Rezdiffra (resmetirom) / Madrigal Pharma - LARVOL DELTA

HK3, a novel oral anti-obesity MASH drug with direct reduction of liver fibrosis (EASL 2025) - "Human hepatic stellate cells (LX2) were treated with TGF-β1 (5 ng/ml, 24h) with HK3 or competitor drugs (semaglutide, lanifibranor and resmetirom, all 10 µM) to assess pro-fibrotic protein levels. This comprehensive study reveals HK3 as a promising candidate for MASH treatment, demonstrating both potent direct anti-fibrotic and anti-obesity effects. Its unique mechanism of action and multi-faceted benefits position HK3 as a potential first-in-class therapy for the concurrent management of MASH and obesity, addressing two critical aspects of metabolic liver disease."

Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • TGFB1

Treatment with resmetirom for up to two years led to improvement in liver stiffness, fibrosis biomarkers, fibrosis scores and portal hypertension risk in 122 patients with compensated MASH cirrhosis (EASL 2025) - "No reproduction, re-use or transcription for any commercial purpose or use of the content is permitted without the written permission of the authors. Permission for re-use must be obtained directly from the authors."

Biomarker • Clinical • Late-breaking abstract • Cardiovascular • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Portal Hypertension

Efficacy of pharmacotherapy in improvement of liver fibrosis and steatohepatitis in patients with metabolic dysfunction associated steatotic liver disease (MASLD): a network meta-analysis (EASL 2025) - "Pegozafermin, Lanafibrinor, Obeticholic acid, Resmetirom, Vitamin E and Pioglitazone were significantly better than placebo in achieving  1 stage fibrosis improvement...Efruxifermin, Pegozafermin, Tirzepatide, Semaglutide, Aldafermin, Pioglitazone, Resmetirom and Lanafibrinor were significantly better than placebo in achieving MASH resolution... This study provides an updated relative rank-order of various therapies in terms of their efficacy in fibrosis improvement and MASH resolution. In future, therapies that improve liver fibrosis in patients with MASLD may be combined with therapies which achieve MASH resolution for better treatment response."

Retrospective data • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

General characteristics of the patients prescribed Resmetirom: data derived from six tertiary care centers in the United States (EASL 2025) - "Cardiometabolic comorbidities were common, with 40.3% on statins, 19.3% on GLP-1 analogs, and 33.3% on metformin. This large real-world cohort of MASH patients prescribed resmetirom reflects the high burden of cardiometabolic comorbidities typical of MASLD populations, with obesity and T2D being especially prevalent. Most patients were diagnosed with advanced fibrosis (F2-F3) using noninvasive methods, such as transient elastography, highlighting a shift from biopsy reliance in clinical trials to real-world practice. These findings underline the importance of integrated management of cardiometabolic risk factors and reinforce the potential of resmetirom as a critical therapy for MASH in real-world settings."

Clinical • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Baseline characteristics in well-compensated NASH cirrhosis patients diagnosed with or without a liver biopsy in MAESTRO-NASH-OUTCOMES, a clinical outcome phase 3 study assessing the effect of resmetirom in well compensated NASH cirrhosis (EASL 2025) - P3 | "These data support the accuracy of using non-invasive testing to accurately diagnose well-compensated NASH cirrhosis."

Biopsy • Clinical • Clinical data • P3 data • Cardiovascular • CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis • Portal Hypertension • Type 2 Diabetes Mellitus

Assessing early changes and responses to resmetirom therapy using real world single center data (EASL 2025) - "In the first 19 patients to reach three months of treatment on resmetirom, LSM reduced from pre-treatment levels, independent of liver enzymes, weight/BMI change, diabetes control or GLP- 1 RA use. These data suggest that response to therapy may be assessable at the 3-month timepoint, helping to guide future management in high-risk patients. Limitations include a small cohort and the lack of a control population."

Clinical • Real-world • Real-world evidence • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Indication of resmetirom in patients with metabolic dysfunction associated steatohepatitis in the real-world setting - data from the german SLD-registry (EASL 2025) - "The selection of eligible patients for resmetirom treatment depends on the method used to identify "at-risk MASH". The availability of diagnostic approaches differs between academic and non-academic centers. Non-invasive assessment may miss patients who would qualify for resmetirom according to biopsy."

Clinical • Real-world • Real-world evidence • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Single-cell transcriptomics reveals THR-β agonist treatment increases macrophage proportion and inhibits complement pathway in mice with metabolic dysfunction-associated steatohepatitis (EASL 2025) - "Background and Aims: Thyroid hormone receptor (THR)-β agonist resmetirom has been approved by the U.S. FDA as the first drug for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Treatment with the THR-β agonist HSK31679 in MASH mice resulted in an increased proportion of liver macrophages and suppressed complement activation pathways in these cells. Additionally, communication between liver cell subsets, particularly between hepatocytes and macrophages, was enhanced."

Preclinical • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Preclinical studies of a novel hydrolysis-based prodrug for treating metabolic dysfunction associated steatohepatitis (EASL 2025) - "Background and Aims: Approval of resmetirom for treating Metabolic dysfunction associated steatohepatitis validated thyroid hormone receptor beta (THR-b) as an effective therapeutic target. Our prodrugs showed a ~15-fold in vitro activity increase over VK-2809 in HepG2 assay. In vivo PK studies showed that they were barely detectable while the active metabolite was preferentially concentrated in the liver compared to VK-2809. The ratio of the active metabolite AUC between liver and heart was 116 (CG-025013), 158 (CG-025016) vs 63 (VK-2809)."

Preclinical • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Comparative anti-fibrotic action of resmetirom, semaglutide, tirzepatide and efruxifermin in the GAN diet-induced obese and biopsy-confirmed mouse model of MASH (EASL 2025) - "RES, SEMA, TZP and EFX improved metabolic, biochemical and histopathological endpoints in GAN DIO-MASH mice, highlighting the model clinical translatability. Longer treatment intervention demonstrated histological improvement in fibrosis, highlighting the importance of treatment duration to alleviate fibrosis burden in the GAN DIO-MASH model."

Biopsy • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • COL1A1 • FGF21 • LGALS3 • TIMP1

Identification of differences in therapeutic mechanisms between Resmetirom and Semaglutide on metabolic dysfunction-associated steatohepatitis treatment in western diet-fed melanocortin 4 receptor knockout mice (EASL 2025) - "These results revealed that the different mechanisms of anti-MASH effects between Resmetirom and Semaglutide. Similar to clinical evidence, Semaglutide treatment might have a problem on muscle mass reduction by food intake suppression. This study provides the first evaluation to compare Resmetirom and Semaglutide simultaneously on MASH phenotypes and revealed their mechanism of action using WD-fed MC4R KO mice."

Preclinical • Anesthesia • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • MC4R

Evaluating noninvasive tests for significant fibrosis in a population-based MASLD cohort: insights from NHANES 2017–2020 (EASL 2025) - "Background and Aims: Resmetirom is FDA-approved for metabolic dysfunction-associated steatotic liver disease (MASLD) with significant (F2) to advanced (F3) fibrosis... While ALADDIN-F2-Lab demonstrated the highest PPV among NITs for high-risk classification and SAFE achieved superior sensitivity, no NIT showed sufficient sensitivity (<50%) to reliably identify the majority of patients with significant fibrosis (LSM ≥8 kPa) in a general population cohort. This highlights the challenge of applying NITs derived from tertiary centers to broader, community-based settings. Reassessing existing cutoffs and optimizing NITs for use in general populations may improve their utility as first-line screening tools for significant fibrosis or higher."

Clinical • Non-invasive • Fibrosis • Hepatology • Immunology • Infectious Disease • Inflammation • Metabolic Dysfunction-Associated Steatotic Liver Disease

Development and validation of two NIS2+®-based models for the detection of MASH resolution and fibrosis improvement (EASL 2025) - P3 | "Background and Aims: The recent approval of Rezdiffra for the treatment of patients (pts) with MASH and fibrosis (F) 2-3 further increases the need for an efficient non-invasive monitoring tool to identify pts who meet the histological endpoints of MASH clinical trials (MASH resolution [EP1], F improvement [EP2])... We developed and validated 2 NIS2+®-based models with high performance in ruling- in/out MASH resolution and F improvement, allowing a potential use for monitoring treatment response. While a ~1-year follow-up could potentially allow for early detection of histological improvement, a design with 4 measures over ~1.5 years using Hc is recommended."

Fibrosis • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

Best buys to diagnose and treat metabolic dysfunction-associated steatohepatitis among people living with diabetes type 2: a multi-country generalized cost-effectiveness analysis (EASL 2025) - "Using an 80% coverage level for each approach, 14 approaches, including the standard of care (SoC) defined as the absence of any systematic intervention, were considered: (1) Fibrosis-4 (FIB-4) screening; (2A) FIB-4 + vibration-controlled transient elastography (VCTE); (2B) FIB-4 + enhanced liver fibrosis test (ELF); (3A) FIB-4, VCTE, hepatologist, intensive lifestyle intervention (ILI); (3B) FIB-4, ELF, hepatologist, ILI; (4A) FIB-4, VCTE, hepatologist, resmetirom; (4B) FIB-4, ELF, hepatologist, resmetirom; (5A) FIB-4, VCTE, hepatologist, resmetirom, ILI; (5B) FIB-4, ELF, hepatologist, resmetirom, ILI; (6A) FIB-4, VCTE, hepatologist, semaglutide; (6B) FIB-4, ELF, hepatologist, semaglutide; (7A) FIB-4, VCTE, hepatologist, semaglutide, ILI; (7B) FIB-4, ELF, hepatologist, semaglutide, ILI... Screening approaches that are followed by both lifestyle and pharmacological treatments aimed at tackling liver fibrosis in patients with T2D and liver fibrosis with MASH were found to..."

Cost effectiveness • HEOR • Diabetes • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • Type 2 Diabetes Mellitus

First construction and validation of new circulating markers (NITs) to assess the risk of early-fibrosis (eF) occurrence in outpatients with type-2 diabetes (T2D) and elevated transaminases (EASL 2025) - "This higher granularity for the diagnosis of eF was already used in the phase- 3 trial of the resmetirom treatment, which demonstrated a superiority to placebo in improving non- cirrhotic stages by at least one-stage with NASH-resolution... If confirmed by independent studies, NITs calibrated for eF could replace liver biopsy for surveillance and approval of anti-fibrosis treatments in T2D outpatients with elevated transaminases."

Clinical • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Metabolic dysfunction-associated steatotic liver disease (MASLD) screening according to EASL guideline is cost-effective (EASL 2025) - "For those who qualified, treatment with resmetirom was provided according to the FDA approval... Screening for MASLD following EASL guidelines is cost-effective in the U.S., reducing advanced fibrosis, mortality, and long-term healthcare costs."

Cost effectiveness • HEOR • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Ongoing fibrosis quantification in paired liver biopsy samples from MASLD patients using AI-based digital pathology: an international multicenter study (EASL 2025) - "These patients were managed through lifestyle intervention during follow-up and did not receive resmetirom... Preliminary clinical data analysis revealed significant improvements in liver histological features in both the lifestyle intervention and placebo groups. And the lifestyle intervention group was considered analogous to a placebo group in the real world. We plan to conduct a standardized unstained scan and quantitative fibrosis analysis of paired liver biopsy samples collected globally."

Biopsy • Clinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Weight dependent, weight independent and non-pharmacological effects on fibroblast activity in metabolic dysfunction associated steatotic liver disease (MASLD) (EASL 2025) - "A weight loss study using VLCD, and data from pharmacological interventions with Resmetirom, GLP1RA and Survodutide previously analyzed for changes in either PRO-C3 and PRO-C6. Pharmacological and non-pharmacological induction of weight loss results in different deactivation of fibroblasts activities, which may have divergent efficacy on heart and liver related outcomes. Furthermore, weight dependent and independent mechanisms of deactivation fibroblasts may result in additional effects on bone and muscle. This understanding may be needed when designing the optimal intervention strategy, including possible combination regimens, for the individual MAFLD patient."

Cardiovascular • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Osteoporosis • FGF19 • FGF21

Use of the LiverRisk score for prediction of moderate to advanced liver fibrosis in United States adults (EASL 2025) - "Background and Aims: Resmetirom is the first approved treatment in the United States (US) for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis [NASH]), conditionally approved for use in adults with moderate to advanced liver fibrosis consistent with stages F2 to F3... In US adults, the LRS demonstrated superior accuracy vs. FIB-4 for prediction of LSM ≥ 8 kPa and ≥ 20 kPa, which could facilitate screening for noncirrhotic MASH with fibrosis stages F2-F3."

Clinical • Metastases • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Liver-related events are uncommon in patients meeting AASLD criteria for Resmetirom and are not seen in those with a liver stiffness measurement < 10 kPa (EASL 2025) - "LRE are uncommon in patients meeting AASLD criteria for Resmetirom therapy and were not seen with a LSM < 10 kPa. Non liver related mortality was predominant. In an era predating specific drug therapy, a majority of patients undergoing follow up LSM demonstrated improvement."

Clinical • Cardiovascular • CNS Disorders • Diabetes • Hepatology • Hypertension • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

The utility of noninvasive tests - LIVERFASt, FIB4 and vibration-controlled transient elastography (VCTE, Fibroscan) - in the initiation and monitoring of the therapy with TNR-beta agonist (resmetirom) in MASH patients (EASL 2025) - "Initiation of RT based on non-invasive assessment of patients using LFAST, FIB4 (fibrosis only) and VCTE is efficient and allows further non-invasive monitoring. A rapid trend in steatosis improvement was observed."

Clinical • Non-invasive • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • APOA1

Novel multiparametric MRI imaging predicts histologic response in resmetirom versus placebo in the multicentre, international, Maestro NASH phase 3 trial (EASL 2025) - P3 | "A positive association with fibrosis stage and with MRI-PDFF was observed for cT1 in this subset analysis. cT1 demonstrated a dose dependent reduction with Resmetirom treatment, with the greatest reductions in the 100mg group, and a negligible placebo response. A reduction in cT1 of >80ms was associated with high likelihood of histological response."

Clinical • P3 data • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Validation of proposed non-invasive criteria for resmetirom treatment in metabolic-associated liver disease in clinical practice (EASL 2025) - "The diagnostic performance and reliability of the proposed non-invasive criteria for initiating resmetirom treatment and for reffering patients to specialized units were suboptimal. More than half of the indicated patients (fibrotic MASH) would not receive treatment under these criteria."

Clinical • Non-invasive • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Use of noninvasive tests (NITs) to diagnose and follow non-alcoholic steatohepatitis (NASH) with liver fibrosis patients treated with resmetirom (EASL 2025) - P3 | "Identification of patients with NASH F2 to F3 was achieved with FibroScan and VCTE. F1B are F2 equivalent (F1B is moderate fibrosis on biopsy). Patients with fibrosis stage F4 were effectively ruled out."

Clinical • Non-invasive • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Non-invasive identification of MASLD patients eligible for resmetirom treatment – data from a multicenter biopsy-proven MASLD cohort (EASL 2025) - "The recommended VCTE cut-offs effectively excluded most MASLD patients with F0/F1 fibrosis from resmetirom treatment. However, in patients with VCTE values of 10–19.9 kPa and no features of cirrhosis, additional diagnostic tools, including liver biopsy or other non-invasive assessments, may be needed to minimize misclassification and optimize the identification of eligible patients."

Biopsy • Clinical • Non-invasive • Cardiovascular • Fibrosis • Hematological Disorders • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Portal Hypertension • Thrombocytopenia