Semaglutide 2.4 mg in Participants With Metabolic Dysfunction-Associated Steatohepatitis: Baseline Characteristics and Design of the Phase 3 ESSENCE Trial.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated potential beneficial effects in metabolic dysfunction-associated steatohepatitis (MASH). AIMS: To describe the trial design and baseline characteristics of the 'Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis' (ESSENCE) trial (NCT04822181). METHODS: ESSENCE is a two-part, phase 3, randomised, multicentre trial evaluating the effect of subcutaneous semaglutide 2.4 mg in participants with biopsy-proven MASH and fibrosis stage 2 or 3. The primary objective of Part 1 is to demonstrate that semaglutide improves liver histology compared with placebo. The two primary endpoints are: resolution of steatohepatitis and no worsening of liver fibrosis, and improvement in liver fibrosis and no worsening of steatohepatitis. The Part 2 objective is based on clinical outcomes. The current work reports baseline characteristics of the first 800 randomised participants which includes demographics, laboratory parameters, liver histology, non-invasive tests and presence of metabolic dysfunction-associated steatotic liver disease (MASLD) cardiometabolic criteria. RESULTS: Of 800 participants, 250 (31.3%) had fibrosis stage 2 and 550 (68.8%) had fibrosis stage 3. In the overall population, mean (standard deviation [SD]) age was 56 (11.6) years, 57.1% were female, mean (SD) body mass index was 34.6 (7.2) kg/m2, 55.5% had type 2 diabetes and > 99% had at least one MASLD cardiometabolic criterion according to the published definition. CONCLUSION: The ESSENCE baseline population includes participants with clinically significant fibrosis stages 2 and 3. Although MASLD cardiometabolic criteria were not a requirement for study enrolment, almost all participants (> 99%) had at least one MASLD cardiometabolic criterion. TRIAL REGISTRATION: NCT04822181.

acFibroMASH Index for the Diagnosis of Fibrotic MASH and Prediction of Liver-related Events: An International Multicenter Study.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) and fibrotic MASH are significant health challenges. This multi-national study aimed to validate the acMASH index (including serum creatinine and aspartate aminotransferase concentrations) for MASH diagnosis and develop a new index (acFibroMASH) for non-invasively identifying fibrotic MASH and exploring its predictive value for liver-related events (LREs). METHODS: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MAFLD to examine associations between the acFibroMASH index and the risk of LREs. RESULTS: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66). CONCLUSIONS: This multi-ethnic study validates the acMASH index as a reliable, noninvasive test for identifying MASH. The newly proposed acFibroMASH index is a reliable test for identifying fibrotic MASH and predicting the risk of LREs.

Reproducibility and Repeatability of US Shear-Wave and Transient Elastography in Nonalcoholic Fatty Liver Disease.

Background US shear-wave elastography (SWE) and vibration-controlled transient elastography (VCTE) enable assessment of liver stiffness, an indicator of fibrosis severity. However, limited reproducibility data restrict their use in clinical trials. Purpose To estimate SWE and VCTE measurement variability in nonalcoholic fatty liver disease (NAFLD) within and across systems to support clinical trial diagnostic enrichment and clinical interpretation of longitudinal liver stiffness. Materials and Methods This prospective, observational, cross-sectional study (March 2021 to November 2021) enrolled adults with NAFLD, stratified according to the Fibrosis-4 (FIB-4) index (≤1.3, >1.3 and <2.67, ≥2.67), at two sites to assess SWE with five US systems and VCTE with one system. Each participant underwent 12 elastography examinations over two separate days within 1 week, with each day's examinations conducted by a different operator. VCTE and SWE measurements were reported in units of meters per second. The primary end point was the different-day, different-operator reproducibility coefficient (RDCDDDO) pooled across systems for SWE and individually for VCTE. Secondary end points included system-specific RDCDDDO, same-day, same-operator repeatability coefficient (RCSDSO), and between-system same-day, same-operator reproducibility coefficient. The planned sample provided 80% power to detect a pooled RDCDDDO of less than 35%, the prespecified performance threshold. Results A total of 40 participants (mean age, 60 years ± 10 [SD]; 24 women) with low (n = 17), intermediate (n = 15), and high (n = 8) FIB-4 scores were enrolled. RDCDDDO was 30.7% (95% upper bound, 34.4%) for SWE and 35.6% (95% upper bound, 43.9%) for VCTE. SWE system-specific RDCDDDO varied from 24.2% to 34.3%. The RCSDSO was 21.0% for SWE (range, 13.9%-35.0%) and 19.6% for VCTE. The SWE between-system same-day, same-operator reproducibility coefficient was 52.7%. Conclusion SWE met the prespecified threshold, RDCDDDO less than 35%, with VCTE having a higher RDCDDDO. SWE variability was higher between different systems. These estimates advance liver US-based noninvasive test qualification by (a) defining expected variability, (b) establishing that serial examination variability is lower when performed with the same system, and (c) informing clinical trial design. ClinicalTrials.gov Identifier NCT04828551 © RSNA, 2024 Supplemental material is available for this article.

Digital quantitation of bridging fibrosis and septa reveals changes in natural history and treatment not seen with conventional histology.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) with bridging fibrosis is a critical stage in the evolution of fatty liver disease. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) provides sensitive and reproducible quantitation of liver fibrosis. This methodology was applied to gain an in-depth understanding of intra-stage fibrosis changes and septa analyses in a homogenous, well-characterised group with MASH F3 fibrosis. METHODS: Paired liver biopsies (baseline [BL] and end of treatment [EOT]) of 57 patients (placebo, n = 17 and tropifexor n = 40), with F3 fibrosis stage at BL according to the clinical research network (CRN) scoring, were included. Unstained sections were examined using SHG/TPEF microscopy with AI. Changes in liver fibrosis overall and in five areas of liver lobules were quantitatively assessed by qFibrosis. Progressive, regressive septa, and 12 septa parameters were quantitatively analysed. RESULTS: qFibrosis demonstrated fibrosis progression or regression in 14/17 (82%) patients receiving placebo, while the CRN scoring categorised 11/17 (65%) as 'no change'. Radar maps with qFibrosis readouts visualised quantitative fibrosis dynamics in different areas of liver lobules even in cases categorised as 'No Change'. Measurement of septa parameters objectively differentiated regressive and progressive septa (p < .001). Quantitative changes in individual septa parameters (BL to EOT) were observed both in the 'no change' and the 'regression' subgroups, as defined by the CRN scoring. CONCLUSION: SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in patients with bridging fibrosis, thus advancing knowledge development of fibrosis evolution in natural history and in clinical trials.

Integrating liver endpoints in clinical trials of cardiovascular and kidney disease.

The intersection of cardiovascular disease, metabolic disorders and chronic kidney disease represents a complex clinical picture challenging healthcare systems worldwide. Metabolic-dysfunction-associated steatotic liver disease (MASLD) often manifests sequentially or concomitantly with these diseases, and may share underlying mechanisms and risk factors. Growing evidence suggests that new therapies could have benefits across these diseases, but trial sponsors and investigators tend to be reluctant to include patients with comorbidities-particularly liver diseases-in clinical trials. In this Perspective, we call for inclusion of patients with MASLD and measurement of liver outcomes in cardio-kidney-metabolic trials, when data suggest mechanistically plausible benefits and liver and cardiovascular safety. We discuss the implications of this new paradigm for clinical trial design and considerations for regulatory approval. Finally, we outline the challenges to implementing such an approach and provide recommendations for future clinical trial conduct.

Novel eicosanoid signature in plasma provides diagnostic for metabolic dysfunction-associated steatotic liver disease.

There is a clinical need for a simple test implementable at the primary point of care to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) in the population. Blood plasma samples from adult patients with varying phenotypes of MASLD were used to identify a minimal set of lipid analytes reflective of underlying histologically confirmed MASLD. Samples were obtained from the NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database prospective cohort study (MASLD group; N = 301). Samples of control subjects were obtained from cohort studies at the University of California San Diego (control group; N = 48). Plasma samples were utilized for targeted quantitation of circulating eicosanoids, related bioactive metabolites, and polyunsaturated fatty acids by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) lipidomics analysis. Bioinformatic approaches were used to discover a panel of bioactive lipids that can be used as a diagnostic tool to identify MASLD. The final panel of fifteen lipid metabolites consists of 12 eicosanoid metabolites and 3 free fatty acids that were identified to be predictive for MASLD by multivariate area under the receiver operating characteristics curve (AUROC) analysis. The panel was highly predictive for MASLD with an AUROC of 0.999 (95% CI = 0.986-1.0) with only one control misclassified. A validation study confirmed the resulting MASLD LIPIDOMICS SCORE, which may require a larger-scale prospective study to optimize. This predictive model should guide the development of a non-invasive "point-of-care" test to identify MASLD patients requiring further evaluation for the presence of metabolic dysfunction-associated steatohepatitis.

Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

AI-based automation of enrollment criteria and endpoint assessment in clinical trials in liver diseases.

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses.

Liver stiffness progression in biopsy-proven metabolic dysfunction-associated steatotic disease among people with diabetes versus people without diabetes: A prospective multicenter study.

BACKGROUND AND AIMS: There are limited data on the progression of liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in people with type 2 diabetes mellitus (T2DM) versus those without T2DM in biopsy-proven metabolic dysfunction-associated steatotic liver disease. We examined LSM progression in participants with T2DM versus those without T2DM in a large, prospective, multicenter cohort study. APPROACH AND RESULTS: This study included 1231 adult participants (62% female) with biopsy-proven metabolic dysfunction-associated steatotic liver disease who had VCTEs at least 1 year apart. LSM progression and regression were defined by a ≥20% increase and an upward or downward change, respectively, in the LSM category in the Baveno VII categories for compensated advanced chronic liver disease, compared between participants with T2DM (n = 680) versus no T2DM (n = 551) at baseline. The mean (±SD) age and body mass index were 51.8 (±12.0) years and 34.0 (±6.5) kg/m 2 , respectively. The median (IQR) time between the first and last VCTE measurements was 4.1 (2.5-6.5) years. Participants with T2DM had higher LSM progression at 4 years (12% vs. 10%), 6 years (23% vs. 16%), and 8 years (50% vs. 39%), p = 0.04. Using a multivariable Cox proportional hazards model adjusted for multiple confounders, the presence of T2DM remained an independent predictor of LSM progression (adjusted HR: 1.35, 95% CI: 1.01-1.81, p = 0.04). T2DM was not associated with LSM regression ( p = 0.71). Mean HbA1c was significantly associated with LSM progression ( p = 0.003) and regression ( p = 0.02). CONCLUSIONS: Using serial VCTE data from a multicenter study of participants with biopsy-proven metabolic dysfunction-associated steatotic liver disease, we demonstrate that T2DM and HbA1c are associated with LSM progression.

Reporting guidelines for precision medicine research of clinical relevance: the BePRECISE checklist.

Precision medicine should aspire to reduce error and improve accuracy in medical and health recommendations by comparison with contemporary practice, while maintaining safety and cost-effectiveness. The etiology, clinical manifestation and prognosis of diseases such as obesity, diabetes, cardiovascular disease, kidney disease and fatty liver disease are heterogeneous. Without standardized reporting, this heterogeneity, combined with the diversity of research tools used in precision medicine studies, makes comparisons across studies and implementation of the findings challenging. Specific recommendations for reporting precision medicine research do not currently exist. The BePRECISE (Better Precision-data Reporting of Evidence from Clinical Intervention Studies & Epidemiology) consortium, comprising 23 experts in precision medicine, cardiometabolic diseases, statistics, editorial and lived experience, conducted a scoping review and participated in a modified Delphi and nominal group technique process to develop guidelines for reporting precision medicine research. The BePRECISE checklist comprises 23 items organized into 5 sections that align with typical sections of a scientific publication. A specific section about health equity serves to encourage precision medicine research to be inclusive of individuals and communities that are traditionally under-represented in clinical research and/or underserved by health systems. Adoption of BePRECISE by investigators, reviewers and editors will facilitate and accelerate equitable clinical implementation of precision medicine.

Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients with MASH/NASH and Moderate to Noncirrhotic Advanced Fibrosis.

Metabolic dysfunction-associated steatotic liver disease affects 1 in 4 people in the United States and western Europe, with an important proportion developing metabolic dysfunction-associated steatohepatitis (MASH), the progressive subtype of metabolic dysfunction-associated steatotic liver disease. Cirrhosis caused by MASH is a leading indication for liver transplantation and the most common cause of hepatocellular carcinoma. Hitherto, there have been no specific pharmacotherapies for MASH. The recent conditional approval by the Food and Drug Administration of resmetirom for the treatment of moderate or advanced MASH presents a much-anticipated therapeutic option for patients with noncirrhotic advanced MASH. Specifically, the intended population for resmetirom are patients with MASH and fibrosis stages 2 or 3. The approval of resmetirom also presents important challenges, including how to noninvasively identify patients with fibrosis stages 2-3, and how to exclude patients with more advanced disease who should not be treated until further data emerge on the use of resmetirom in this population. Herein we consider the available literature with regard to identifying the intended population for treatment with resmetirom and in proposing criteria for stopping treatment.

The Liver Cirrhosis Network Cohort Study: Cirrhosis Definition, Study Population, and Endpoints.

INTRODUCTION: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified. DISCUSSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion. REGISTRATION: NCT05740358.

AI-based digital pathology provides newer insights into lifestyle intervention-induced fibrosis regression in MASLD: An exploratory study.

BACKGROUND AND AIMS: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH. METHODS: We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. RESULTS: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region. CONCLUSION: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging.

Acute kidney injury in severe alcohol-associated hepatitis treated with anakinra plus zinc or prednisone.

BACKGROUND AND AIMS: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. APPROACH AND RESULTS: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005). CONCLUSIONS: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .

Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis. METHODS: This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted. GOV IDENTIFIER: NCT05296733.

A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.

BACKGROUND: Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear. METHODS: In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage. RESULTS: A total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo. CONCLUSIONS: Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.).