Introduction

Eosinophilic oesophagitis (EoE) is a rare, chronic, inflammatory disorder with few approved treatments. Thymic stromal lymphopoietin (TSLP) is a pro-inflammatory epithelial cytokine. TSLP genetic variants are associated with EoE risk, and oesophageal TSLP mRNA and protein levels are elevated in patients with active EoE. Tezepelumab, a human monoclonal antibody approved for the treatment of severe asthma, specifically binds to and blocks the activity of TSLP.

Aims & Methods

This analysis aimed to determine whether TSLP-mediated gene expression changes are enriched in patients with EoE to understand whether tezepelumab could be a potential treatment for EoE. Gene signature analyses were performed to generate TSLP gene lists from two independent transcriptomic data sets obtained from: 1) bronchial brushings at week 28 from patients with moderate-to-severe, uncontrolled asthma, treated with tezepelumab in the phase 2 CASCADE study (NCT03688074); and 2) human myeloid dendritic cells (mDCs) treated ex vivo with recombinant TSLP for 24 hours. Using these TSLP gene lists, gene set variation analyses were performed on publicly available gene expression data from oesophageal biopsies in healthy individuals and patients with chronic oesophagitis, active untreated EoE, inactive treated EoE (responsive to swallowed topical corticosteroids [STCs]) and active treated EoE (unresponsive to STCs).

Results

The TSLP gene lists comprised 18 upregulated genes and 32 downregulated genes in bronchial brushings from CASCADE, and 183 upregulated and 161 downregulated genes in human mDCs. The TSLP gene scores from bronchial brushings were elevated in patients with active EoE, untreated and unresponsive to STCs, compared with healthy individuals (upregulated genes: p≤0.05 and p≤0.001, respectively; downregulated genes: p>0.05 and p≤0.01, respectively). The TSLP gene scores from human mDCs were elevated in patients with active EoE, untreated and unresponsive to STCs, compared with healthy individuals (upregulated genes: p≤0.05 and p≤0.01, respectively; downregulated genes: p≤0.05 and p≤0.001, respectively). In both data sets, compared with patients who had inactive treated EoE, TSLP gene scores were elevated in patients with active treated EoE that was unresponsive to STCs (upregulated genes: p<0.001; downregulated genes: p≤0.05 [bronchial brushings] and p≤0.0001 [human mDCs]). These data support clinical evaluation of tezepelumab in the treatment of EoE, which is being conducted in the ongoing phase 3 CROSSING study (NCT05583227). CROSSING is a double-blind, placebo-controlled study that will evaluate the efficacy and safety of tezepelumab in approximately 360 patients (12–80 years old) with symptomatic and histologically active EoE. Patients will be randomized (1:1:1) to receive one of two dose options for tezepelumab or placebo subcutaneously every 4 weeks for 52 weeks. The study includes an optional 24-week active treatment extension period in which patients previously receiving placebo will be re-randomized to receive one of the two tezepelumab doses. The co-primary endpoints are to assess the effect of tezepelumab on symptom improvement and histologic response.

Conclusion

Gene lists indicative of elevated TSLP activity were enriched in patients with active EoE (untreated or unresponsive). These data suggest that blocking TSLP with tezepelumab may be a therapeutic option for EoE. The efficacy and safety of tezepelumab in patients with symptomatic and histologically active EoE are being assessed in the ongoing CROSSING study.

Disclosure

J D Sherrill, P G Gavin, L Öberg, T Li, A Péterffy, W Rae, R Tsotsoros, R Trivedi, K Domek-Lopacinska, C Seminario, A Platt and D Muthas are employees of AstraZeneca and may own stock or stock options in AstraZeneca. D Ivanič was an employee of AstraZeneca at the time of the study and may own stock options in AstraZeneca; he is a freelance data scientist at Kickresume. S Caveney is an employee of Amgen and owns stock in Amgen.

Introduction

The molecular pathogenesis of the type 2 inflammatory disease eosinophilic oesophagitis (EoE) is largely driven by IL-13-mediated effects. A humanised monoclonal anti-IL-13 antibody (cendakimab) lowered oesophageal eosinophils and improved outcomes in clinical trials.

Aims & Methods

We aimed to determine how systemic cendakimab administration impacted local oesophageal gene expression in a substudy of a double-blind, placebo-controlled phase 2 trial (NCT02098473). EoE-related transcripts were quantified in biopsies collected at baseline (week 0) and after 16 weekly injections (week 16) of cendakimab (180 mg or 360 mg).

Results

Cendakimab at either dose reversed the gene expression profiles of cardinal genes and molecular pathways involved in EoE pathogenesis compared with placebo. These changes included those in genes involved in IL-13 signalling (eg, CCL26, 180 mg: 16-fold decrease, p=3.6×10^-11; 360 mg: 16-fold decrease, p=4.9×10^-18), mastocytosis (eg, CPA3, 180 mg: 4.1-fold decrease, p=4.01×10^-4; 360 mg: 4.7-fold decrease, p=1.1×10^-6; TPSB2/TPSAB1, 180 mg: 2.6-fold decrease, p=3.1×10^-3; 360 mg: 4.2-fold decrease, p=6.6×10^-8), epithelial differentiation (eg, DSG1, 180 mg: 12.3-fold increase, p=5.0×10^-4; 360 mg: 6.7-fold increase, p=2.8×10^-3), and remodelling (eg, POSTN, 180 mg: 16-fold decrease, p=8.9×10^-10; 360 mg: 16-fold decrease, p=1.0×10^-11). Transcript changes correlated with histological and endoscopic observations. Patients who achieved histological remission after cendakimab treatment (ie, responders) exhibited significantly greater improvement in post-treatment versus baseline expression in a subset of genes (n = 8, including CCL26 and CPA3) compared with patients who did not (ie, non-responders).

Conclusion

Cendakimab treatment improves oesophageal gene expression in patients with EoE, and the changes in transcripts correlate with histological and endoscopic improvements.

References

Presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting; February 24–27, 2023; San Antonio, Texas

Disclosure

Julie M. Caldwell was supported by Celgene/Bristol Meyers Squibb for this abstract, and she was funded by the Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center to travel to and present at the 79th Annual Meeting of the American Academy of Allergy, Asthma, and Immunology. Adina Y. Ballaban and Marc E. Rothenberg have no relationships/activities/interests to disclose. Jie Li and Rachel Maddux are employees and shareholders at Bristol Myers Squibb. Sarah Harris was supported by Bristol Myers Squibb and Cincinnati Children’s Hospital Medical Center for this abstract.

Introduction

Eosinophilic oesophagitis (EoE) is a chronic progressive type 2 inflammatory disease clinically characterized by oesophageal dysfunction symptoms (dysphagia, food impaction, odynophagia, chest discomfort) and histologically by eosinophil predominance.^1-3 The global incidence and prevalence of EoE are increasing; therefore, real-world data can aid in identifying current disease management challenges.

Aims & Methods

Aim: This study aimed to describe demographics, clinical features, treatment patterns, health outcomes, and healthcare resource utilization (HCRU) among real-world patients with EoE.
Methods: We analysed medical record data collected from a multinational cohort of EoE patients diagnosed between January 1, 2009, and December 31, 2019. Physicians from Canada, France, Germany, Spain, and the United Kingdom provided data for eligible patients aged ≥12 years with an eosinophil (eos) count ≥15 eos/hpf within 90 days of diagnosis and at least one follow-up endoscopy within 24 months. We collected data on patient demographics, clinical characteristics, treatment patterns, outcomes, and HCRU. Patients were followed until their last medical record entry or death, whichever occurred first. Outcomes are from three-year follow-up period from the index date. Descriptive statistics were employed to estimate continuous variables and categorical variables.

Results

This study included 415 patients diagnosed with EoE, with a mean age of 31.8 ± 14.6 years. The majority of patients were white (91.8%) and male (74.0%). The average (±SD) follow-up duration was 5.2 (±3.2) years post-EoE diagnosis. The mean (±SD) delay between symptom onset and the diagnosis was 3.4 (±4.8) years. At EoE diagnosis, the mean (±SD) peak eosinophil count was 41.4 (±43.4) eos/hpf and endoscopic abnormalities were found in 80.2% of patients. After EoE diagnosis, patients were treated with proton pump inhibitors (PPIs) (77.1%), swallowed topical corticosteroids (STCs) (68.2%), dietary modifications (48.4%), oesophageal dilation (18.8%), and systemic corticosteroids (10.8%). At third-year follow-up (n = 392), patients continued to experience dyspepsia (20.4%), heartburn (23.5%), dysphagia (24.5%), and food impaction (5.4%) despite treatment. A relatively small percentage of patients achieved histologic remission during the first 5 years after EoE diagnosis; 4.1% with ≤1 eos/hpf (mean time to histologic remission [±SD]: 2.0 [±1.3] years), 20.0% with ≤6 eos/hpf (1.5 [±1.2] years), and 42.4% with <15 eos/hpf (1.4 [±1.1] years). During follow-ups, 98.8% (first year) and 97.3% (third year) of patients had at least one office visit, and 39.9% (first year) and 25.6% (third year) had at least one consultation with an allergist/immunologist.

Table 1. Overview of treatment patterns after eosinophilic oesophagitis diagnosis

Conclusion

This study highlights a significant delay in diagnosing EoE from the onset of symptoms. Along with PPIs and dietary modifications, a high percentage of patients received STCs and oesophageal dilation, indicating a substantial burden. Despite these treatments, optimal histologic remission rates and symptomatic control remain unmet needs. Addressing EoE burden necessitates developing strategies for earlier diagnosis and additional therapies to improve long-term management.

References

1. Mansoor E, Cooper GS. The 2010-2015 Prevalence of Eosinophilic Esophagitis in the USA: A Population-Based Study. Dig Dis Sci. 2016;61(10):2928-2934. doi:10.1007/s10620-016-4204-4.
2. Lu M, Goodwin B, Vera-Llonch M, Williams J. Disease Burden and Treatment Patterns Associated With Eosinophilic Esophagitis in the United States: A Retrospective Claims Study. J Clin Gastroenterol. 2022 Feb 1;56(2):133-140. doi: 10.1097/MCG.0000000000001491. PMID: 33443967; PMCID: PMC8754098.
3. Katzka DA. Eosinophilic Esophagitis. Ann Intern Med. 2020;172(9):ITC65-ITC80. doi:10.7326/AITC202005050.

Disclosure

CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Takeda; royalties from Springer Publishing; research support from Ferring, Pfizer.
TP, JJN, KB, and STT are employees and stockholders of Sanofi.
AR, AK and RBT are employees and stockholders of Regeneron Pharmaceuticals, Inc.
RP is a full-time employee of RTI Health Solutions, which received research funding from Sanofi to perform this study. RTI Health Solutions is a unit of Research Triangle Institute, an independent, non-profit, research organization that does work for government.

Introduction

Eosinophilic oesophagitis (EoE) is a chronic, progressive type 2 inflammatory disease. Proton-pump inhibitors (PPIs), swallowed topical corticosteroids (STCs), and elimination diets have been used as standard treatments for EoE patients. However, the real-world evidence (RWE) highlighting disease burden in Europe are limited.

Aims & Methods

To assess disease burden and treatment patterns among adolescent and adult patients with EoE in real-world practice.
Medical records were retrospectively reviewed for patients (aged ≥12 years) who were newly diagnosed with EoE between 1 January 2009 and 31 December 2019 (index) in Germany, France, Spain, and the United Kingdom. Patients with a peak eosinophil (eos) count (PEC) of ≥15 eos/hpf within 90 days of the index date and ≥1 follow-up endoscopy within 24 months of the index date were included. Demographics, clinical features, treatment patterns, and health outcomes were assessed from the 12-month pre-index period to the last medical record entry or death. Disease progression was assessed via physician-defined (based on symptoms, endoscopy findings, histology, need for dilation, and food impaction) and proxy-reported outcomes (dilation performed, strictures, dysphagia, evidence of food impaction, treatment initiation in treatment-naïve patients and switching/augmentation).

Results

Overall, 385 patients were included, with 70.1%–78.1% being male; the mean age was 27.8 to 33.9 years. At EoE diagnosis, the PEC was 35.3–46.1 eos/hpf, the endoscopic appearance of the oesophagus was abnormal in 73.7%–85.6% of patients, and dysphagia was present in 59.8%–82.8% of patients. Most of the patients across all 4 countries were treated with PPIs (61.5%–91.8%), STCs (56.7%–82.3%) and elimination diets (41.4%–55.2%) after EoE diagnosis. Of the patients with available data, abnormal histology (≥15 eos/hpf) was reported in 44.8%–72.0% of patients during the first 5 years after EoE diagnosis. The abnormal endoscopic appearance of the oesophagus was observed in 34.6%–83.3% of patients after approximately 2 years of EoE diagnosis and dysphagia was present in 10.2%–25.0% of patients after 4 years of EoE diagnosis across all 4 countries. While physician-defined disease progression occurred in 6.1%–16.1% of patients, 19.4%–35.1% of patients experienced proxy-reported outcomes of potential disease progression (including oesophageal dilation performed in 10.8%–21.7% of patients) after EoE diagnosis. An overview of patient and clinical characteristics at EoE diagnosis and treatment patterns and disease progression (physician-defined and proxy-reported) after EoE diagnosis across Germany, France, Spain, and the United Kingdom is provided in the Table.

Conclusion

Adolescent and adult patients with EoE chronically experienced substantial disease burden. A subset demonstrated disease progression, perhaps underrecognised despite treatment with PPIs, STCs, and elimination diets. Hence, successful EoE management may include proactive disease monitoring, treating underlying pathophysiology and prescribing maintenance therapies to achieve long-term clinical remission.

References

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Disclosure

Ulrike von Arnim: Consulting and/or speaker fees from Dr. Falk Pharma, Sanofi, Astra Zeneca, EsoCap, Abbvie, Janssen, Takeda, Pfizer, Bristol Myers Squibb.
Frank Zerbib: Consulting and/or speaker fees from Sanofi, Dr Falk pharma, Bristol Myers Squibb, Bioprojet, AstraZeneca.
Tiffany Pela, Juby A. Jacob-Nara, Gaelle Le-Bagousse-Bego, Sarette T. Tilton: Employees of Sanofi; may hold stocks and/or stock options in the company.
Bram P. Raphael, Amr Radwan, Ryan B. Thomas: Employees of Regeneron Pharmaceuticals, Inc.; may hold stocks and/or stock options in the company.
Rohan C. Parikh, Fareedat Bello: Employees of RTI Health Solutions, which received research funding from Sanofi to design and execute this study.
Funding: This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
Acknowledgement: Medical writing support was provided by Akshata Rao and Ali Nasir Siddiqui, PhD, of Sanofi.

Introduction

Until a few years ago, there existed only off-label medical treatment options for eosinophilic esophagitis (EoE) such as proton pump inhibitors (PPI) or swallowed topical corticosteroids (STC) with various formulations and ingredients. Since the approval of a budesonide orodispersible tablet (BOT), the first biological agent (Dupilumab) has been approved by the EMA and FDA, and another budesonide oral suspension has been received approval by the FDA recently. Currently, many phase 3 trials with different drugs are running, resulting in various treatment options in the next years. However, data about patients’ perspectives are lacking. We therefore aimed to assess patients’ awareness, beliefs and restrictions to medical treatment options in EoE

Aims & Methods

We developed a web-based survey using SurveyMonkey and sent a questionnaire comprised of 47 questions about patients’ preferences regarding medical treatment options to patients with established EoE in Switzerland, Austria and Germany.

Results

A total of 56 patients (64% male, 66% with other atopic diseases) from Switzerland (64%), Austria (34%) and Germany (2%) answered the questionnaire. A swallowed topical therapy was ranked first (71% of patients) in terms of patient’s preference followed by a subcutaneous therapy every 4 weeks (21.4%) and by an oral therapy with systemic effect (7%). Although one third do not have reservations against long-term medical therapy, nearly half of patients (42%) are skeptical about long-term treatment and 65% are afraid of adverse events. However, a third of patients are not aware that STC are locally effective medications with nearly no systemic effect. Furthermore, 48% of patients believe that physicians underemphasize adverse events of medication. Nearly all patients understand the importance of not only treating symptoms but also inflammation (85%).

Conclusion

Patients with EoE prefer topical agents over other available routes of administration. Patient education should be carried out to address reservations about long-term treatment.

Disclosure

Falk Pharma, Sanofi (both consultency meetings)

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder from the atopic disease spectre. Despite being studied for years, the EoE-specific therapy has been approved only recently and includes budesonide orodispersible tablet (1) and IL-4R antagonist, dupilumab (2). Therefore, data on the management of the patients who do not respond to this treatment is scarce. Especially those who were diagnosed long in the past and have undergone different therapeutical approaches remain an understudied group. The aim of this project was to provide information on the treatment courses in a real-world setting over past 10 years.

Aims & Methods

This was a retrospective nation-wide project collecting data on patients with EoE in 7 Austrian centres since January 2014. The last follow-up was marked as of February 2025. Information on patients’ demographics, previous medical history, number of esophageal food impactions and different treatment lines were recorded. Due to the descriptive character of the work, no power analysis was carried out.

Results

In total, 336 patients (30.1% female) were included. Approximately one third of them (119/336) experienced an esophageal food impaction before the diagnosis was made. The most common 1st line therapy was budesonide orodispersible tablet (193/336, 57.4%), followed by proton pump inhibitors (87/336, 25.9%) and food elimination diet (20/336, 6.0%). Two hundred twenty (220/336, 65.5%) patients did not remain on the 1^st line treatment. Forty-four (44/336, 13.1%) subjects required more than 2 therapies and one person received even 7^th line medication. Biologic treatment – dupilumab – was given to forty-one (12.2%) patients. It was the first line treatment in 1 person, the others received it in the further course. These drugs were well-tolerated and 97.6% (40/41) patients remained on it until the last follow-up and reached symptomatic remission. Three patients were diagnosed more than 10 years before they received biologic treatment and 2 of them responded to it. One person discontinued due to side effects. The most common reasons for switch for dupilumab were clinical and/or histological activity (24/41, 58.5%), side effects (10/41, 24.4%) and patients’ preference (2/41, 4.9%).

Conclusion

This is the first study on different therapy courses in patients with EoE in Europe. Due to its retrospective character, no direct conclusions on the superiority of one approach upon another in case of refractoriness are possible.

References

1. Lucendo AJ, Miehlke S, Schlag C, Vieth M, von Arnim U, Molina-Infante J, et al. Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial. Gastroenterology. 2019;157(1):74-86.e15.
2. Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, et al. Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. Gastroenterology. 2020;158(1):111-22.e10.

Disclosure

JP: travel grants from Johnson&Johnson and Tillots Pharma AG
MW: no conflicts of interest
PD: consulting and speakers fees from Falk Pharma, Sanofi, Abbvie, MSD, Takeda, Janssen, Pfizer
KS: support from: Abbvie, Astro Pharma, Takeda, Johnson&Johnson, MSD, Falk Pharma, Galapagos
TH: speaker fee from Falk
MH: no conflicts of interest
LKS: •Past/present Principal investigator für Studien gesponsort durch: SigmaTau, Sanofi , Tigenix und Falk;
•Speaker fee: MSD, AbbVie, Ferring, MerckSerono/Dr Falk, Chiesi, Novartis, Roche, Abbott, Phadia Austria/Thermo Fisher Scientific, CSL-Behring , Janssen-Cilag Pharma, Labors.at GmbH, Vertex, ENML Laborbetriebs GmbH, Johnson&Johnson
•Conference support: Mylan, Abbott, MSD, Gilead, MerckSerono/Dr Falk, Novartis, Pfizer, Janssen-Cilag Pharma, Chiesi, Shire, Abbvie, Takeda, Vertex, Astropharma
•Consultancy for: MSD, Takeda
GN: lecturing fees, consulting fees, and advisory fees from AbbVie, Merck Sharp & Dohme, Takeda, Janssen-Cilag, Pfizer, Gilead, Galapagos, Ferring, Vifor, AstroPharma, Falk, Bristol Myers Squibb, Arena Pharmaceuticals and Amgen
MT: received grant support from Albireo, Alnylam, Cymabay, Falk, Genentech, Gilead, Intercept, MSD, Takeda and UltraGenyx, honoraria for consulting from AbbVie, Albireo, Agomab, Boehringer Ingelheim, BiomX, Chemomab, Dexoligo Therapeutics, Falk, Genfit, Gilead, GSK, Hightide, Intercept, Ipsen, Jannsen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire, speaker fees from Albireo, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Gilead, Intercept, Ipsen, Madrigal, Mirum and MSD , as well as travel support from AbbVie, Falk, Gilead, Jannsen and Intercept. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid filed by the Medical University of Graz (service inventions).
WS: no conflicts of interest
HS: consulting and speakers fees from Falk Pharma, Sanofi, Medtronic
PS: consulting fees and/or speaker fees from Dr. Falk Pharma, GmbH, Takeda, Regerenon-Sanofi Pharmaceuticals, AbbVie, Janssen-Cilag, Receptos-Celgene-BMS