simtuzumab (GS 6624) / Gilead - LARVOL DELTA

Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2. (PubMed, Cell Rep Med) - "Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases."

Journal • Fibrosis • Immunology

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis. (PubMed, Hepatol Commun) - P2b | "Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC."

Biomarker • Clinical • Journal • P2b data • Fibrosis • Hepatology • Immunology • Liver Cirrhosis

Translational Studies Reveal the Divergent Effects of Simtuzumab Targeting LOXL2 in Idiopathic Pulmonary Fibrosis. (PubMed, Fibrosis (Hong Kong)) - "Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis. Consistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • LOXL2

Paired assessment of enhanced liver fibrosis (ELF) and fibrosis-4 (FIB-4) scores is associated with an elevated risk of liver-related clinical events in participants with advanced fibrosis due to metabolic dysfunction-associated steatohepatitis (MASH) (EASL-ILC 2024) - P2, P2b, P3 | " Data from participants with advanced fibrosis due to MASH enrolled in four placebo- controlled trials evaluating simtuzumab (NCT02466516, NCT01672879) and selonsertib (NCT03053050, NCT03053063) were analyzed. In this cohort of participants with advanced fibrosis due to MASH, paired evaluation of ELF and FIB-4 demonstrated a significant association with liver-related clinical events. Further research is required to validate this model, which could serve to identify and enrich trials designed to test drugs that could prevent or attenuate MASH disease progression."

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

Comparative efficacy of pharmacologic therapies in MASH: Systematic review and meta-analysis (APASL 2024) - "Aldafermin had the highest probability of being ranked as the most effective intervention for MRI-PDFF decline (SUCRA = 89.59), followed by Pegozafermin (SUCRA = 88.99), and Pioglitazone (SUCRA = 61.41) at week 24. For MRI-PDFF response, Aldafermin (SUCRA = 92.61), Efruxifermin (SUCRA = 81.00) and Resmetirom (SUCRA = 55.54) had the highest probability of being ranked the most effective intervention for achieving MRI-PDFF response at week 12. These data provide relative rank-order efficacy of various MASH therapies in terms of improvements in MRI-PDFF."

Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Treatment of liver fibrosis: Past, current, and future. (PubMed, World J Hepatol) - "Many treatments for liver fibrosis have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment (e.g., simtuzumab), drug (e.g., pegbelfermin and natural herbs), genetic regulation (e.g., non-coding RNAs), and transplantation of stem cells (e.g., hematopoietic stem cells)...To avoid the life-threatening stage of liver fibrosis, anti-fibrotic treatments, especially for combined behavior prevention, biological treatment, drugs or herb medicines, and dietary regulation are needed. This review summarizes the past studies and current and future treatments for liver fibrosis."

Journal • Review • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Non-alcoholic Fatty Liver Disease • Transplantation

Elevated JAG1-NOTCH Signaling is Associated with Fibrosis Stages in Patients with PSC (EASL-ILC 2023) - P2b | " The study population comprised participants in a phase 2b, placebo-controlled trial of simtuzumab in PSC (NCT01672853)... JAG1-NOTCH signaling in PSC increases with fibrosis stages. The spatial expression pattern of JAG1 in the liver, cellular interactions, and non-invasive tests to monitor elevated NOTCH signaling in PSC patients warrant further investigation. Figure: Associations between JAG1-NOTCH Signaling and Ishak Fibrosis Stages in PSC"

Clinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • HES1 • JAG1 • NOTCH1 • NOTCH2 • SERPINA1 • SOX9

Proteomic Analysis of IPF Patient Serum Using the Somascan® Platform Identifies Potential Biomarkers of Disease and Outcome (ATS 2023) - P2 | "However, biomarkers for IPF remain poorly characterized, leading to a significant need for reliable biomarkers of disease outcome, treatment response and patient stratification. Serum samples from 55 IPF patients in the previously terminated Phase 2 study for Simtuzumab in IPF (NCT01769196) were analyzed on the large-scale SomaScan® proteomics platform (SomaLogic, Boulder CO)... SomaScan® based serum proteomic analysis identified several novel biomarkers that differentiate IPF disease from healthy cohorts, as well as previously published markers of IPF disease. Longitudinal analysis additionally suggests that early changes in specific proteins associated with senescence and apoptosis may be associated with mortality. This initial analysis supports the utility of a large-scale proteomic approach in identifying novel biomarker candidates."

Biomarker • Clinical • Omic analysis • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL13 • MMP7

[VIRTUAL] Serum bile acid species are associated with liver fibrosis and clinical disease progression in patients with primary sclerosing cholangitis (EASL-ILC-I 2020) - P2b | " Levels of 15 BAs and the BA intermediate, 7α-hydroxy-4-cholesten-3-one (C4), were quantified by LC-MS/MS (Agilent 1290/Sciex, Metabolon) in fasting serum samples from patients with compensated large-duct PSC at baseline (BL) in a 96-week, phase 2 trial of simtuzumab (NCT01672879)... In patients with compensated PSC, total serum BAs, as well as conjugated primary BAs, are markers of liver fibrosis and predict clinical disease progression. These data support ongoing evaluation of therapies that reduce BA levels (e.g. FXR agonists) for the treatment of PSC."

Clinical • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • Transplantation • FGF • FGF19

[VIRTUAL] A deep learning approach to analysis of MRCP images predicts clinical events and progression to cirrhosis in patients with primary sclerosing cholangitis (EASL-ILC 2021) - P2b | " Baseline MRCP and liver biopsy images were available from 122 patients with compensated PSC enrolled in a 96-week, phase 2b clinical trial of simtuzumab (NCT01672853)... The median age was 45 years, 63% were male, 54% had bridging fibrosis or cirrhosis, 52% had ulcerative colitis, 52% were on Figure: (Poster Session1644): Discrimination of the ML MRCP score and other parameters for disease progression in PSC ursodeoxycholic acid, and the median ALP at baseline was 265 U/L (IQR, 126–455)...Adeep learning approach toMRCP image analysis is able to predict disease progression in PSC and its prognostic utility exceeds that of other clinical and histologic assessments. Validation of these findingsmay provide a quantitative, ML-based assessment of PSC-related prognosis based on routinely collected MRCP images."

Clinical • Biliary Cancer • Cholangiocarcinoma • CNS Disorders • Fibrosis • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Immunology • Inflammatory Bowel Disease • Liver Failure • Oncology • Solid Tumor • Ulcerative Colitis

Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis. (PubMed, Gut) - "The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis."

Clinical data • Journal • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Non-alcoholic Steatohepatitis

ASSOCIATIONS OF AST TO PLATELET RATIO INDEX (APRI), ENHANCED LIVER FIBROSIS (ELF) SCORE, FIBROSIS-4 (FIB-4) AND LIVER STIFFNESS MEASUREMENT (LSM) WITH FIBROSIS STAGES IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) (AASLD 2022) - P2b | "Methods : 234 patients were enrolled in a 96-week, phase 2 clinical trial of simtuzumab in PSC (NCT01672853)...Conclusion : Blood-based and imaging-based NITs are useful in identifying significant fibrosis (F2-F4) in patients with PSC, with ELF score, APRI and LSM performing similarly. FIB-4 appears to have inferior accuracy except when cirrhosis is already established."

Clinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis

New Liver Stiffness Thresholds Refine NASH Risk Stratification [Google translation] - "These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported senior author Rohit Loomba...Seeking clarity, Loomba and colleagues drew on data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab."

Media quote

Cirrhosis Regression is Associated with Improved Clinical Outcomes in Patients with Nonalcoholic Steatohepatitis. (PubMed, Hepatology) - "In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis."

Clinical • Clinical data • Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease. (PubMed, Hepatology) - "Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC."

Journal • P2 data • Fibrosis • Hepatology • Liver Cirrhosis

Associations between novel serum biomarkers chitinase-2-like protein (YKL-40), type IV collagen, and thrombospondin-2 (TSP-2) with fibrosis stage and clinical outcomes in patients with primary sclerosing cholangitis (PSC) (EASL-ILC 2022) - P2b | " Serum biomarkers YKL-40, TSP-2, and COL4A1 were measured via ELISA at baseline (BL) and Week 96 (W96) in PSC patients enrolled in a 96-week, phase 2 trial of simtuzumab (NCT01672853)... Serum levels of the novel fibrosis markers YKL-40, TSP- 2, and COL4A1 are associated with fibrosis stage, progression to cirrhosis, and liver-related clinical events in patients with PSC. The utility of these biomarkers for the staging of fibrosis, risk stratification, and disease monitoring in PSC will be explored in additional studies."

Biomarker • Clinical • Clinical data • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Oncology • Solid Tumor • CHI3L1 • COL4A1 • Collagen Type IV • THBS2

Changes in the gut microbiome associated with liver stiffness improvement in nonalcoholic steatohepatitis. (PubMed, Therap Adv Gastroenterol) - "Gut microbial profiling was performed at baseline and study completion (24 weeks) using 16 S rRNA gene sequencing in 69 adults with biopsy-confirmed NASH and significant fibrosis (stages 2-3) enrolled in a multi-center randomized controlled trial evaluating selonsertib alone or in combination with simtuzumab. Significant shifts in 10 and 12 bacterial taxa were associated with improvement in LSM in addition to MRI-PDFF and fibrosis regression, respectively, indicating consistent taxonomic changes across multiple clinical endpoints. Longitudinal changes in the gut microbiota are observed in adults with NASH and clinical improvement and represent a shift toward a healthy microbiome."

Journal • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

[VIRTUAL] IMPACT OF MODEST WEIGHT REDUCTION ON SERUM MARKERS, LIVER HISTOLOGY, AND DISEASE PROGRESSION IN PATIENTS WITH ADVANCED FIBROSIS DUE TO NONALCOHOLIC STEATOHEPATITIS (NASH) (AASLD 2021) - " The study included NASH patients with advanced fibrosis (NASH CRN F3-F4) from four placebo-controlled trials of simtuzumab and selonsertib which were discontinued due to lack of efficacy. In clinical trials, weight loss ≥5% over 48 weeks is uncommon in NASH with advanced fibrosis. Although ≥5% weight loss lead to improvements in disease activity and NITs, it was not significantly associated with fibrosis assessed histologically over 48 weeks . An increased risk of liver-related complications in patients with cirrhosis and weight loss likely reflects weight loss driven by disease progression."

Clinical • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity • Transplantation

[VIRTUAL] LIVER STIFFNESS-BASED AGILE SCORES PREDICT DISEASE PROGRESSION IN PATIENTS WITH ADVANCED FIBROSIS DUE TO NASH (AASLD 2021) - " NASH patients with advanced fibrosis (NASH CRN F3-F4) were enrolled in four placebo-controlled trials of simtuzumab and selonsertib . The Agile scores may be useful for risk stratification of patients with advanced fibrosis due to NASH."

Clinical • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Transplantation

[VIRTUAL] Liver stiffness by vibration-controlled transient elastography predicts disease progression in patients with advanced fibrosis due to NASH (EASL-ILC 2021) - " Patients with advanced fibrosis (NASH CRN F3-F4) due to NASH were enrolled in four placebo-controlled trials of simtuzumab and selonsertib. 1, 398 patients with bridging fibrosis (n = 664) or cirrhosis (n = 734) were included in this analysis (median age 59 years, 60% female, 73% with diabetes). Median (IQR) LS at BL was 12.7 kPa (9.7, 17.3) in those with bridging fibrosis and 21.1 kPa (14.2, 29.3) in those with cirrhosis. During amedian follow-up (FU) of 17mos (range 1, 40), 16% of patients with bridging fibrosis (96/103 with post-baseline biopsies) progressed to cirrhosis."

Clinical • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Transplantation • PER3

[VIRTUAL] A MACHINE LEARNING MODEL BASED ON LIVER HISTOLOGY PREDICTS THE HEPATIC VENOUS PRESSURE GRADIENT (HVPG) IN PATIENTS WITH COMPENSATED CIRRHOSIS DUE TO NONALCOHOLIC STEATOHEPATITIS (NASH) (AASLD 2020) - " Adults with compensated cirrhosis (Ishak 5-6) due to NASH enrolled in a phase 2b trial of simtuzumab were included... An ML-based HVPG score based on histologic patterns of fibrosis discriminates CSPH in patients with compensated cirrhosis due to NASH. These preliminary data support the potential of ML-based interpretation of histology as a surrogate measure of HVPG."

Clinical • Fibrosis • Hepatology • Hypertension • Immunology • Non-alcoholic Steatohepatitis • Portal Hypertension

[VIRTUAL] CIRRHOSIS REGRESSION IS ASSOCIATED WITH IMPROVED CLINICAL OUTCOMES IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS (NASH) (AASLD 2020) - " Patients with compensated cirrhosis (NASH CRN F4) due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as endpoints in clinical trials of therapies for NASH cirrhosis."

Clinical • Clinical data • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Transplantation

[VIRTUAL] A RANDOM FOREST CLASSIFIER BASED ON A 30-GENE SIGNATURE DISTINGUISHES PATIENTS WITH BRIDGING FIBROSIS FROM THOSE WITH CIRRHOSIS DUE TO NASH (AASLD 2020) - " The study included 1,120 adults with advanced fibrosis (F3-F4) due to NASH enrolled in the simtuzumab and STELLAR trials (discovery cohort, n=994) and the ATLAS trial (validation cohort, n=126)... A machine learning technique applied to hepatic transcriptomic data identified a 30-gene expression signature that accurately differentiates NASH patients with cirrhosis from those with bridging fibrosis. The functional activities of these genes may suggest novel drivers of fibrosis progression in NASH."

Clinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

[VIRTUAL] Convolutional neural networks of H&E-stained biopsy images accurately quantify histologic features of non-alcoholic steatohepatitis (EASL-ILC-I 2020) - " We analyzed 4,641 whole-slide images of H&E-stained biopsies from five NASH clinical trials evaluating simtuzumab and selonsertib. CNNs trained on whole slide liver biopsy images can be utilized to extract continuous scores that recapitulate the key histologic features of NASH. These scores show improved correlations with multiple biomarkers of NASH severity, and represent a novel strategy for quantitative histological analysis and association studies with other data types."

Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • TIMP1

[VIRTUAL] Machine learning models accurately interpret liver histology and are associated with disease progression in patients with primary sclerosing cholangitis (EASL-ILC-I 2020) - " ML models were developed using whole slide images of biopsies from 141 PSC patients enrolled in a trial of simtuzumab... ML models demonstrated high concordance with pathologist assessment of PSC-related fibrosis, and ML-derived metrics were associated with the risk of disease progression. These data highlight the potential of ML for automated and quantitative assessment of liver histology and risk stratification in PSC."

Clinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • Transplantation