Rezdiffra (resmetirom) / Madrigal Pharma - LARVOL DELTA

Pathogenesis-Informed Phenotype-Guided Therapy for MASH: A Three-Axis Translational Framework Within the MASLD Spectrum. (PubMed, Biomedicines) - "Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive inflammatory and fibrotic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), and its treatment landscape is rapidly moving from nonspecific liver fat reduction towards mechanism-based drug positioning. Since 2024, resmetirom and semaglutide have received U.S. Food and Drug Administration accelerated approval for non-cirrhotic MASH with moderate-to-advanced fibrosis, while tirzepatide, survodutide, and fibroblast growth factor 21 analogues have shown biopsy-based phase 2 or 2b efficacy signals...In particular, weight-centred treatment should not be assumed to apply to all patients, including normal-weight or lean MASH. Overall, future MASH therapy will likely depend on matching drug mechanisms, fibrosis stage, cardiometabolic phenotype, and treatment goals."

Journal • Review • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • FGF21

Cardiovascular-Kidney-Metabolic Syndrome and Its Hepatic Dimension: A Narrative Review. (PubMed, Medicina (Kaunas)) - "Particular attention is given to the recent approvals of resmetirom and semaglutide for metabolic dysfunction-associated steatohepatitis and to the expanding roles of sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and non-steroidal mineralocorticoid receptor antagonists...Other individuals may develop this high-risk cluster over time. The aim of this article is to define the interplay between different metabolic conditions and to outline the best approach to diagnosis, monitoring, and effective integrated therapy."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Genetic Disorders • Hepatology • Hypertension • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

The Role of the OSM/OSMRβ Axis in Chronic Liver Disease Progression and Hepatocellular Carcinoma Development: A Focus on MASLD/MASH. (PubMed, Int J Mol Sci) - "Although two drugs (Resmetirom and Semaglutide) have been recently approved for clinical use, their ability to block or slow down disease progression to metabolic dysfunction-associated Steatohepatitis (MASH) and liver fibrosis is limited to a subset of patients, and no data are available at present for the efficacy of these drugs in compensated cirrhosis or in relation to hepatocellular carcinoma (HCC) development...The OSM/OSMRβ axis is proposed to be involved in MASH-related HCC development by affecting proliferation, angiogenesis, invasiveness and metastasis as well as by reshaping the MASH-related tumor immune microenvironment. OSM and the OSM/OSMRβ axis are emerging as a candidate biomarker and putative MASH-related therapeutic target."

Journal • Review • Diabetes • Fibrosis • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • IL6

From Single Agents to Synergy: Redefining Therapeutic Strategies in MASLD. (PubMed, Int J Mol Sci) - "The recent approvals of resmetirom and semaglutide have marked a pivotal advance in the management of metabolic dysfunction-associated steatotic liver disease (MASLD)...Finally, we address key challenges related to patient selection, disease heterogeneity, treatment duration, safety, cost-effectiveness, and regulatory approval. We propose that the future of combination therapy in MASLD will likely rely on precision-medicine approaches that align therapeutic mechanisms with individual disease biology and stage."

Clinical • Journal • Review • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Pruritus in Progressive Familial Intrahepatic Cholestasis on Resmetirom for MASLD Treated With Ileal Bile Acid Transporter Inhibitor (ACG 2026) - "Subsequently, patient was started on IBATi odevixibat at 40μg/day. Figure: Figure 1A: Change in Fibrosis Score and Serum Liver Enzymes (alanine transaminase, aspartate transaminase) before resmetirom treatment and four months after starting remetirom treatment. Figure 1B: Change in Serum Bile Acids and 5-D Itch Score before IBATi (Ileal Bile Acid Transport Inhibitor) treatment and two months after starting IBATi treatment."

Cardiovascular • Cholestasis • Dermatology • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Hypertension • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Pruritus • ABCB4

Severe Abnormal Uterine Bleeding in Premenopausal Women Following ResmetiromTherapy: Case Series (ACG 2026) - "4- Decreased GnRH reduces LH and FSH secretion 5- PCOS leads to decreased FSH but increased LH, along with chronic anovulation, leading to relative estrogen dominance and decreased progesterone, culminating in endometrial instability 6- Resmetirom may increase sex hormone binding globulin (SHBG), increasing total estrogen 7- In obesity, there is excess adipose tissue. The adipose tissue contains the enzyme aromatase, which converts androgens to estrogens, contributing to estrogen dominance 8- Relative estrogen dominance and decreased progesterone, leading to proliferative, unstable endometrium, result in heavy menstrual bleeding"

Clinical • Endocrine Disorders • Genetic Disorders • Gynecology • Hepatology • Infectious Disease • Long-acting Reversible Contraceptives • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Polyendocrine Metabolic Ovarian Syndrome • Women's Health • PGR • THRA

Significant Clinical Burden of Metabolic Dysfunction-Associated Steatohepatitis With F2 or Greater Fibrosis Among a National Cohort of U.S. Veterans (ACG 2026) - "Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a major cause of liver-related morbidity and mortality in the U.S. Two FDA approved therapies (i.e. resmetirom and semaglutide) have shown efficacy in treating patients with MASH with F2-F3 fibrosis... Among 1,058,877 adults with MASLD (93.0% men, mean age 63.1y, 62.7% had BMI > 30kg/m 2 , 54.5% with diabetes mellitus), 119,660 patients with MASH with > F2 fibrosis were identified. The proportion of MASLD patients who had MASH with > F2 fibrosis was significantly higher in men vs. women (11.7% vs."

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

Reducing Cardiovascular Risk in Patients With MASH Independent of Baseline Based on Lp(a) and LDL Lowering by Resmetirom (ACG 2026) - "Introduction: Patients with MASH have high CV morbidity and mortality. Approximately half (n = 473; 49%) of MAESTRO-NASH participants were on statins at baseline. Atorvastatin was the most commonly used statin (47.1%), and 26.9% of statin-treated patients were receiving high-intensity statin therapy. Baseline characteristics were generally similar across statin subgroups; however, a greater proportion of patients receiving statins, compared with those not receiving statins, had diabetes (79.5% vs 55.0%), dyslipidaemia (100% vs 43.8%), and advanced fibrosis (F3: 64.3% vs 56.6%) at baseline."

Clinical • Cardiovascular • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • APOB

A Multimodal Noninvasive Approach to Initiation and Monitoring of Resmetirom Therapy in MASH - Update (ACG 2026) - "N=147 Eligible patients without RT discontinuation, 62% 80mg-dose, 39%-male, 55%-T2D, 46% GLP-1RA, mean(se) age 62.4(1.3), BMI 33.7(0.7), ALT 44(4), FIB4 1.79(0.14). T0-prevalence of F2F3 were 61%(LFAST) and 44%(VCTE). Median(max) delays(mths) t0-to-t1 were 3.4(LFAST), 7.6(VCTE) and 6.7(FIB4)."

Non-invasive • Fibrosis • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • APOA1

Comparative Efficacy and Safety of FGF21 Analogues in MASH: Which Agents Are Advancing and Why? (ACG 2026) - "Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of progressive liver fibrosis and cirrhosis... A structured literature review of PubMed/MEDLINE was conducted through April 2026 using keywords and MeSH terms including âMASH,â âNASH,â âfibroblast growth factor 21,â âFGF21 analogues,â âefruxifermin,â âpegozafermin,â âefimosfermin,â âpegbelfermin,â âresmetirom,â âsemaglutide,â âtirzepatide,â âsurvodutide,â âlanifibranor,â and âclinical trial.â Included studies were randomized controlled trials in biopsy-confirmed MASH or MASLD reporting histologic data...Trials of pegbelfermin and MK-3655 did not meet primary endpoints... Twelve trials (N=3,640) were included. Among FGF21 analogues, efruxifermin 50 mg showed the greatest response, with fibrosis improvement up to 75% and MASH resolution up to 62%..."

Clinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • FGF21

Comparative Effectiveness of GLP-1/GIP Receptor Agonists and Thyroid Hormone Receptor-β Agonist Resmetirom for Histologic Improvement in MASH: A Systematic Review of Randomized Controlled Trials (ACG 2026) - "Introduction: Metabolic associated steatohepatitis (MASH) is characterized by hepatic fat accumulation, hepatocyte damage, and inflammation in patients without significant alcohol consumption... Four trials met inclusion criteria (n=2,276). SYNERGY-NASH (n=190, 52 weeks) showed tirzepatide achieved MASH resolution in 44% (5 mg), 56% (10 mg), and 62% (15 mg) versus 10% placebo (P< 0.001 for 15 mg). Fibrosis improvement â¥1 stage occurred in 55% (5 mg), 51% (10 mg), and 51% (15 mg) versus 30% placebo."

Clinical • HEOR • Review • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • Pruritus

Machine Learning Models of Non-invasive Tests to Predict MASH and Fibrosis Stage Based on MAESTRO-NAFLD-1 and MAESTRO-NASH Liver Biopsies (ACG 2026) - " Data from 1,970 biopsy-confirmed patients who screened for phase 3 resmetirom trials (MAESTRO-NASH, MAESTRO-NAFLD-1) were retrospectively analyzed... Random forest models to predict three classes of fibrosis stages (F0/F1 vs. F2/F3 vs. F4) resulted in one-vs-rest cross-validation mean AUCs for the full data model (0.76, 0.75, and 0.94, respectively) and best performing lean model (0.83, 0.78, and 0.89, respectively)."

Biopsy • Machine learning • Non-invasive • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Assessing Fibrosis Improvement With Resmetirom in MASLD/MASH Patients in a Predominately Hispanic Population in El Paso: A Retrospective Cohort Study (ACG 2026) - "Our study included a total of 9 Hispanic adults of which the mean age was 62 years, consisted of 7 females, with type 2 diabetes present in 44% of patients who received treatment with resmetirom. CAP changes before vs after treatment were significant (p=0.0286), with a mean difference of -42.44. LSM changes before after treatment were not significant (p=0.1593), with a mean difference of -1.722 kPa."

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

Liver, Cardiovascular, and Renal Outcomes in MASLD Patients Receiving Semaglutide Versus Resmetirom: A Propensity Score-Matched Analysis (ACG 2026) - "After PSM, 2,153 patients per cohort were analyzed. Mean age was 57.7±13.8 vs. 58.1±13.3 years; 58% were female in both groups."

Clinical • Acute Kidney Injury • Atrial Fibrillation • Autoimmune Hepatitis • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Dyslipidemia • Fibrosis • Gastroenterology • Heart Failure • Hepatology • Hypertension • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Obstructive Sleep Apnea • Renal Disease • Respiratory Diseases • Sleep Disorder • Type 2 Diabetes Mellitus

Real-World Practice Patterns in a Cohort of At-Risk MASH Patients on >12 Months of Treatment With Resmetirom (ACG 2026) - "Of 115 patients; 50.4% female, mean age 57.8 years, 92.2% Caucasian. Mean BMI 35.2. Mean baseline labs were ALT 48, AST 38, ALP 76, Total bilirubin 0.7, Platelet count 236."

Clinical • Real-world • Real-world evidence • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Pruritus

Resmetirom in Metabolic Dysfunction-Associated Steatohepatitis: A Review of Efficacy, Safety, and Comparative Outcomes (ACG 2026) - "Resmetirom demonstrated consistent histologic and metabolic benefit. In the pivotal phase 3 MAESTRO-NASH trial, MASH resolution without worsening fibrosis occurred in up to 29.9% versus 9.7% with placebo, and fibrosis improvement in up to 25.9% versus 14.2%. Meta-analyses showed significant reductions in hepatic fat, MRI-PDFF, LDL cholesterol, triglycerides, apolipoprotein B, and liver enzymes."

Clinical • Review • Cardiovascular • Dyslipidemia • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Solid Tumor • APOB

Real-World Safety Profile of Resmetirom: A Pharmacovigilance Analysis of Predictors of Serious Adverse Events and Mortality (ACG 2026) - "Of 1,573 reports (81.5% US, median age 64), 35.3% were serious; 81 deaths (5.1%) occurred. Critically, 50/81 deaths (61.7%) were likely attributable to underlying disease progression and were excluded to reduce indication confounding. Cardiovascular (aOR 4.51, 95% CI 2.08-9.76), hepatobiliary (4.36, 3.44-5.54), infection (3.64, 1.57-8.44), GU/renal (2.86, 1.59-5.15), and immune AEs (2.77, 1.35-5.68) were identified as predictors of serious cases."

Adverse events • Clinical • Real-world • Real-world evidence • Serious adverse event • Cardiovascular • Fibrosis • Hepatology • Immunology • Infectious Disease • Metabolic Dysfunction-Associated Steatohepatitis • Musculoskeletal Diseases • Septic Shock

Hepatobiliary Safety Signals of AASLD Recommended MASH Therapies: A Comparative FAERS Disproportionality Analysis of Resmetirom and Semaglutide (ACG 2026) - "Among 132,586 primary suspect FAERS reports, semaglutide demonstrated a strong disproportionality signal for cholecystitis (n= 873; ROR 3.17, 95% CI 2.95-3.41; PRR 3.12, 95% CI 2.90-3.35), but significantly lower reporting signals for jaundice (ROR 0.70, 95% CI 0.57-0.86), liver-related adverse events (ROR 0.33, 95% CI 0.30-0.36; PRR 0.33, 95%CI 0.30-0.37), and composite hepatobiliary events (ROR 0.84, 95% CI 0.80â0.89; PRR 0.85, 95%CI 0.80-0.90). In contrast, resmetirom demonstrated markedly elevated hepatic reporting signals, including jaundice (86 cases; ROR 23.52, 95%CI 18.81-29.40; PRR 21.79, 95%CI 17.72-26.79), liver-related adverse events (n= 250; ROR 8.23, 95% CI 7.14-9.47; PRR 6.62, 95% CI 5.93-7.39), and composite hepatobiliary adverse events (296 cases; ROR 8.06, 95% CI 7.05-9.21; PRR 6.20, 95% CI 5.62-6.84). Cholecystitis reporting with resmetirom was comparatively modest (ROR 1.78, 95% CI 1.11-2.85)."

Clinical • Gastroenterology • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • ROR1

Fibroscan (VCTE)-Based Fibrosis Staging Reveals Gaps in FIB-4 Risk Stratification and Resmetirom Prescribing: A Real-World Health System Analysis (ACG 2026) - "VCTE data was available for 581 patients (4.5% of cohort; mean age 61.3 years, BMI 31.2 kg/m², LSM 10.6 kPa, CAP 280.3 dB/m). Resmetirom prescribing was higher in this subgroup than the overall cohort (5.5% vs.1.56%) ⯠LSM-based prescribing had highest prescription rate in F3 patients (16.9%) and lower prescribing in F4 patients (3.9%), consistent with the noncirrhotic indication. Coversely, similar rates seen between FIB-4 High and Low groups (1.5%vs1.2%), showing no risk-based pattern using blood markers alone (Table1)."

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

Real-World Prescribing Patterns of Resmetirom Among Eligible MASLD/MASH Patients: A Health System Analysis of Utilization Gaps and Clinical Risk Stratification (ACG 2026) - "Of 12,949 eligible patients, only 202 (1.56%) received a resmetirom prescription since FDA approval. Prescribing did not differ significantly by fibrosis risk: high-risk patients (FIB-4 >2.67; n=1,717) had a prescription rate of 1.5% versus 1.2% in low-risk patients (Table 1). Previously diagnosed patients had a higher prescription rate than newly diagnosed patients (1.84% vs."

Clinical • Real-world • Real-world evidence • Cardiovascular • Dyslipidemia • Fibrosis • Genetic Disorders • Hepatology • Hypertension • Hypertriglyceridemia • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

Cardiovascular Outcomes of Resmetirom Versus Semaglutide in Patients With MASLD/MASH: A Propensity-Matched Real-World Analysis (ACG 2026) - "After matching, 4,253 patients were included in each cohort. At 1 year, resmetirom was associated with lower risks of MACE (HR 0.50, 95% CI 0.32-0.80; p=0.003), all-cause mortality (HR 0.29, 95% CI 0.16-0.54; p< 0.001), and HF (HR 0.64, 95% CI 0.42-0.99; p=0.042). No significant differences were observed for MI or AF."

Clinical • Real-world • Real-world evidence • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Diabetes • Fibrosis • Genetic Disorders • Heart Failure • Hepatology • Immunology • Ischemic stroke • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Myocardial Infarction • Obesity

Understanding Diagnosis, Referral, and Management Patterns of MASLD in the Primary Care Setting (ACG 2026) - "Most subjects have never treated a patient with resmetirom (84%) and 38% were unaware there were FDA-approved medications for MASLD... In total, 45 subjects completed the survey, 9% of whom were interns, 32% residents, 53% attending physicians, and 6% advanced practice providers. Greater than 30% of subjects felt not at all or only slightly comfortable with screening, diagnosis, and management of MASLD. Subjects in practice less than 5 years felt least comfortable with MASLD management compared to 5-15 years, and more than 15 years (p = 0.02)."

Clinical • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Delay-Metabolic-Fibrosis Interaction Model (DMFIM): A Delay-Differential Optimal Control Framework for Precision Combination Therapy in Metabolic Dysfunction-Associated Steatohepatitis (ACG 2026) - "Model-derived adaptive combination protocols project ~ 20-25% faster fibrosis regression, ~ 15-18% lower cumulative drug exposure, and ~ 22% reduced cirrhosis progression versus fixed-dose strategies. DMFIM is a Python-based, translatable decision-support tool positioning precision hepatology for the post-resmetirom era with multiple approved therapies. This represents the first DDE optimal control model for MASH, addressing an important gap in the current literature."

Combination therapy • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Resmetirom Versus GLP-1 Receptor Agonists in the Prevention of MASH in Cirrhosis: Insights From a Large Global Database (ACG 2026) - "Before PSM, the resmetirom cohort (n = 1073) had lower odds of development of cirrhosis compared to the GLP1RA cohort (n = 20,819) with an odds ratio (OR) of 0.51 (95% CI = 0.36, 0.73; p < 0.001). This protective association persisted following rigorous 1:1 PSM. After PSM (1067 patients per group), patients with MASH on resmetirom had a significantly reduced incidence of cirrhosis compared to those on GLP1RA alone (OR = 0.38, 95% CI = 0.25, 0.58; p < 0.001), confirming the robustness of this observed effect across adjusted analyses."

Clinical • Cardiovascular • Diabetes • Dyslipidemia • Fibrosis • Genetic Disorders • Hepatocellular Cancer • Hepatology • Hypertension • Immunology • Infectious Disease • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Solid Tumor

Real-World Hepatic Outcomes of Resmetirom Versus Semaglutide in MASH: A Propensity-Matched Study (ACG 2026) - "After propensity score matching, cohorts were well balanced. At 1 year, resmetirom was associated with a lower risk of hepatic encephalopathy (HR 0.47, 95% CI 0.23â0.96; p=0.034) and all-cause mortality (HR 0.29, 95% CI 0.16â0.53; p< 0.001). Composite hepatic decompensation was numerically lower (HR 0.73, 95% CI 0.50â1.05)."

Clinical • Real-world • Real-world evidence • Cardiovascular • CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatocellular Cancer • Hepatology • Immunology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Renal Disease • Solid Tumor