Structures already discussed alongside esophageal disease in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
RCSB Protein Data Bank · entry 2A26 · 1.2 Å · ligand 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID (CXS). Experimental structure, not a prediction.
Dupilumab was approved by the FDA for eosinophilic esophagitis in May 2022 at a dose of 300 mg weekly, based on a phase 3 trial that showed significant improvement in signs and symptoms compared to placebo. A retrospective single-centre study of 79 patients found that dupilumab induced histologic remission and clinical benefit before 12 weeks of treatment. In the 12 patients treated for 0–12 weeks, median composite symptom score fell from 5.5 to 0, and median peak eosinophil count fell from 44.5 to 2 eos/hpf. Endoscopic reference scores did not change significantly, possibly due to small numbers. No significant differences in symptom, histologic, or endoscopic changes were seen between patients treated for 0–12, 12–24, or more than 24 weeks. Among 7 patients with multiple biopsies, some who were unresponsive early became responsive after 24 weeks, but one remained unresponsive even after 24 weeks; two others had started combination therapy with omeprazole or mometasone, so their remission may not be attributable to dupilumab alone.
Topical budesonide orodispersible tablets (BUD-ODT) were studied in a retrospective real-world analysis of 221 adults with active eosinophilic esophagitis at two German centres. Clinical-histological remission was achieved in 75.1% after 6–12 weeks of induction therapy (1 mg twice daily), maintained in 73.4% after 14–24 weeks of maintenance (0.5 mg twice daily or 1 mg daily), and in 76.4% after 52–104 weeks. Relapse rates were 26.6% and 23.6% at the two maintenance time points; re-induction produced remission in 36.0% and 46.2% of those relapsed patients. Endoscopic remission was seen in 88.1% after induction. The most common side effect was oral-esophageal candidiasis.
A 2024 review notes that orodispersible budesonide tablets (Jorveza) are approved in Europe, Canada, and Australia but not in the USA, while an orodispersible budesonide suspension (Eohilia) was approved in the USA for 12-week induction in patients aged 11 and older. Proton-pump inhibitors are used off-label but the evidence for histologic remission with PPIs is very low and inconsistent. The same review lists a number of drugs not recommended for eosinophilic esophagitis due to lack of efficacy or safety concerns: systemic steroids, sodium cromoglycate, montelukast, azathioprine, TNF-antagonists, vedolizumab, benralizumab, mepolizumab, reslizumab, omalizumab, and lirentelimab.
What is still missing are long-term effectiveness and safety data for the approved drugs, prospective studies that define the optimal timing of repeat biopsies on dupilumab, and head-to-head comparisons between dupilumab and topical budesonide. The retrospective studies are small and from single centres or two centres, and the real-world budesonide data come only from Germany. No trial has yet stratified patients by prior treatment response, atopic background, or disease duration to predict who benefits from which drug.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Gastroenterology Insights · 2022 · 29 citations · open access
First Therapeutic Approval for Eosinophilic Esophagitis
AbstractEosinophilic esophagitis (EE) is a chronic, immune-mediated or antigen-mediated esophageal disease. Treatment for patients with EE can be challenging with no previously approved medications. Current management strategies follow the four D's paradigm of drugs, dietary elimination, dilation, and disease anxiety and hypervigilance therapy. On 20 May 2022, dupilumab was approved by FDA for EE. A dose of 300 mg dupilumab weekly significantly improved signs and symptoms of EE compared to placebo in a phase 3 trial. The approval of dupilumab will fulfill an unmet need for the increasing number of patients with EE.
https://doi.org/10.3390/gastroent13030024Clinical and Translational Allergy · 2024 · 2 citations · open access
Dupilumab improves clinical and histologic features of eosinophilic esophagitis prior to 12 weeks of treatment
AbstractDupilumab is a human monoclonal antibody against interleukin-4 receptor alpha subunit. Dupilumab is an approved treatment for inducing remission of eosinophilic esophagitis (EoE).1 EoE histologic remission with dupilumab has only been demonstrated in patients after at least 12 weeks of treatment.2-6 Current guidelines recommend waiting for histologic re-evaluation of EoE until after 20–24 weeks of dupilumab.1 It is unknown if increasing dupilumab treatment length improves its efficacy. Because histologic re-evaluation of EoE requires invasive biopsies, and inducing remission of EoE is important to prevent progressive esophageal damage, research investigating the effects of dupilumab on EoE prior to 12 weeks of treatment is warranted. We conducted a retrospective study at a single medical clinic. The electronic medical record was searched between 2017 and 2023 using International Classifications of Disease, 10th revision code K20.0 eosinophilic esophagitis. We excluded patients who had (1) never started dupilumab; (2) no histologic confirmation of EoE defined by ≥ 15 eos/hpf; or (3) no histologic re-evaluation of EoE while on dupilumab. Histologic evaluation of EoE assessed at least 2 biopsies each of the proximal, middle, and distal esophagus. Endpoints were peak eosinophil counts (eosinophils per high-power field; eos/hpf), EoE endoscopic reference scores (EREFS), and a composite symptom score in which each symptom (dysphagia, food impaction/choking, regurgitation/vomiting, heartburn/chest pain, and abdominal pain) was graded (0 = absent, 1 = mild, 2 = moderate, and 3 = severe) and summed. This study was deemed exempt from institutional review board approval by the WCG IRB. From the electronic medical record, 658 patients with EoE were identified, of which 534 had never initiated dupilumab, 6 did not have histologic confirmation of EoE, and 39 did not have a repeat histologic evaluation after dupilumab initiation. Therefore, 79 patients were included in this study. The median age was 27.6 years (Q1 to Q3, 21.8–36.1), 48 patients (60.8%) were male, and 12 patients (15.2%) were pediatric (Table 1). Sixty patients (75.9%) had an atopic comorbidity, including allergic rhinitis (43 patients, 54.4%), asthma (27 patients, 34.2%), atopic dermatitis (13 patients, 16.5%), and food allergies (30 patients, 38.0%). Patients were on dupilumab for median 22.7 weeks (Q1 to Q3, 16–26.7). Dosages included 300 mg every week (71 patients, 89.9%), 300 mg every other week with a loading dose of 600 mg for atopic dermatitis (7 patients, 8.9%), and 200 mg every other week with a loading dose of 400 mg for atopic dermatitis (1 patient, 1.3%). Of 79 patients, 12 patients (15.2%) were on dupilumab for 0–12 weeks. Patients on dupilumab for 0–12 weeks had a median composite symptom score of 5.5 (Q1 to Q3, 4–6), which significantly decreased to 0 (Q1 to Q3, 0–1; Wilcoxon matched-pairs signed rank test, p = 0.000488) on dupilumab. Median peak eosinophil counts in patients on dupilumab for 0–12 weeks significantly decreased from 44.5 eos/hpf (Q1 to Q3, 32.5–53.5) at baseline to 2 eos/hpf (Q1 to Q3, 0–15.5; Wilcoxon matched-pairs signed rank test, p = 0.000977) on dupilumab. Endoscopic reference scores were only available for 15 patients (19%) in our cohort. In patients on dupilumab for 0–12 weeks, EREFS did not significantly decrease from baseline (median, 2; Q1 to Q3, 1–4) versus on dupilumab (median, 0; Q1 to Q3, 0–1.5; Wilcoxon matched-pairs signed rank test, p = 0.25). However, change in EREFS was also insignificant in patients on dupilumab for 12–24 weeks (p = 0.13), and greater than 24 weeks (p = 0.25), suggesting insignificance may be due to low n. Therefore, dupilumab may induce histologic remission and clinical benefit in patients prior to 12 weeks of treatment. There were no significant differences in changes in median composite symptom score (p = 0.1350), peak eosinophil count (p = 0.0746); and EREFS (p = 0.8771) between patients on dupilumab between 0 and 12, 12–24, and greater than 24 weeks (Table 1). In terms of histologic response, 9 patients (75%) were histologically responsive in the 0–12 weeks group, 28 patients (73.7%) were responsive in the 12–24 weeks group, and 26 patients (89.7%) were responsive in the longer than 24 weeks group. There was no significant difference in the proportion of histologic response between the 3 groups (Fisher's exact test, p = 0.2569). Subanalysis in 7 patients with >1 histologic evaluations on dupilumab is summarized in Figure 1. Three patients who were histologically unresponsive to dupilumab at early timepoints (Patient 4 between 0 and 12 weeks, Patient 3 and 5 between 12 and 24 weeks) were responsive after 24 weeks of treatment without addition of combination therapy. In contrast, Patient 1 was unresponsive at 0–12 weeks of dupilumab and remained unresponsive after over 24 weeks of dupilumab. Patient 2 and 6 had started combination therapy with omeprazole or mometasone, respectively. Therefore, their histologic remission may be due to combination therapy. Our subanalysis suggests that certain patients who are histologically unresponsive at early EGDs may or may not respond at later timepoints. Further research is needed to predict which patients benefit from repeat EGDs. Swimmer plot of patients with eosinophilic esophagitis that had multiple histologic evaluations while on dupilumab therapy. * indicates combination therapy with mometasone 1.6 mg twice daily. ** indicates combination therapy with omeprazole 20 mg once daily. *** indicates dupilumab 300 mg once every 2 weeks, loading dose 600 mg, as opposed to dupilumab 300 mg once a week. In conclusion, dupilumab induced histologic remission and clinical benefit before 12 weeks of treatment, and there were no significant differences in clinical, histologic, or endoscopic changes between patients on dupilumab for 0–12 weeks, 2–24 weeks, and greater than 24 weeks. It may be beneficial to identify treatment response earlier than previous guidelines indicate.1 Further research should investigate the appropriate window of treatment before repeat EGDs are performed. Twan Sia: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Amanda Miller: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Leeon Bacchus: Data curation (equal); formal analysis (equal); validation (equal); visualization (equal); writing—original draft (equal); writing—review and editing (equal). Jennie Young: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). Aditya P. Narayan: Data curation (equal); validation (equal); visualization (equal); writing—review and editing (equal). Rachel Solecki: Investigation (equal); validation (equal); writing—review and editing (equal). Jerry Fu: Investigation (equal); validation (equal); writing—review and editing (equal). Yuting Jiang: Investigation (equal); validation (equal); writing—review and editing (equal). Raisa Khuda: Investigation (equal); validation (equal); writing—review and editing (equal). Stanley Liu: Investigation (equal); validation (equal); writing—review and editing (equal). Kathleen Love: Investigation (equal); validation (equal); writing—review and editing (equal). Shibani Mallik: Investigation (equal); validation (equal); writing—review and editing (equal). Amina Sara Matmatte: Investigation (equal); validation (equal); writing—review and editing (equal). Paige McDonald: Investigation (equal); validation (equal); writing—review and editing (equal). Tanvi Telukunta: Investigation (equal); validation (equal); writing—review and editing (equal). Alyssa Roby: Investigation (equal); validation (equal); writing—review and editing (equal). Saad Shami: Investigation (equal); validation (equal); writing—review and editing (equal). Michelle Zheng: Investigation (equal); validation (equal); writing—review and editing (equal). Madison Headen: Investigation (equal); validation (equal); writing—review and editing (equal). John Leung: Conceptualization (equal); methodology (equal); project administration (equal); resources (equal); supervision (equal); writing—review and editing (equal). None. John Leung: is a consultant for Devine; Millimet and Branch Professional Education; Sanofi; Huron Consulting Services LLC; Takeda; Ribon Therapeutics; Tegus; Slingshot; Guidepoint; Cowen; AstraZeneca; Regeneron; and AbbVie. None of the other authors have relevant conflicts of interests to disclose. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. All relevant de-identified data and study materials are stored in a HIPPA-compliant, password-protected, cloud-based storage. Access to these files will be provided upon reasonable request to the corresponding author, John Leung.
https://doi.org/10.1002/clt2.12333Therapeutic Advances in Gastroenterology · 2025 · 1 citations · open access
Real-world-data on efficacy and safety of topical budesonide therapy (orodispersible tablet) in induction and maintenance therapy in adult patients with active eosinophilic esophagitis
AbstractBackground: Eosinophilic esophagitis (EoE) is a chronic, progressive, immune-mediated disease of the esophagus. Esophageal dysfunction in solid food dysphagia combined with eosinophil-dominant inflammation (⩾15 eos/high-power-field (hpf)) serves as diagnostic criteria. Treatment objectives for active EoE include induction and maintenance of clinical-histological remission. Topical budesonide therapy in the form of an orodispersible tablet (BUD-ODT) has shown effectiveness in both scenarios. Objectives: To examine the efficacy and safety of BUD-ODT therapy in adults with active EoE in a Real-World-Setting. Design: This retrospective study from two German EoE centers examined the efficacy and safety of BUD-ODT therapy in adults with active EoE between June 2018 and August 2022. Methods: Patient demographics, clinical characteristics, and EoE history were extracted from medical records. Evaluations included clinical (Straumann Dysphagia Index, range: 0–9, remission: ⩽3 points), histological (remission: ⩽15 eos/hpf), and endoscopic assessment (endoscopic reference scoring system (EREFS) score, range: 0–9, remission: ⩽2 points). Three periods were analyzed: Induction phase (induction therapy (IT): 1 mg BID, 6–12 weeks; n = 201), maintenance phase I (RM1: 0.5 mg BID or 1 mg QD, 14–24 weeks; n = 109), and maintenance phase II (RM2: same dosage as RM1, 52–104 weeks; n = 72). Results: A total of 221 adults with clinical-histologically proven active EoE were included. Clinical-histological remission was achieved in 75.1% (151/201) of patients after IT, maintained in 73.4% (80/109) after RM1, and in 76.4% (55/72) after RM2. The relapse rate was 26.6% (29/109) after RM1 and 23.6% (17/72) after RM2. Those patients underwent re-induction therapy for 6–8 weeks and were re-evaluated separately (remission: 36.0% after RM1 and 46.2% after RM2). Endoscopic remission was demonstrated in 88.1% (177/201) after IT. The most prevalent side effect was endoscopically detected combined oral-esophageal candidiasis. Conclusion: BUD-ODT demonstrated high effectiveness in inducing and maintaining remission in a real-world setting. The spectrum of side effects did not reveal any new aspects compared to known clinical data.
https://doi.org/10.1177/17562848251382791The American Journal of Gastroenterology · 2016 · 1 citations
Response to Elias and Castell
Abstract1Joy McCann Culverhouse Center for Esophageal Diseases, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA Correspondence: Joel E. Richter, MD, MACP, Joy McCann Culverhouse Center for Esophageal Diseases, Morsani College of Medicine, University of South Florida, 12901 Bruce B, Downs Boulevard, Box 72, Tampa, Florida 33612, USA. E-mail: [email protected] The authors declare no conflict of interest.
https://doi.org/10.1038/ajg.2016.280Open Access CRIS of the University of Bern · 2024 · 0 citations · open access
Pharmacologic Treatment of Eosinophilic Esophagitis: Efficacious, Likely Efficacious, and Failed Drugs.
AbstractBackground Eosinophilic esophagitis (EoE) is a chronic, food allergen-mediated, esophageal disease that will lead, if left untreated, to esophageal remodeling. As such, the vast majority of EoE patients need treatment. Treatment strategies include drugs, food elimination diets, and esophageal dilation. This review focuses on pharmacologic options for treatment of EoE. Summary Orodispersible budesonide tablets (Jorveza®) have been approved by regulatory authorities for EoE treatment of adults in Europe, Canada, and Australia, but not in the USA. Jorveza®, as compared to placebo, is effective in inducing and maintaining histologic and clinical remission over time. An orodispersible budesonide suspension (BOS, Eohilia®) was recently approved in the USA as induction treatment (12 weeks) in adolescents of at least 11 years and adults with active EoE. Before the approval of Jorveza® and Eohilia®, several investigator-initiated randomized controlled clinical studies evaluated esophagus-targeted formulations of either budesonide or fluticasone to treat pediatric and adult EoE patients. These drugs were generally efficacious in inducing and maintaining histological and clinical remission. Proton-pump inhibitors (PPIs) are used off-label for EoE treatment of pediatric and adult EoE patients given that they are able to induce histologic and clinical remission. However, when compared to the moderate certainty of evidence with regard to the failure to achieve histologic remission with swallowed topical corticosteroids, the certainty of evidence for PPIs is very low with very inconsistent results in absolute terms. Dupilumab (Dupixent®), a monoclonal antibody targeted against IL-4 and IL-13, was approved by regulatory authorities in the USA, Europe, Canada, but not yet Australia. In Europe, including Switzerland, Dupixent® is approved to treat EoE patients of at least 12 years of age with at least 40 kg body weight if they are either unresponsive or intolerant to or not candidates for conventional EoE therapies. Due to lack of efficacy or unfavorable safety profile, the following drugs are not recommended for EoE treatment: systemic steroids, sodium cromoglycate, montelukast, azathioprine, TNF-antagonists (e.g., infliximab), vedolizumab (mAb against α4β7), benralizumab (mAb against IL-5 receptor), mepolizumab (mAb against IL-5), reslizumab (mAb against IL-5), omalizumab (mAb against IgE), and lirentelimab (mAb against Siglec-8). Key Messages Long-term effectiveness and safety data on different drugs are currently sparse. Concerted efforts of different stakeholders will be necessary to continue the endeavor of providing our patients with much-needed therapies.
https://doi.org/10.48620/76962Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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