Introduction

Eosinophilic esophagitis (EoE) is a chronic, progressive, immune-mediated inflammatory disease characterized by esophageal inflammation with infiltration of eosinophils (eos) and symptoms of esophageal dysfunction. Interleukin (IL)-13, a type 2 inflammatory cytokine, plays a key role in the pathophysiology of EoE. Cendakimab (CEN) is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody targeting IL-13, inhibiting binding to both its receptors, IL-13Rα1 and IL-13Rα2. CEN reduced mean esophageal eos counts and improved symptoms and endoscopic features of EoE in a phase 2 study. We report results from a pivotal phase 3 trial (NCT04753697) of CEN in adult and adolescent patients (pts) with EoE after 24 wk of treatment.

Aims & Methods

This multicenter, multinational, randomized, double-blind, placebo (PBO)-controlled study enrolled pts aged 12–75 y with active EoE (peak esophageal eos count [PEC] ≥ 15 eos/high power field [hpf] at any 2 levels of the esophagus), ≥ 4 dysphagia days (DD) over the 14-day period prior to day 1 evaluated using the modified Daily Symptom Diary (mDSD), and lack of complete response to ≥ 8 wk proton pump inhibitor treatment. The study planned to enroll ~70% of pts who were steroid inadequate responders or intolerant (steroid IR/I). Pts were randomized 1:1:1 to receive subcutaneous CEN 360 mg weekly for 48 wk (QW/QW), CEN 360 mg QW for 24 wk followed by CEN 360 mg every other wk for 24 wk (QW/Q2W), or PBO QW for 48 wk. Coprimary endpoints were mean change from baseline (BL) to wk 24 in DD and proportion of pts with eos histologic response, defined as PEC ≤ 6/hpf at wk 24. Key secondary endpoints included eos histologic response < 15/hpf at wk 24, endoscopic response (mean change in Endoscopic Reference Score [EREFS] total score), mean change in EoE Histology Scoring System (EoEHSS) grade/stage score, and mean change in mDSD composite score, from BL to wk 24. Safety was also evaluated.

Results

Overall, 430 pts (~66% steroid IR/I) were randomized to CEN (n = 286; QW/QW, n = 143, QW/Q2W, n = 143), or PBO (n = 144). In pts treated with CEN 360 mg QW, there was a statistically significant reduction from BL to wk 24 in DD vs PBO (−6.1 vs −4.2 days; difference [95% CI] vs PBO: −1.9 [−3.0 to −0.8]; P = 0.0005) and a statistically significantly higher proportion of pts with eos histologic response at wk 24 vs PBO (28.6% vs 2.2%; difference [95% CI] vs PBO: 26.4 [20.6 to 32.2]; P < 0.0001) (Table). Statistically significant improvements in all key secondary endpoints were observed for CEN-treated vs PBO-treated pts (Table). At wk 24, adverse events (AE) related to study drug occurred in 30.3% and 18.9% of pts in the CEN and PBO arms, with AEs leading to discontinuation in 1.4% and 0.7% of pts, respectively. No deaths occurred.

Table. Efficacy results at wk 24

Conclusion

Treatment with CEN demonstrated statistically significant improvement in symptoms and histologic and endoscopic features of EoE vs PBO. CEN was generally safe and well-tolerated through wk 24.

Disclosure

AS has served a consultant for Adare/Ellodi, AbbVie, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Dr. Falk Pharma, Gossamer Bio, GSK, Janssen, MSD, Pfizer, Regeneron/Sanofi, Takeda, and Vifor; and has received grant/research support from Adare/Ellodi, Celgene/Receptos/Bristol Myers Squibb, GSK, and Regeneron/Sanofi. CMC, SZ, KL, AV, AY, and YSO are employees and shareholders of Bristol Myers Squibb. CLZ is a contractor to Bristol Myers Squibb. ESD has served as a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Bryn, Calypso, Celgene/Receptos/Bristol Myers Squibb, 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, and Upstream Bio; has received grant/research support from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolov, and Shire/Takeda; and has received educational grants from Allakos, Aqilion, Holoclara, and Invea. GF has served as a consultant for Adare/Ellodi, Allakos, Celgene/Receptos/Bristol Myers Squibb, LucidDx, Nexstone Immunology/Uniquity, Phathom, Regeneron/Sanofi, Shire/Takeda, and Upstream Bio; has received grant/research support from Adare/Ellodi, Allakos, Arena/Pfizer, Celldex, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Sanofi, Revolov, and Shire/Takeda. CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, 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, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer. HP has served as a consultant for Dr. Falk Pharma, Arena/Pfizer, GSK and Abbott. TV is a speaker for Dr. Falk Pharma and Bristol Myers Squibb; consultancy for Dr. Falk Pharma, Bristol Myers Squibb; research grant from Dr. Falk Pharma. SO has served a consultant for Dr. Falk Pharma, Medtronic, Regeneron/Sanofi, Celgene/Receptos/Bristol Myers Squibb; and has received grant/research support from Medtronic, Regeneron/Sanofi, Alfasigma.

Introduction

Colorectal cancer (CRC) often develops from precancerous lesions such as tubular adenomas (TA) and sessile serrated lesions (SSL). The gut microbiome has been implicated in colorectal carcinogenesis, but specific microbial signatures associated with different adenoma subtypes remain incompletely characterized. This study aimed to identify microbial biomarkers associated with TA and SSL, and explore their correlations with dietary macronutrients.

Aims & Methods

Stool samples were collected from 801 patients prior to colonoscopy from National University Hospital and Tan Tock Seng Hospital, Singapore. After colonoscopy, the patients were classified as having TA (n=315), SSL (n=24), both (n=8), or neither (controls, n=454). Shotgun metagenomic sequencing was performed using Novaseq6000, and microbial taxonomy was annotated with MetaPhlAn4. Multivariate linear regression adjusted for age, gender, and BMI was used to identify species associated with polyp subtypes. A subset of 172 participants completed a validated food frequency questionnaire (FFQ) assessing 19 macronutrients, enabling correlation analysis between diet and adenoma-associated microbes.

Results

Patients with TA were older (mean age 64.0±7.8 vs 62.3±7.5 years in controls, p=0.02) and more likely to be male (69.5% vs 52.4%, p<0.01). After adjustment for confounders, we identified 38 microbial species significantly associated with polyp subtypes; 20 were associated with SSL and 18 with TA, with minimal overlap between the two polyp subtypes. Only two species showed associations with both polyp types: Holdemanella biformis and GGB3277_SGB4327, with the latter showing opposing directional relationships (negative for TA, positive for SSL). Of note, SSL were associated with increased abundance of Faecalibacterium SGB15346 and Bifidobacterium adolescentis. In the dietary analysis, we identified significant correlations between SSL-associated microbes and sugar intake, particularly Faecalibacterium SGB15346 (r=0.170, p=0.03) and Clostridium sp_AM49_4BH (r=0.156, p=0.04). E. hominis, positively associated with SSL, showed the strongest dietary associations overall, correlating positively with carbohydrate intake (r=0.243, p<0.01) and starch consumption (r=0.246, p<0.01).

Conclusion

Our study identified distinct microbial signatures associated with TA and SSL, with minimal overlap, suggesting separate host-microbial biological pathways in their development. The positive correlation between SSL-associated microbes and sugar intake provides a potential mechanistic link between dietary habits and SSL formation, which may be particularly relevant given the increasing incidence of early-onset colorectal neoplasia. These findings offer potential microbial biomarkers for early detection of colorectal polyps and suggest targeted dietary interventions as a strategy for precision chemoprevention.

Introduction

Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a feature ranking method based on a novel One-Class Support Vector Machine (SVM) model.

Aims & Methods

A dataset containing clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations were conducted according to the updated Sydney system. CAG patients with any missing data or a GNL diagnosis at the baseline gastroscopy were excluded from the final analysis. A Fisher score-based feature ranking method and One-Class SVM were used to select the optimal subset of baseline variables associated with GNL development, aiming to achieve average sensitivity (Se) and specificity (Sp) above 80%.

Results

Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median age 68 (35-83) years] and without GNL at follow-up [81 patients (F 72.8%), median age 59(26-84) years]. After a median follow-up of 60 (12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with both epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic symptoms at CAG diagnosis were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusion

This is the first study in which an AI model simultaneously considers clinical, endoscopic, and histological characteristics from a dataset of CAG patients, showing good sensitivity and specificity in identifying those variables associated with developing GNL. Nonetheless, we acknowledge the need for improved variable standardization and data balancing between groups to enhance model performance further.

Introduction

Metabolic dysfunction-associated steatohepatitis (MASH) increases the risk of cardiovascular (CV) events and liver fibrosis. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces CV risk associated with overweight and obesity in the absence of diabetes and has a profound effect on weight reduction and MASH resolution. Management of MASH may benefit from a deeper understanding of the mechanistic basis of semaglutide-induced MASH resolution.

Aims & Methods

This study used a multi-omics approach to investigate the effects of semaglutide on the hepatic microenvironment and fibrosis development in the context of semaglutide-induced MASH resolution. GLP-1 receptor expression was assessed using RNA in situ hybridization and immunohistochemistry in human liver tissue and immunohistochemistry in liver tissue from DIO‑NASH and CDA-HFD mice. The effect of semaglutide treatment on liver fibrosis was also assessed using liver transcriptome analysis in both of these mouse models of MASH. Proteomic analyses of 4,979 proteins using the SomaScan Platform were conducted on serum samples from 293 patients with MASH who received semaglutide or placebo in a phase 2b study (NCT02970942), and an independent cohort of 141 patients with MASH and 89 healthy volunteers.

Results

GLP-1 receptor mRNA or protein expression were not detected in human or mouse liver tissue. However, semaglutide improved histological markers of fibrosis and expression of genes involved in collagen turnover in two distinct mouse models of MASH; one that phenocopies the metabolic-associated features of human disease and another that exhibits non-abdominal obesity-induced advanced steatohepatitis and rapid fibrosis. In semaglutide-treated patients with MASH, proteomics identified 72 proteins significantly associated with MASH resolution after 72 weeks of treatment. These 72 proteins were also identified as differentially expressed in patients with MASH who were not treated for MASH, relative to healthy individuals. In semaglutide-treated patients with MASH, the abundance of the 72 proteins was similarly altered; however, semaglutide reverted the altered disease profile to that seen in non-pharmacologically treated healthy individuals. In contrast, changes in the levels of the 72 proteins in patients who received placebo were negligible. Notably, changes in the abundance of 26 of the 72 proteins were significant even after correction for weight loss. Although most of these 26 proteins are associated with metabolic functions, several are implicated in fibrosis-related pathways and CV disease (e.g. ADAMTSL2 and ACY1), and hepatocellular carcinoma (e.g. SERPINC1).

Conclusion

Based on circulating proteomic profiling, semaglutide-induced MASH resolution is associated with changes in multiple pathogenic pathways even after correction for weight loss. Semaglutide appears to re-balance the expression levels of disease-associated proteins in MASH to levels found in healthy individuals.

Disclosure

MJ is an employee of Novo Nordisk A/S. JN is an employee of Novo Nordisk A/S. MSK is an employee of Novo Nordisk A/S. KA is an employee of Novo Nordisk A/S. KMB is an employee of Novo Nordisk A/S. EB served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento. Grants from Gilead Sciences for fatty liver research, Speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, and Pfizer. KC served as a consultant for Aligos Therapeutics, Arrowhead, AstraZeneca, 89Bio, BMS, Eli Lilly & Co., Merck, Novo Nordisk, Prosciento, Sagimet Biosciences, Siemens, and Terns Pharma. Received research support (University of Florida; Principal Investigator) from Boehringer Ingelheim, Echosens, Inventiva, Labcorp, and Perspectum. EDG is an employee of Novo Nordisk A/S. MG is an employee of Novo Nordisk A/S. LLG is an employee of Novo Nordisk A/S. LMH is an employee of Novo Nordisk A/S. RL is a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. His institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. GM is an employee of Novo Nordisk A/S. PNN is a consultant for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol Myers Squibb (BMS), Pfizer, Sun Pharma, Madrigal and GSK. He also reports honoraria as a speaker for Novo Nordisk and AiCME; support for attending meetings from for Novo Nordisk; and participation on an advisory board for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, Madrigal, and GSK. LMN is an employee of Novo Nordisk A/S. MSP is an employee of Novo Nordisk A/S. VR received consulting fees from Novo-Nordisk, Sagimet, Madrigal, Enyo, Poxel, Northsea, Intercept Pharmaceuticals, Prosciento. Research grants (to institution) from Gilead Sciences and Intercept Pharmaceuticals. A-SS is an employee of Novo Nordisk A/S. VWW served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, and TARGET PharmaSolutions. Has received a research grant from Gilead Sciences. Speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. Co-founder of Illuminatio Medical Technology Limited. Has received travel support from AbbVie and Gilead Sciences. QMA is coordinator of the IMI2 Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium, which is funded by the European Union Horizon 2020 programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This multi-stakeholder consortium includes industry partners. He reports research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept; consultancy on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GlaxoSmithKline, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGMBio, Novartis, Novo Nordisk, PathAI, Pfizer, Prosciento, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; speaker fees/honoraria from Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and royalties from Elsevier. LBK is an employee of Novo Nordisk A/S.