Background Despite achieving undetectable hepatitis B virus (HBV) DNA levels with nucleos(t)ide analogue (NA) therapy, patients with chronic hepatitis B (CHB) remain at risk of hepatocellular carcinoma (HCC). Novel covalently closed circular DNA activity biomarkers may improve risk stratification. Aims To comprehensively assess the association between serum HBV RNA and hepatitis B core‐related antigen (HBcrAg) levels, measured upon achieving undetectable HBV DNA levels, and subsequent HCC development in NA‐treated patients with CHB. Methods We retrospectively analysed 311 patients with CHB who achieved undetectable HBV DNA levels during NA therapy between 2000 and 2024. Serum HBV RNA (≥ 10 copies/mL) and HBcrAg (≥ 2.1 log U/mL) were measured in stored samples collected when HBV DNA first became undetectable. Cox regression analysis was performed to identify the factors associated with HCC development. Results During a median follow‐up of 11.0 years, 31 (10.0%) patients developed HCC. At viral suppression, 132 (42.4%) patients had HBV RNA ≥ 10 copies/mL. HCC incidence was significantly higher in patients with quantifiable HBV RNA than in those with unquantifiable HBV RNA (15‐year incidence, 17.8% vs. 8.8%, p = 0.026). Quantifiable HBV RNA independently predicted HCC (adjusted hazard ratio [aHR], 3.313; 95% confidence interval [CI]: 1.154–9.507; p = 0.026). HBcrAg showed no association (aHR, 0.821; 95% CI: 0.253–2.669; p = 0.743). Patients with quantifiable HBV RNA and albumin‐bilirubin score ≥ −2.60 had the highest risk (5‐year incidence: 15.8%). Conclusions HBV RNA levels at viral suppression predict HCC development in NA‐treated patients with CHB, outperforming HBcrAg. Incorporating HBV RNA assessment can improve risk‐stratified HCC surveillance strategies.
{"title":"Hepatitis B Virus RNA Predicts Hepatocellular Carcinoma Despite Viral Suppression","authors":"Takashi Kumada, Hidenori Toyoda, Satoshi Yasuda, Yuichi Koshiyama, Takanori Ito, Tomoyuki Akita, Junko Tanaka","doi":"10.1111/apt.70483","DOIUrl":"https://doi.org/10.1111/apt.70483","url":null,"abstract":"Background Despite achieving undetectable hepatitis B virus (HBV) DNA levels with nucleos(t)ide analogue (NA) therapy, patients with chronic hepatitis B (CHB) remain at risk of hepatocellular carcinoma (HCC). Novel covalently closed circular DNA activity biomarkers may improve risk stratification. Aims To comprehensively assess the association between serum HBV RNA and hepatitis B core‐related antigen (HBcrAg) levels, measured upon achieving undetectable HBV DNA levels, and subsequent HCC development in NA‐treated patients with CHB. Methods We retrospectively analysed 311 patients with CHB who achieved undetectable HBV DNA levels during NA therapy between 2000 and 2024. Serum HBV RNA (≥ 10 copies/mL) and HBcrAg (≥ 2.1 log U/mL) were measured in stored samples collected when HBV DNA first became undetectable. Cox regression analysis was performed to identify the factors associated with HCC development. Results During a median follow‐up of 11.0 years, 31 (10.0%) patients developed HCC. At viral suppression, 132 (42.4%) patients had HBV RNA ≥ 10 copies/mL. HCC incidence was significantly higher in patients with quantifiable HBV RNA than in those with unquantifiable HBV RNA (15‐year incidence, 17.8% vs. 8.8%, <jats:italic>p</jats:italic> = 0.026). Quantifiable HBV RNA independently predicted HCC (adjusted hazard ratio [aHR], 3.313; 95% confidence interval [CI]: 1.154–9.507; <jats:italic>p</jats:italic> = 0.026). HBcrAg showed no association (aHR, 0.821; 95% CI: 0.253–2.669; <jats:italic>p</jats:italic> = 0.743). Patients with quantifiable HBV RNA and albumin‐bilirubin score ≥ −2.60 had the highest risk (5‐year incidence: 15.8%). Conclusions HBV RNA levels at viral suppression predict HCC development in NA‐treated patients with CHB, outperforming HBcrAg. Incorporating HBV RNA assessment can improve risk‐stratified HCC surveillance strategies.","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"8 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Supachaya Sriphoosanaphan,Jane Macnaughtan,Haw Lu,Rohit Sawhney,Qianwen Zhao,Lin Su,Rocio Gallego-Duran,Emmanuel Wey,Nathan Davies,Rajeshwar P Mookerjee,Rajiv Jalan
BACKGROUND AND AIMSBacterial infection is a major cause of morbidity and mortality in patients with acute decompensation (AD) of cirrhosis. This study aimed to investigate patient plasma-induced dysfunction of healthy neutrophils (PIND) as a predictor of subsequent infection and mortality in patients with AD.METHODSOne hundred sixty AD patients (117 AD-NoACLF and 43 AD-ACLF), with a predominantly alcohol-related liver disease, were prospectively recruited. Plasma from 21 healthy controls and 74 patients with stable compensated cirrhosis was used as controls. Patient plasma was co-incubated with neutrophils from healthy donors to assess neutrophil function, including reactive oxygen species (ROS) production and phagocytic capacity, and CD62L surface expression.RESULTSPlasma from AD patients induced a primed state in healthy neutrophils, characterised by increased constitutive and N-formyl-Met-Leu-Phe (fMLP)-induced ROS production. However, effector functions were impaired, with significantly reduced phorbol 12-myristate 13-acetate (PMA)-induced ROS production, phagocytic capacity and CD62L expression. Escherichia coli- induced ROS production predicted subsequent infection in the total AD and AD-NoACLF cohorts (p = 0.043 and p = 0.013, respectively), while PMA-induced ROS production predicted 90-day mortality in the AD-NoACLF group (p = 0.041). None of the neutrophil function assays were predictive of clinical outcomes in AD-ACLF patients.CONCLUSIONSPlasma from patients with AD induces a 'primed but exhausted' neutrophil phenotype, characterised by a paradoxical failure to respond to stimuli. This dysfunction was associated with an increased risk of infection and mortality, particularly in AD-NoACLF patients. PIND offers a promising strategy to improve risk stratification in this high-risk population.
{"title":"Patient Plasma-Induced Neutrophil Dysfunction Is Associated With Infection Risk and Mortality in Patients With Acute Decompensation of Cirrhosis.","authors":"Supachaya Sriphoosanaphan,Jane Macnaughtan,Haw Lu,Rohit Sawhney,Qianwen Zhao,Lin Su,Rocio Gallego-Duran,Emmanuel Wey,Nathan Davies,Rajeshwar P Mookerjee,Rajiv Jalan","doi":"10.1111/apt.70480","DOIUrl":"https://doi.org/10.1111/apt.70480","url":null,"abstract":"BACKGROUND AND AIMSBacterial infection is a major cause of morbidity and mortality in patients with acute decompensation (AD) of cirrhosis. This study aimed to investigate patient plasma-induced dysfunction of healthy neutrophils (PIND) as a predictor of subsequent infection and mortality in patients with AD.METHODSOne hundred sixty AD patients (117 AD-NoACLF and 43 AD-ACLF), with a predominantly alcohol-related liver disease, were prospectively recruited. Plasma from 21 healthy controls and 74 patients with stable compensated cirrhosis was used as controls. Patient plasma was co-incubated with neutrophils from healthy donors to assess neutrophil function, including reactive oxygen species (ROS) production and phagocytic capacity, and CD62L surface expression.RESULTSPlasma from AD patients induced a primed state in healthy neutrophils, characterised by increased constitutive and N-formyl-Met-Leu-Phe (fMLP)-induced ROS production. However, effector functions were impaired, with significantly reduced phorbol 12-myristate 13-acetate (PMA)-induced ROS production, phagocytic capacity and CD62L expression. Escherichia coli- induced ROS production predicted subsequent infection in the total AD and AD-NoACLF cohorts (p = 0.043 and p = 0.013, respectively), while PMA-induced ROS production predicted 90-day mortality in the AD-NoACLF group (p = 0.041). None of the neutrophil function assays were predictive of clinical outcomes in AD-ACLF patients.CONCLUSIONSPlasma from patients with AD induces a 'primed but exhausted' neutrophil phenotype, characterised by a paradoxical failure to respond to stimuli. This dysfunction was associated with an increased risk of infection and mortality, particularly in AD-NoACLF patients. PIND offers a promising strategy to improve risk stratification in this high-risk population.","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"52 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brooke Maracle, Steven Quan, Patrick Hamilton, Asma Shaikh, Deepan Hazra, Diane L. Lorenzetti, Stephanie L. Gold, Maitreyi Raman, Joëlle St-Pierre
Background
Obesity and metabolic disease are increasingly prevalent in patients with inflammatory bowel disease (IBD) and can influence disease activity and treatment outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for weight loss and metabolic control, yet their safety and effects in IBD remain uncertain as patients with IBD have been excluded from pivotal trials.
Aims
To systematically evaluate the weight-related, metabolic, IBD-specific, and safety outcomes of GLP-1 receptor agonists in adults with IBD.
Methods
We conducted a systematic review according to PRISMA guidelines (PROSPERO CRD42025628850). We searched MEDLINE, Embase, Cochrane Library and ClinicalTrials.gov to 9 September 2025 for studies evaluating GLP-1 RAs in adults with IBD. Primary outcomes were weight-related measures. Secondary outcomes included metabolic parameters, IBD activity, and safety. Risk of bias was assessed using Joanna Briggs Institute (JBI) checklists.
Results
We included 14 studies of which 13 were retrospective cohort studies. Ten reported significant reductions in body weight, BMI, or percent weight loss. Four demonstrated improvements in metabolic markers, including decreased haemoglobin A1c and favourable lipid changes. Across multiple datasets, GLP-1 RA use was not associated with increased IBD exacerbations. Several large registries reported reduced risks of corticosteroid use, hospitalisation and surgery among GLP-1 RA users. Adverse events were primarily gastrointestinal, consistent with non-IBD populations.
Conclusion
GLP-1 RAs appear to be well tolerated in patients with IBD, with observational evidence suggesting potential associations with improved weight, metabolic, and disease-related outcomes. Prospective, IBD-specific studies are required to confirm safety, clarify mechanisms, and define optimal patient selection.
{"title":"Systematic Review: Efficacy, Safety and Metabolic Outcomes of GLP-1 Receptor Agonists in Inflammatory Bowel Disease","authors":"Brooke Maracle, Steven Quan, Patrick Hamilton, Asma Shaikh, Deepan Hazra, Diane L. Lorenzetti, Stephanie L. Gold, Maitreyi Raman, Joëlle St-Pierre","doi":"10.1111/apt.70485","DOIUrl":"10.1111/apt.70485","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Obesity and metabolic disease are increasingly prevalent in patients with inflammatory bowel disease (IBD) and can influence disease activity and treatment outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for weight loss and metabolic control, yet their safety and effects in IBD remain uncertain as patients with IBD have been excluded from pivotal trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To systematically evaluate the weight-related, metabolic, IBD-specific, and safety outcomes of GLP-1 receptor agonists in adults with IBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a systematic review according to PRISMA guidelines (PROSPERO CRD42025628850). We searched MEDLINE, Embase, Cochrane Library and ClinicalTrials.gov to 9 September 2025 for studies evaluating GLP-1 RAs in adults with IBD. Primary outcomes were weight-related measures. Secondary outcomes included metabolic parameters, IBD activity, and safety. Risk of bias was assessed using Joanna Briggs Institute (JBI) checklists.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 14 studies of which 13 were retrospective cohort studies. Ten reported significant reductions in body weight, BMI, or percent weight loss. Four demonstrated improvements in metabolic markers, including decreased haemoglobin A1c and favourable lipid changes. Across multiple datasets, GLP-1 RA use was not associated with increased IBD exacerbations. Several large registries reported reduced risks of corticosteroid use, hospitalisation and surgery among GLP-1 RA users. Adverse events were primarily gastrointestinal, consistent with non-IBD populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>GLP-1 RAs appear to be well tolerated in patients with IBD, with observational evidence suggesting potential associations with improved weight, metabolic, and disease-related outcomes. Prospective, IBD-specific studies are required to confirm safety, clarify mechanisms, and define optimal patient selection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"63 1","pages":"17-39"},"PeriodicalIF":6.7,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70485","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michelle Spaan,Ellen Werner,Willemijn Dijkstra,Nicole E Erler,Diederik Bijdevaate,Sarwa Darwish Murad,Milan J Sonneveld,Caroline M den Hoed,Anne van Eldere,Dave S Sprengers,Willem-Pieter Brouwer,Robert J de Knegt,Harry L A Janssen,Kay Pieterman,Sandra Coenen,Raoel Maan,Adriaan J van der Meer
OBJECTIVESTransjugular intrahepatic portosystemic shunt (TIPS) placement effectively decreases portal pressure in patients with decompensated cirrhosis. However, many patients develop hepatic encephalopathy (HE) post-TIPS. We investigated the relation between the presence of Diabetes Mellitus (DM) and the occurrence of HE following TIPS placement in patients with cirrhosis.METHODSIn this retrospective cohort study all patients with cirrhosis who received a TIPS from 2007 through 2021 were included. Baseline characteristics and decompensating events including hospital admission for HE were recorded. In cases where hospital admission was required, HE was considered severe.RESULTSIn total, 325 patients were included and 113 (34.8%) had DM at the time of TIPS placement. One hundred and fifty-one patients developed HE of whom 86 (57.0%) were hospitalised. The cumulative 6-month incidences of HE and severe HE were 45.2% (95% CI 39.5-51.8) and 25.1% (95% CI 20.2-31.3), respectively. Multivariable Cox regression with competing risk analyses demonstrated that DM was independently associated with the risk of both HE (aHR 1.56, 95% CI 1.08-2.26, p = 0.018) and severe HE (aHR 1.76, 95% CI 1.07-2.90, p = 0.026). These associations were independent of the relation between HE and age (aHR 1.03, 95% CI 1.01-1.05, p < 0.001) or MELD-Na score (aHR 1.07, 95% CI 1.03-1.10, p < 0.001).CONCLUSIONSThis study highlights the high incidence of HE following TIPS and shows that DM is a significant and independent risk factor for the development of HE. Given the increase in patients with metabolic dysfunction-associated liver cirrhosis and DM, this study offers additional insights into the balance of risks and benefits associated with TIPS placement.
目的：经颈静脉肝内门静脉系统分流术（TIPS）可有效降低肝硬化失代偿期患者门静脉压力。然而，许多患者在tips后发展为肝性脑病（HE）。我们调查了肝硬化患者在TIPS放置后糖尿病（DM）的存在与HE的发生之间的关系。方法在这项回顾性队列研究中，纳入了2007年至2021年接受TIPS治疗的肝硬化患者。记录基线特征和失代偿事件，包括HE住院。在需要住院的情况下，HE被认为是严重的。结果共纳入325例患者，其中113例（34.8%）在TIPS放置时患有糖尿病。151例患者发生HE，其中86例（57.0%）住院。HE和重度HE的6个月累计发病率分别为45.2% （95% CI 39.5-51.8）和25.1% （95% CI 20.2-31.3）。多变量Cox回归与竞争风险分析显示，DM与HE （aHR 1.56, 95% CI 1.08-2.26, p = 0.018）和重度HE （aHR 1.76, 95% CI 1.07-2.90, p = 0.026）的风险独立相关。这些关联与HE与年龄（aHR 1.03, 95% CI 1.01-1.05, p < 0.001）或MELD-Na评分（aHR 1.07, 95% CI 1.03-1.10, p < 0.001）的关系无关。结论提示TIPS后HE发生率较高，DM是HE发展的重要独立危险因素。鉴于代谢功能障碍相关肝硬化和糖尿病患者的增加，本研究提供了与TIPS放置相关的风险和收益平衡的额外见解。
{"title":"Diabetes Mellitus is a Risk Factor for Hepatic Encephalopathy Following Transjugular Intrahepatic Portosystemic Shunt.","authors":"Michelle Spaan,Ellen Werner,Willemijn Dijkstra,Nicole E Erler,Diederik Bijdevaate,Sarwa Darwish Murad,Milan J Sonneveld,Caroline M den Hoed,Anne van Eldere,Dave S Sprengers,Willem-Pieter Brouwer,Robert J de Knegt,Harry L A Janssen,Kay Pieterman,Sandra Coenen,Raoel Maan,Adriaan J van der Meer","doi":"10.1111/apt.70453","DOIUrl":"https://doi.org/10.1111/apt.70453","url":null,"abstract":"OBJECTIVESTransjugular intrahepatic portosystemic shunt (TIPS) placement effectively decreases portal pressure in patients with decompensated cirrhosis. However, many patients develop hepatic encephalopathy (HE) post-TIPS. We investigated the relation between the presence of Diabetes Mellitus (DM) and the occurrence of HE following TIPS placement in patients with cirrhosis.METHODSIn this retrospective cohort study all patients with cirrhosis who received a TIPS from 2007 through 2021 were included. Baseline characteristics and decompensating events including hospital admission for HE were recorded. In cases where hospital admission was required, HE was considered severe.RESULTSIn total, 325 patients were included and 113 (34.8%) had DM at the time of TIPS placement. One hundred and fifty-one patients developed HE of whom 86 (57.0%) were hospitalised. The cumulative 6-month incidences of HE and severe HE were 45.2% (95% CI 39.5-51.8) and 25.1% (95% CI 20.2-31.3), respectively. Multivariable Cox regression with competing risk analyses demonstrated that DM was independently associated with the risk of both HE (aHR 1.56, 95% CI 1.08-2.26, p = 0.018) and severe HE (aHR 1.76, 95% CI 1.07-2.90, p = 0.026). These associations were independent of the relation between HE and age (aHR 1.03, 95% CI 1.01-1.05, p < 0.001) or MELD-Na score (aHR 1.07, 95% CI 1.03-1.10, p < 0.001).CONCLUSIONSThis study highlights the high incidence of HE following TIPS and shows that DM is a significant and independent risk factor for the development of HE. Given the increase in patients with metabolic dysfunction-associated liver cirrhosis and DM, this study offers additional insights into the balance of risks and benefits associated with TIPS placement.","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"107 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial: Caught in the Middle-Exploring the Grey Zone Between Decompensated and Recompensated HBV-Related Cirrhosis.","authors":"Stephanie Tsai,Mohammad Amin Fallahzadeh","doi":"10.1111/apt.70456","DOIUrl":"https://doi.org/10.1111/apt.70456","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"146 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial: Caught in the Middle-Exploring the Grey Zone Between Decompensated and Recompensated HBV-Related Cirrhosis. Authors' Reply.","authors":"Bingqiong Wang,Shuai Xia,Xiaoning Wu,Hong You","doi":"10.1111/apt.70482","DOIUrl":"https://doi.org/10.1111/apt.70482","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"10 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan Frias, Robert Schmouder, Eric Lawitz, Yiming Zhang, Heng Zhou, Michael K. Badman, Chinweike Ukomadu, H. Markus Weiss, Julia Zack, Brijesh Yadav, Miljen Martic, Clive Drakeford, Phillip Koo, Nikolai V. Naoumov, Linda E. Greenbaum
Background Drug combinations have potential for additive or synergistic efficacy in patients with metabolic dysfunction–associated steatohepatitis (MASH). Aim To assess the safety, efficacy and pharmacokinetics of single or combination treatments in patients with MASH. Methods In this multicentre, open‐label, platform phase 2 study, patients ( N = 41) were randomised 1:1 to LYS006 20 mg twice‐daily (bid) monotherapy or LYS006 20 mg bid+tropifexor 200 μg once‐daily (qd) combination therapy for 12 weeks. The primary endpoint was safety; secondary endpoints were efficacy and pharmacokinetics. Results Pruritus adverse events (AEs) were reported in 62% of patients in the combination arm. Other AEs were similar between the treatment arms. A greater reduction in alanine aminotransferase (ALT) and liver fat was observed in the combination versus monotherapy arm (ALT: 43% vs. 13% reduction; liver fat: 37% vs. 20% reduction, respectively). No significant impact on biomarkers for liver fibrosis was observed in either treatment arm, but there was an indication for lower plasma exposure to LYS006 upon co‐administration with tropifexor. Conclusions LYS006 20 mg bid monotherapy and LYS006 20 mg bid+tropifexor 200 μg qd therapy were well tolerated with the exception of a high frequency of pruritus in the combination arm, consistent with the now known pharmacologic effect of farnesoid X receptor agonists. The greater reductions in ALT and liver fat in the combination arm versus monotherapy arm were similar to those observed with tropifexor as monotherapy in a previously reported phase 2 clinical trial, and clear additional benefit was not observed in combination treatment with LYS006. This study design allowed for rapid screening of potentially high efficacy drug combinations in MASH. Trial Registration ClinicalTrials.gov identifier: NCT04147195
{"title":"Clinical trial: A Phase 2 Randomised Platform Study to Assess Monotherapy and Combination Treatment Regimens in Metabolic Dysfunction–Associated Steatohepatitis","authors":"Juan Frias, Robert Schmouder, Eric Lawitz, Yiming Zhang, Heng Zhou, Michael K. Badman, Chinweike Ukomadu, H. Markus Weiss, Julia Zack, Brijesh Yadav, Miljen Martic, Clive Drakeford, Phillip Koo, Nikolai V. Naoumov, Linda E. Greenbaum","doi":"10.1111/apt.70475","DOIUrl":"https://doi.org/10.1111/apt.70475","url":null,"abstract":"Background Drug combinations have potential for additive or synergistic efficacy in patients with metabolic dysfunction–associated steatohepatitis (MASH). Aim To assess the safety, efficacy and pharmacokinetics of single or combination treatments in patients with MASH. Methods In this multicentre, open‐label, platform phase 2 study, patients ( <jats:italic>N</jats:italic> = 41) were randomised 1:1 to LYS006 20 mg twice‐daily (bid) monotherapy or LYS006 20 mg bid+tropifexor 200 μg once‐daily (qd) combination therapy for 12 weeks. The primary endpoint was safety; secondary endpoints were efficacy and pharmacokinetics. Results Pruritus adverse events (AEs) were reported in 62% of patients in the combination arm. Other AEs were similar between the treatment arms. A greater reduction in alanine aminotransferase (ALT) and liver fat was observed in the combination versus monotherapy arm (ALT: 43% vs. 13% reduction; liver fat: 37% vs. 20% reduction, respectively). No significant impact on biomarkers for liver fibrosis was observed in either treatment arm, but there was an indication for lower plasma exposure to LYS006 upon co‐administration with tropifexor. Conclusions LYS006 20 mg bid monotherapy and LYS006 20 mg bid+tropifexor 200 μg qd therapy were well tolerated with the exception of a high frequency of pruritus in the combination arm, consistent with the now known pharmacologic effect of farnesoid X receptor agonists. The greater reductions in ALT and liver fat in the combination arm versus monotherapy arm were similar to those observed with tropifexor as monotherapy in a previously reported phase 2 clinical trial, and clear additional benefit was not observed in combination treatment with LYS006. This study design allowed for rapid screening of potentially high efficacy drug combinations in MASH. Trial Registration <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"http://clinicaltrials.gov\">ClinicalTrials.gov</jats:ext-link> identifier: NCT04147195","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"97 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra Hickey, Chaonan Dong, Christopher A. Lamb
{"title":"Editorial: High‐Grade Dysplasia in Colonic Inflammatory Bowel Disease Is Associated With a High Risk of Synchronous or Metachronous Colorectal Cancer","authors":"Alexandra Hickey, Chaonan Dong, Christopher A. Lamb","doi":"10.1111/apt.70442","DOIUrl":"https://doi.org/10.1111/apt.70442","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"136 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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