dose trials assessing the pharmacokinetics (PK), safety, and tolerability of CEN in healthy Chinese (NCT05638282) and US (NCT05337345) populations.

Aims & Methods

In the China study (NCT05638282), healthy participants (age, 18–55 years; body mass index [BMI], 18.0–28.0 kg/m²; weight, ≥50.0 kg) were sequentially assigned to 2 groups. Participants in each group were randomized 5:1 to receive: group 1, single-dose CEN 360 mg subcutaneous (SC) via 1 injection (n=10) or placebo (n=2), and group 2, single-dose CEN 720 mg SC via 2 injections (n=10) or placebo (n=2). All doses were administered in the abdomen using an autoinjector (AI). In 1 of 4 groups of the US study (NCT05337345), healthy participants (age, 18–55 years; BMI, 18.0–30.0 kg/m²; weight, ≥40.0 kg) received single-dose CEN 360 mg SC via 1 injection in the abdomen using an AI (n=32). Data from groups that received CEN via AI are presented here. The PK parameters assessed in both studies were maximum observed serum concentration (C_max), time of C_max (T_max), area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC_0-T), AUC from time 0 to infinite time (AUC_∞), terminal elimination half-life (T_1/2), apparent total body clearance (CL/F), and apparent volume of distribution of terminal phase (Vz/F). Safety and tolerability were also evaluated.

Results

Demographic characteristics were generally similar in the China and US studies, eg. median BMI was 23 and 26 kg/m², respectively. In the China study, following SC doses of 360 and 720 mg, the absorption of CEN was slow, with a median T_max of 96 and 143 hours; mean T_1/2 was 565 and 535 hours, and Vz/F was 11.8 and 10.7 liters, respectively (Table). The geometric mean C_max, AUC_∞, and AUC_0-T increased in a dose-proportional manner between the 360 and 720 mg CEN doses. Antidrug antibodies (ADAs) were detected in 50% of participants in each of the 360 and 720 mg CEN groups, with a low titer in most of them. Results for the 360 mg AI group from the China study were consistent with those of the 360 mg AI group in the US study. ADAs were detected in 16% of the participants in the US study. In both studies, the ADA response did not impact the safety or PK of CEN, and CEN (360 mg or 720 mg) was well tolerated with no deaths, serious adverse events (AEs), or discontinuations due to an AE.

Conclusion

Single-dose 360 mg or 720 mg SC CEN was safe and well tolerated in all healthy participants. CEN PK was generally dose-proportional for C_max and AUC from 360 mg to 720 mg. Overall, the PK, tolerability, and safety profiles of a single dose of 360 mg SC CEN in the China study were consistent with those observed in the US study, supporting the use of similar doses across both populations.

Table. Summary of serum pharmacokinetic parameters^a

Disclosure

YC and SP have nothing to disclose; CX, SB, BW, YQ, KY, BM, and PZ are employees of Bristol Myers Squibb; LL, JR, WK, BY, CDO, MT, JM, PZ are employees and stockholders of Bristol Myers Squibb

Introduction

Currently there is no single strategy that has a clear benefit as primary therapy for Eosinophilic Esophagitis (EoE). Because of the continuous emergence of randomized clinical trials on various pharmacological and nonpharmacological approaches, we conducted a network meta-analysis in order to evaluate the efficacy and safety of available treatments for EoE in adult patients.

Aims & Methods

Histologic remission, clinical and endoscopic response, and serious adverse events (SAEs) were evaluated. Direct and indirect comparisons between treatments (proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), monoclonal antibodies (mAb), placebo) were performed. Results are expressed as risk ratio (RR) and 95% confidence interval (CI).

Results

A total of eight eligible randomized controlled trials (1057 patients) were included in the meta-analysis. When the three interventions were compared with each other, none was significantly more effective in terms of histologic remission (STC vs mAb RR 5.03, 95% CI 0.96-26.24, PPI vs mAb RR 0.87, 95% CI 0.41-3.12, PPI vs STC RR 0,75, 95% CI 0.60-5.09) while all three interventions were significantly superior to placebo (mAb vs placebo RR 31, 95% CI 10.91-88, STC vs placebo RR 54.26, 95% CI 12.1-241.83, PPI vs placebo RR 10.78, 95% CI 5.33-21.78). STC and mAB resulted as the best interventions (SUCRA 0.93 and 0.78, respectively) followed by PPI (SUCRA 0.38). None of the interventions tested resulted in a significant increase in SAE rate compared with placebo (mAb vs placebo RR 3.41, 95% CI 0.61-19.12, STC vs placebo RR 1.28, 95% CI 0.25-6.44). As a consequence, placebo ranked as the safest treatment (SUCRA 0.73), followed by STC (SUCRA 0.63) and mAb (SUCRA 0.51).

Conclusion

The results of this network meta-analysis show that mAb and STC were the most effective treatments among those available for EoE as assessed by histologic remission, both with a relatively low rate of serious adverse events.

Introduction

Cendakimab is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) and blocks interaction with both its receptors, IL-13Rα1 and IL-13Rα2. IL-13 is a cytokine implicated in the pathogenesis of atopic dermatitis (AD) and is thought to be a key driver of the complex pathophysiology of eosinophilic esophagitis (EoE). IL-13 signals through both IL-13Rα1 and IL-13Rα2 to regulate cellular and molecular pathways across a variety of cell types. The binding of IL-13 to IL-13Rα1 promotes a Type 2 immune response and eosinophil recruitment, whereas the binding of IL-13 to IL-13Rα2 is believed to play a role in fibrosis and epithelial tissue remodeling. Several biomarkers associated with Type 2 inflammatory diseases are known to be regulated by IL-13. Eotaxin-3, a key biomarker, plays a central role in attracting eosinophils to the site of inflammation. Periostin, an extracellular matrix protein linked to activated fibroblasts, is implicated in tissue remodeling and fibrosis. Another enzyme governed by IL-13 is matrix metalloproteinase-12 (MMP-12)—this enzyme contributes to tissue remodeling and breakdown of extracellular matrix components. Here, we evaluate the pharmacodynamic effects of IL-13 inhibition with cendakimab on the key serum biomarkers eotaxin-3, periostin, and MMP-12 in patients with AD, with a focus on exploring potential implications for EoE.

Aims & Methods

In this phase 2, multicenter, global, randomized, double-blinded, placebo-controlled, parallel-group study (NCT04800315), 220 adults with moderate-to-severe AD received cendakimab 360 mg Q2W, 720 mg QW, 720 mg Q2W, or placebo for 16 weeks. Blood samples were collected, and a panel of biomarkers were assessed. The current analysis focuses on the assessment of serum levels of eotaxin-3, periostin, and MMP-12 using Proximity Extension Assay pre- and post-treatment on day 1 (baseline), at week 1 and week 2, and then biweekly until week 16. The least square mean percent change from baseline at week 16 for each treatment group was evaluated.

Results

For all 3 doses of cendakimab, there was a significant decrease from baseline in the levels of eotaxin-3, periostin, and MMP-12 as early as week 1 post-treatment and continued through week 16 of cendakimab treatment (Table). Compared with placebo, cendakimab resulted in significantly greater reductions in these biomarker levels through week 16.

Conclusion

Cendakimab decreased levels of key inflammatory and remodeling biomarkers over 16 weeks of treatment in patients with AD. These findings suggest that cendakimab modulates pathways of inflammation, fibrosis, and tissue remodeling in AD and add to the existing clinical evidence of its modulation in other Type 2 inflammatory diseases such as EoE.
​
Table. Least square mean percent change from baseline in key serum biomarker levels at week 16 in patients with AD

Disclosure

ESD served as a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GlaxoSmithKline, 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, received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/ Bristol Myers Squibb, Regeneron, Revolo, Shire/Takeda, and received educational grant from Allakos, Aqilion, Holoclara, and Invea. JL, SH, LG, CDO, and CC are employees and stockholders of Bristol Myers Squibb. JS served as consultant for Abbvie, Alamar, Aldena, Amgen, AObiome, Apollo, Arcutis, Arena, Asana, Aslan, Attovia, BioMX, Biosion, Bodewell, Boehringer-Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant, Eli Lilly, FIDE, Galderma, GlaxoSmithKline, Incyte, Invea, Kiniksa, Leo Pharma, Merck, My-Or Diagnostics, Nektar, Novartis, Optum, Pfizer, RAPT, Recludix, Regeneron, Sandoz, Sanofi-Genzyme, Shaperon, TARGET-RWE, Teva, Union, UpToDate, participated on a data safety monitoring board or advisory board for Biosion and Sanofi, received grants or contracts from Galderma, Incyte, Pfizer, received honoraria from Abbvie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, Sanofi-Genzyme.

Introduction

Eosinophilic esophagitis (EoE) is a chronic, progressive Type 2 inflammatory disease characterized by esophageal dysfunction and eosinophilic inflammation. Interleukin (IL)-13 is a key mediator in the pathogenesis of EoE. Cendakimab, a humanized monoclonal anti–IL-13 antibody, lowered esophageal eosinophil counts and improved dysphagia, histologic and endoscopic measures of inflammation, and fibrosis in a phase 2 trial of patients with EoE regardless of steroid response. Previous studies have shown that cendakimab reversed the expression of genes and molecular pathways involved in EoE pathogenesis vs placebo, including genes involved in IL-13 signaling, remodeling, and epithelial differentiation. Transcript changes correlated with histological and endoscopic findings. In this substudy, we performed a detailed analysis of the relationship between endoscopic responder populations and changes in tissue transcript expression.

Aims & Methods

In a double-blind, placebo-controlled phase 2 trial (NCT02098473), patients with EoE received cendakimab 180 mg or 360 mg once weekly or placebo. This substudy evaluated the impact of systemic cendakimab treatment on local esophageal gene expression, as well as correlations between gene expression and endoscopic outcomes (endoscopic reference score [EREFS] range, 0–18). EoE-related transcripts were quantified in biopsies collected at baseline and at week 16.

Results

POSTN (r=0.43; P<0.0001) and ALOX15 (r=0.43; P<0.0001) showed the strongest correlation with total EREFS across placebo and cendakimab groups. Endoscopic responders on cendakimab (post-treatment EREFS <2) exhibited improved expression of 33 genes vs baseline. Interestingly, endoscopic nonresponders showed improvement in the same 33 genes plus 6 additional genes (ALOX12, GRPEL2, UPK1A, SPINK7, FAM25A, SPRR2D). Patients with endoscopic improvement (post-treatment EREFS decrease ≥4) showed normalization in a subset of genes (n=15, including TPSB2/TPSAB1, CPA3, and TGFB1) that did not reverse in patients showing less EREFS improvement. However, patients with less EREFS improvement (post-treatment EREFS decrease <4) showed corrected expression of 2 key epithelial genes, SPINK7 and UPK1A, that did not reverse in in patients with endoscopic improvement.

Conclusion

Molecular analysis of biopsies from patients with EoE demonstrates that after 16 weeks of treatment with cendakimab, endoscopic responders and nonresponders both show improvement in gene expression. Heterogeneous changes in inflammatory-, mast cell-, and epithelial-related genes may impact endoscopic findings. These findings indicate that cendakimab broadly modifies molecular biomarkers even in patients who do not show early endoscopic improvement, raising the possibility that biomarker improvement may precede endoscopic changes in some patients.

Disclosure

JMC, AYB, and MER have no relationship/activities/interests to disclose. JL, SH, and RM are employees at Bristol Myers Squibb. ESD served as a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GlaxoSmithKline, 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, received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/ Bristol Myers Squibb, Regeneron, Revolo, Shire/Takeda, and received educational grant from Allakos, Aqilion, Holoclara, and Invea.

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

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.