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Tan Y, Zhang X. Diagnostic accuracy of FibroScan-AST (FAST) score, non-alcoholic fatty liver fibrosis score (NFS), FibroScan, and liver fibrosis index (FIB-4) for identifying fibrotic non-alcoholic steatohepatitis in patients with chronic hepatitis B with metabolic dysfunction-associated fatty liver disease. Ann Med 2024; 56:2420858. [PMID: 39460547 PMCID: PMC11514388 DOI: 10.1080/07853890.2024.2420858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 06/19/2024] [Accepted: 09/10/2024] [Indexed: 10/28/2024] Open
Abstract
OBJECTIVE To evaluate the diagnostic value of the FibroScan-AST (FAST) score, non-alcoholic fatty liver fibrosis score (NFS), FibroScan, and liver fibrosis index (FIB-4) for identifying fibrotic non-alcoholic steatohepatitis (NASH) in patients with chronic hepatitis B (CHB) with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS All patients with CHB and MAFLD who underwent liver biopsy at the Zhenjiang Third Hospital affiliated with Jiangsu University between August 2010 and December 2022 were included in the analysis. The diagnostic accuracy of FAST, NFS, FibroScan, and FIB-4 for diagnosing NASH and liver fibrosis were evaluated based on the area under the receiver-operating characteristic curve (AUC). RESULTS A total of 156 patients with CHB combined with MAFLD were included, including 69 with NASH and fibrosis stage 2 or higher (NASH+F ≥ 2), and 16 with NASH and cirrhosis (NASH+F4). The AUC of FAST, NFS, liver stiffness measurement (LSM), and FIB-4 for diagnosing NASH+F ≥ 2 was 0.739 (p < 0.001), 0.643 (p = 0.006), 0.754 (p < 0.001), and 0.665 (p = 0.003), respectively. The specificity of FAST, NFS, LSM, and FIB-4 was 67%, 51.8%, 78.6% and 76.8%, respectively, and the sensitivity was 75%, 78.6%, 67.9%, and 53.6%, respectively. No significant differences were found between groups. The AUC of FAST, NFS, LSM, and FIB-4 for diagnosing NASH+F4 was 0.650 (p = 0.038), 0.725 (p = 0.001), 0.851 (p < 0.001), and 0.560 (p = 0.533), respectively. The specificity of the FAST, NFS, LSM, and FIB-4 was 55.9%, 50.0%, 71.6%, and 75.5%, respectively and the sensitivity was 80.0%, 100%, 100%, and 50.0%, respectively. The differences between AUCs of FIB-4 and FAST compared with LSM were 0.291 and 0.201, respectively (p < 0.05). CONCLUSION In patients with CHB combined with MAFLD, FAST did not have better accuracy than NFS and FIB-4 for predicting fibrotic NASH, whereas LSM had better accuracy than FAST and FIB-4.
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Affiliation(s)
- Youwen Tan
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
| | - Xinyue Zhang
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, China
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Ratziu V. Cirrhose métabolique : une entité en plein essor. BULLETIN DE L'ACADÉMIE NATIONALE DE MÉDECINE 2024. [DOI: 10.1016/j.banm.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Naoumov NV, Kleiner DE, Chng E, Brees D, Saravanan C, Ren Y, Tai D, Sanyal AJ. Digital quantitation of bridging fibrosis and septa reveals changes in natural history and treatment not seen with conventional histology. Liver Int 2024; 44:3214-3228. [PMID: 39248039 PMCID: PMC11586893 DOI: 10.1111/liv.16092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/31/2024] [Accepted: 08/22/2024] [Indexed: 09/10/2024]
Abstract
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.
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Affiliation(s)
| | - David E. Kleiner
- Laboratory of Pathology, Post‐Mortem SectionNational Cancer InstituteBethesdaMarylandUSA
| | | | | | | | - Yayun Ren
- Histoindex Pte. Ltd.SingaporeSingapore
| | - Dean Tai
- Histoindex Pte. Ltd.SingaporeSingapore
| | - Arun J. Sanyal
- Stravitz‐Sanyal Institute of Liver Disease and Metabolic HealthVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
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Do A, Zahrawi F, Mehal WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov 2024:10.1038/s41573-024-01084-2. [PMID: 39609545 DOI: 10.1038/s41573-024-01084-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 11/30/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.
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Affiliation(s)
- Albert Do
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Division of Gastroenterology, University of California, Davis, Davis, USA
| | - Frhaan Zahrawi
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Wajahat Z Mehal
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
- West Haven Veterans Hospital, West Haven, CT, USA.
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Abdurrachim D, Lek S, Lin Ong CZ, Wong CK, Zhou Y, Wee A, Soon G, Kendall TJ, Idowu MO, Hendra C, Saigal A, Krishnan R, Chng E, Tai D, Ho G, Forest T, Raji A, Talukdar S, Chin CL, Baumgartner R, Engel SS, Bakar Ali AA, Kleiner DE, Sanyal AJ. Utility of AI digital pathology as an aid for pathologists scoring fibrosis in MASH. J Hepatol 2024:S0168-8278(24)02734-X. [PMID: 39612947 DOI: 10.1016/j.jhep.2024.11.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND & AIMS Intra and inter-pathologist variability poses a significant challenge in metabolic dysfunction-associated steatohepatitis (MASH) biopsy evaluation, leading to suboptimal selection of patients and confounded assessment of histological response in clinical trials. We evaluated the utility of an artificial intelligence (AI) digital pathology (DP) platform to aid pathologists improve the reliability of fibrosis staging. METHODS A total of 120 digitized histology slides from two trials (NCT03517540, NCT03912532) were analysed by four expert hepatopathologists, with and without AI-assistance in a randomized, cross-over design. We utilized the HistoIndex AI DP platform, consisting of unstained second harmonic generation/two photon excitation fluorescence (SHG/TPEF) images and AI quantitative fibrosis (qF) values. RESULTS AI-assistance significantly improved inter-pathologist kappa for fibrosis (F)-staging, particularly for early fibrosis (F0-F2), with reduced variance around the median reads. Intra-pathologist kappa was unchanged. AI-assistance increased pathologist concordance for identifying clinical trial inclusion subjects (F2-F3) from 45% to 71%, exclusion subjects (F0/F1/F4) from 38% to 55%, and evaluation of fibrosis response to treatment from 49% to 61%. SHG/TPEF images, qFibrosis continuous values, and qF-stage were considered useful by at least 3 out of 4 pathologists in 83%, 55%, and 38% cases, respectively. In the context of a clinical trial, the increase in inter-pathologist concordance in this study is modeled to result in a ∼25% reduction in the potential need for adjudication as well as a ∼50% increase in the study power. CONCLUSIONS The use of AI DP enhances inter-rater reliability of fibrosis staging for MASH. This indicates that the SHG/TPEF-based AI DP tool is useful for assisting pathologists in assessing fibrosis, thereby enhancing clinical trial efficiency and reliability of fibrosis readouts in response to treatments.
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Affiliation(s)
| | | | | | | | | | - Aileen Wee
- Department of Pathology, National University Hospital, Singapore
| | - Gwyneth Soon
- Department of Pathology, National University Hospital, Singapore
| | - Timothy J Kendall
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, United Kingdom
| | - Michael O Idowu
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | | | - Ashmita Saigal
- Cardiometabolic Diseases, Merck & Co., Inc., South San Francisco, CA, USA
| | | | | | | | | | - Thomas Forest
- Non-clinical Drug Safety, Merck & Co., Inc., West Point, PA, USA
| | - Annaswamy Raji
- Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA
| | - Saswata Talukdar
- Cardiometabolic Diseases, Merck & Co., Inc., South San Francisco, CA, USA
| | - Chih-Liang Chin
- Cardiometabolic Diseases, Merck & Co., Inc., South San Francisco, CA, USA
| | - Richard Baumgartner
- Biostatistics and Research Decision Sciences, Merck & Co., Inc., Rahway, NJ, USA
| | - Samuel S Engel
- Global Clinical Development, Merck & Co., Inc., Rahway, NJ, USA
| | | | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, NIH, USA
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School Of Medicine, Richmond, VA, USA
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Hudson D, Afzaal T, Bualbanat H, AlRamdan R, Howarth N, Parthasarathy P, AlDarwish A, Stephenson E, Almahanna Y, Hussain M, Diaz LA, Arab JP. Modernizing metabolic dysfunction-associated steatotic liver disease diagnostics: the progressive shift from liver biopsy to noninvasive techniques. Therap Adv Gastroenterol 2024; 17:17562848241276334. [PMID: 39553445 PMCID: PMC11565685 DOI: 10.1177/17562848241276334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 07/27/2024] [Indexed: 11/19/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern worldwide. Liver biopsy is the gold standard for diagnosing and staging MASLD, but it is invasive and carries associated risks. In recent years, there has been significant progress in developing noninvasive techniques for evaluation. This review article discusses briefly current available noninvasive assessments and the various liver biopsy techniques available for MASLD, including invasive techniques such as transjugular and transcutaneous needle biopsy, intraoperative/laparoscopic biopsy, and the evolving role of endoscopic ultrasound-guided biopsy. In addition to discussing the various biopsy techniques, we review the current state of knowledge on the histopathologic evaluation of MASLD, including the various scoring systems used to grade and stage the disease. We also explore current and alternative modalities for histopathologic evaluation, such as whole slide imaging and the utility of immunohistochemistry. Overall, this review article provides a comprehensive overview of the progress in liver biopsy techniques for MASLD and compares invasive and noninvasive modalities. However, beyond clinical trials, the practical application of liver biopsy may be limited, as ongoing advancements in noninvasive fibrosis assessments are expected to more effectively identify candidates for MASLD treatment in real-world settings.
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Affiliation(s)
- David Hudson
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Tamoor Afzaal
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Hasan Bualbanat
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Raaed AlRamdan
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Nisha Howarth
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Pavithra Parthasarathy
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Alia AlDarwish
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Emily Stephenson
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Yousef Almahanna
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Maytham Hussain
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University and London Health Sciences Centre, London, ON, Canada
| | - Luis Antonio Diaz
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
- MASLD Research Center, Division of MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA, USA
| | - Juan Pablo Arab
- Stravitz-Sanyal Institute of Liver Disease and Metabolic Health, Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, 1201 E. Broad St. P.O. Box 980341, Richmond, VA 23284, USA
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7
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Harvey BE. How improvements in US FDA regulatory process and procedures led to the drug approval for first ever treatment of a common liver disease. Acta Pharmacol Sin 2024:10.1038/s41401-024-01396-4. [PMID: 39511464 DOI: 10.1038/s41401-024-01396-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 09/13/2024] [Indexed: 11/15/2024] Open
Abstract
Metabolic-associated liver disease is a growing public health crisis, with phenotypes from fatty liver to steatohepatitis, previously known as NASH (Non-Alcoholic SteatoHepatitis) and currently rebranded as MASH (Metabolic dysfunction-Associated SteatoHepatitis). Dysfunction in liver metabolism can progress to liver fibrosis, end stage cirrhosis and death. MASH (NASH) is associated with an increased risk of cardiovascular disease, elevation in serum lipids and Type 2 Diabetes Mellitus. There is now a US-approved drug to treat patients with NASH (MASH) under the FDA Accelerated Approval Pathway, which requires follow-up outcome studies to confirm clinical benefit or risk drug withdrawal by the agency. Despite extra-hepatic factors that contribute to MASH and complicate clinical trial design, reorganization of the FDA drug premarket review divisions, improvements to agency policies and procedures, as well as updates to the US Food, Drug & Cosmetic Act (FD&C Act) upon which FDA regulation is based, have provided new agency tools that facilitated such a drug approval to address the profound unmet medical need for patients with this metabolic-based liver disease. There is reason for hope that continued evolution of the regulatory process will lead to additional drug approvals, as well as the ability for clinical trial endpoints studying MASH treatments to include both liver-based and traditional metabolic measures, independent of the specific FDA review division. This initial NASH/MASH FDA approval has also opened the door for initiation of Combination Clinical Trials, where the approved drug is paired with an experimental drug with a different mechanism of action, to increase overall efficacy and potentially minimize risks. It is envisioned that future treatment of NASH/MASH will mirror what is currently observed with Type 2 Diabetes Mellitus practice patterns, where multiple drugs with different mechanisms of actions are used to optimize treatment benefit/risk in the selected patient populations.
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Pulaski H, Mehta SS, Manigat LC, Kaufman S, Hou H, Nalbantoglu ILK, Zhang X, Curl E, Taliano R, Kim TH, Torbenson M, Glickman JN, Resnick MB, Patel N, Taylor CE, Bedossa P, Montalto MC, Beck AH, Wack KE. Validation of a whole slide image management system for metabolic-associated steatohepatitis for clinical trials. J Pathol Clin Res 2024; 10:e12395. [PMID: 39294925 PMCID: PMC11410674 DOI: 10.1002/2056-4538.12395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 07/04/2024] [Accepted: 07/15/2024] [Indexed: 09/21/2024]
Abstract
The gold standard for enrollment and endpoint assessment in metabolic dysfunction-associated steatosis clinical trials is histologic assessment of a liver biopsy performed on glass slides. However, obtaining the evaluations from several expert pathologists on glass is challenging, as shipping the slides around the country or around the world is time-consuming and comes with the hazards of slide breakage. This study demonstrated that pathologic assessment of disease activity in steatohepatitis, performed using digital images on the AISight whole slide image management system, yields results that are comparable to those obtained using glass slides. The accuracy of scoring for steatohepatitis (nonalcoholic fatty liver disease activity score ≥4 with ≥1 for each feature and absence of atypical features suggestive of other liver disease) performed on the system was evaluated against scoring conducted on glass slides. Both methods were assessed for overall percent agreement with a consensus "ground truth" score (defined as the median score of a panel of three pathologists' glass slides). Each case was also read by three different pathologists, once on glass and once digitally with a minimum 2-week washout period between the modalities. It was demonstrated that the average agreement across three pathologists of digital scoring with ground truth was noninferior to the average agreement of glass scoring with ground truth [noninferiority margin: -0.05; difference: -0.001; 95% CI: (-0.027, 0.026); and p < 0.0001]. For each pathologist, there was a similar average agreement of digital and glass reads with glass ground truth (pathologist A, 0.843 and 0.849; pathologist B, 0.633 and 0.605; and pathologist C, 0.755 and 0.780). Here, we demonstrate that the accuracy of digital reads for steatohepatitis using digital images is equivalent to glass reads in the context of a clinical trial for scoring using the Clinical Research Network scoring system.
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Affiliation(s)
| | | | | | | | | | - ILKe Nalbantoglu
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Emily Curl
- Foundation Medicine, Inc, Boston, MA, USA
| | - Ross Taliano
- Department of Pathology, Rhode Island Hospital, Providence, RI, USA
| | - Tae Hun Kim
- Pathology Medical Group of Riverside, Providence, RI, USA
| | - Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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9
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Peng Z, Wei G, Huang P, Matta H, Gao W, An P, Zhao S, Lin Y, Tan L, Vaid K, Skelton-Badlani D, Nasser I, Budas G, Lopez D, Li L, Breckenridge D, Myers R, McHutchison J, Kuang M, Popov YV. ASK1/ p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer. Hepatology 2024; 80:346-362. [PMID: 38377458 PMCID: PMC11477174 DOI: 10.1097/hep.0000000000000801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 12/14/2023] [Indexed: 02/22/2024]
Abstract
BACKGROUND AND AIMS Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems. APPROACH AND RESULTS Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group. CONCLUSIONS ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.
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Affiliation(s)
- Zhenwei Peng
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Guangyan Wei
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Pinzhu Huang
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Heansika Matta
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Wen Gao
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Ping An
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Shuangshuang Zhao
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yi Lin
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Li Tan
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
- Center of Hepatopbiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kahini Vaid
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Disha Skelton-Badlani
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Imad Nasser
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Grant Budas
- Gilead Sciences, Inc., Foster City, California, USA
| | - David Lopez
- Gilead Sciences, Inc., Foster City, California, USA
| | - Li Li
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Rob Myers
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Ming Kuang
- Center of Hepatopbiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yury V Popov
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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Ciardullo S, Muraca E, Vergani M, Invernizzi P, Perseghin G. Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions. Gastroenterol Rep (Oxf) 2024; 12:goae029. [PMID: 38681750 PMCID: PMC11052658 DOI: 10.1093/gastro/goae029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 02/27/2024] [Indexed: 05/01/2024] Open
Abstract
In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.
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Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy
- Department of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Emanuele Muraca
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy
| | - Michela Vergani
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy
- Department of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER) San Gerardo Hospital, Monza, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy
- Department of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
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11
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Noureddin M. MASH clinical trials and drugs pipeline: An impending tsunami. Hepatology 2024:01515467-990000000-00811. [PMID: 38502810 DOI: 10.1097/hep.0000000000000860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 02/24/2024] [Indexed: 03/21/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease, formerly known as NAFLD, has ascended to prominence as the predominant chronic liver disease in Western countries and now stands as a leading cause of liver transplantations. In the more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH) may lead to fibrosis, a gateway to cirrhosis, liver cancer, and liver failure. Despite extensive research and exploration of various drug mechanisms, the anticipation for the inaugural approved drug to materialize by 2024 is palpable, marking a significant milestone. Numerous pathways have been investigated for MASH treatment, exploring thyroid hormone receptors, glucagon-like peptides 1, peroxisome proliferator-activated receptors, and agents influencing hepatic steatosis synthesis, inflammatory pathways, genetic components, fibrosis mechanisms, and an array of other avenues. Over time, key regulatory directions have crystallized, now manifesting in 2 primary endpoints under investigation: resolution of steatohepatitis without worsening fibrosis and/or improvement of fibrosis stage without worsening of steatohepatitis, especially used in phase 3 clinical trials, while alternative noninvasive endpoints are explored in phase 2 trials. The prospect of proving efficacy in clinical trials opens doors to combination therapies, evaluating the ideal combination of drugs to yield comprehensive benefits, extending beyond the liver to other organs. Certain combination drug trials are already underway. In this review, we discuss the forefront of MASH drug research as of 2023/2024, illuminating mechanisms, outcomes, and future trajectories. Furthermore, we tackle the challenges confronting MASH trials and propose potential strategies for surmounting them.
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Affiliation(s)
- Mazen Noureddin
- Sherrie & Alan Conover Center for Liver Disease & Transplantation, Underwood Center for Digestive Disorders Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA
- Houston Research Institute, Houston, Texas, USA
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12
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Rinella ME, Lieu HD, Kowdley KV, Goodman ZD, Alkhouri N, Lawitz E, Ratziu V, Abdelmalek MF, Wong VWS, Younes ZH, Sheikh AM, Brannan D, Freilich B, Membreno F, Sinclair M, Melchor-Khan L, Sanyal AJ, Ling L, Harrison SA. A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis. Hepatology 2024; 79:674-689. [PMID: 37732990 PMCID: PMC10871650 DOI: 10.1097/hep.0000000000000607] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 08/17/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND AND AIMS Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. APPROACH AND RESULTS In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was -0.5 (95% CI, -0.7 to -0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events. CONCLUSIONS Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.
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Affiliation(s)
- Mary E. Rinella
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
| | - Hsiao D. Lieu
- NGM Biopharmaceuticals, South San Francisco, California, USA
| | - Kris V. Kowdley
- Washington State University, Spokane, Washington, USA
- Liver Institute Northwest, Seattle, Washington, USA
| | | | | | - Eric Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas, USA
| | - Vlad Ratziu
- Sorbonne Université, ICAN Institute for Cardiometabolism and Nutrition, Assistance Publique Hôpitaux de Paris, INSERM UMRS 1138 CRC
| | | | | | | | | | | | | | | | | | | | - Arun J. Sanyal
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Lei Ling
- NGM Biopharmaceuticals, South San Francisco, California, USA
| | - Stephen A. Harrison
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Pinnacle Clinical Research, San Antonio, Texas, USA
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13
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Sanyal AJ, Loomba R, Anstee QM, Ratziu V, Kowdley KV, Rinella ME, Harrison SA, Resnick MB, Capozza T, Sawhney S, Shelat N, Younossi ZM. Utility of pathologist panels for achieving consensus in NASH histologic scoring in clinical trials: Data from a phase 3 study. Hepatol Commun 2024; 8:e0325. [PMID: 38126958 PMCID: PMC10749704 DOI: 10.1097/hc9.0000000000000325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 09/21/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Liver histopathologic assessment is the accepted surrogate endpoint in NASH trials; however, the scoring of NASH Clinical Research Network (CRN) histologic parameters is limited by intraobserver and interobserver variability. We designed a consensus panel approach to minimize variability when using this scoring system. We assessed agreement between readers, estimated linear weighted kappas between 2 panels, compared them with published pairwise kappa estimates, and addressed how agreement or disagreement might impact the precision and validity of the surrogate efficacy endpoint in NASH trials. METHODS Two panels, each comprising 3 liver fellowship-trained pathologists who underwent NASH histology training, independently evaluated scanned whole slide images, scoring fibrosis, inflammation, hepatocyte ballooning, and steatosis from baseline and month 18 biopsies for 100 patients from the precirrhotic NASH study REGENERATE. The consensus score for each parameter was defined as agreement by ≥2 pathologists. If consensus was not reached, all 3 pathologists read the slide jointly to achieve a consensus score. RESULTS Between the 2 panels, the consensus was 97%-99% for steatosis, 91%-93% for fibrosis, 88%-92% for hepatocyte ballooning, and 84%-91% for inflammation. Linear weighted kappa scores between panels were similar to published NASH CRN values. CONCLUSIONS A panel of 3 trained pathologists independently scoring 4 NASH CRN histology parameters produced high consensus rates. Interpanel kappa values were comparable to NASH CRN metrics, supporting the accuracy and reproducibility of this method. The high concordance for fibrosis scoring was reassuring, as fibrosis is predictive of liver-specific outcomes and all-cause mortality.
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Affiliation(s)
- Arun J. Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Quentin M. Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Vlad Ratziu
- Sorbonne Université, Institute of Cardiometabolism and Nutrition, Pitié Salpêtriére University Hospital, Paris, France
| | | | - Mary E. Rinella
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | | | - Murray B. Resnick
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA
| | - Thomas Capozza
- Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA
| | | | - Nirav Shelat
- Intercept Pharmaceuticals, Inc., Morristown, New Jersey, USA
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14
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Lin Y, Yang M, Huang L, Yang F, Fan J, Qiang Y, Chang Y, Zhou W, Yan L, Xiong J, Ping J, Chen S, Men D, Li F. A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase. Cell Rep 2023; 42:113453. [PMID: 37976162 DOI: 10.1016/j.celrep.2023.113453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/30/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023] Open
Abstract
Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.
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Affiliation(s)
- Yan Lin
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Mingkun Yang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Li Huang
- Research Center for Medicine and Structural Biology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Fan Yang
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Jiachen Fan
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Yulong Qiang
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Yuting Chang
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Wenjie Zhou
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Leilei Yan
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Jie Xiong
- Department of Immunology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Jie Ping
- Department of Pharmacology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China
| | - Shizhen Chen
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China
| | - Dong Men
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China.
| | - Feng Li
- Department of Medical Genetics, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China.
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15
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Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, Sheikh MY, Trotter JF, Knapple W, Lawitz EJ, Abdelmalek MF, Newsome PN, Boursier J, Mathurin P, Dufour JF, Berrey MM, Shiff SJ, Sawhney S, Capozza T, Leyva R, Harrison SA, Younossi ZM. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023; 79:1110-1120. [PMID: 37517454 DOI: 10.1016/j.jhep.2023.07.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/30/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND & AIMS Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.
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Affiliation(s)
- Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute for Cardiometabolism and Nutrition, Paris, France
| | - Rohit Loomba
- University of California, San Diego, La Jolla, CA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | | | - Mary E Rinella
- University of Chicago, Pritzker School of Medicine, Chicago, IL, USA
| | | | | | | | - Eric J Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Philip N Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Jérôme Boursier
- Angers University Hospital, Angers University, Angers, France
| | | | | | | | | | | | | | - Rina Leyva
- Intercept Pharmaceuticals, Morristown, NJ, USA
| | | | - Zobair M Younossi
- Beatty Liver and Obesity Research Program, Center for Liver Diseases, Inova Medicine, Falls Church, VA, USA
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16
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Tun KM, Noureddin N, Noureddin M. Noninvasive tests in the evaluation of nonalcoholic fatty liver disease: A review. Clin Liver Dis (Hoboken) 2023; 22:103-112. [PMID: 37799634 PMCID: PMC10550044 DOI: 10.1097/cld.0000000000000066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/08/2023] [Indexed: 10/07/2023] Open
Abstract
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Affiliation(s)
- Kyaw Min Tun
- Department of Internal Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Nevada, USA
| | - Nabil Noureddin
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, California, USA
| | - Mazen Noureddin
- Houston Research Institute and Houston Liver Institute, Texas, USA
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17
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Boursier J, Roux M, Costentin C, Chaigneau J, Fournier-Poizat C, Trylesinski A, Canivet CM, Michalak S, Le Bail B, Paradis V, Bedossa P, Sturm N, de Ledinghen V, Newsome PN. Practical diagnosis of cirrhosis in non-alcoholic fatty liver disease using currently available non-invasive fibrosis tests. Nat Commun 2023; 14:5219. [PMID: 37633932 PMCID: PMC10460420 DOI: 10.1038/s41467-023-40328-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 07/24/2023] [Indexed: 08/28/2023] Open
Abstract
Unlike for advanced liver fibrosis, the practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD remain not well defined. Here, we report the derivation and validation of a stepwise diagnostic algorithm in 1568 patients with NAFLD and liver biopsy coming from four independent cohorts. The study algorithm, using first the elastography-based tests Agile3+ and Agile4 and then the specialized blood tests FibroMeterV3G and CirrhoMeterV3G, provides stratification in four groups, the last of which is enriched in cirrhosis (71% prevalence in the validation set). A risk prediction chart is also derived to allow estimation of the individual probability of cirrhosis. The predicted risk shows excellent calibration in the validation set, and mean difference with perfect prediction is only -2.9%. These tools improve the personalized non-invasive diagnosis of cirrhosis in NAFLD.
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Affiliation(s)
- Jérôme Boursier
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France.
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France.
| | - Marine Roux
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
| | - Charlotte Costentin
- Univ. Grenoble Alpes, Clinique Universitaire d'Hépato-gastroentérologie, CHU Grenoble Alpes, Grenoble, France
- Univ. Grenoble Alpes; Institute for Advanced Biosciences, CNRS UMR 5309-INSERM U1209, Grenoble, France
| | - Julien Chaigneau
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
| | | | | | - Clémence M Canivet
- Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
| | - Sophie Michalak
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
- Pathology Department, Angers University Hospital, Angers, France
| | - Brigitte Le Bail
- Pathology Department, Bordeaux University Hospital, Bordeaux, France
- Bordeaux Institute of Oncology, BRIC UMR U1312, INSERM, Université de Bordeaux, Bordeaux, France
| | - Valérie Paradis
- Department of Pathology, Physiology and Imaging, Beaujon Hospital Paris Diderot University, Paris, France
| | - Pierre Bedossa
- Department of Pathology, Physiology and Imaging, Beaujon Hospital Paris Diderot University, Paris, France
- Liverpat, Paris, France
| | - Nathalie Sturm
- Pathology Department, CHU Grenoble Alpes, Grenoble, France
| | - Victor de Ledinghen
- Bordeaux Institute of Oncology, BRIC UMR U1312, INSERM, Université de Bordeaux, Bordeaux, France
- Hepatology Unit, Haut Leveque hospital, Bordeaux University Hospital, Bordeaux, France
| | - Philip N Newsome
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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18
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Lee J, Westphal M, Vali Y, Boursier J, Petta S, Ostroff R, Alexander L, Chen Y, Fournier C, Geier A, Francque S, Wonders K, Tiniakos D, Bedossa P, Allison M, Papatheodoridis G, Cortez-Pinto H, Pais R, Dufour JF, Leeming DJ, Harrison S, Cobbold J, Holleboom AG, Yki-Järvinen H, Crespo J, Ekstedt M, Aithal GP, Bugianesi E, Romero-Gomez M, Torstenson R, Karsdal M, Yunis C, Schattenberg JM, Schuppan D, Ratziu V, Brass C, Duffin K, Zwinderman K, Pavlides M, Anstee QM, Bossuyt PM. Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study. Hepatology 2023; 78:258-271. [PMID: 36994719 DOI: 10.1097/hep.0000000000000364] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 12/22/2022] [Indexed: 03/31/2023]
Abstract
BACKGROUND AND AIMS Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. APPROACH AND RESULTS Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). CONCLUSIONS Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.
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Affiliation(s)
- Jenny Lee
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
| | - Max Westphal
- Fraunhofer Institute for Digital Medicine MEVIS, Bremen, Germany
| | - Yasaman Vali
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
| | - Jerome Boursier
- Department of Hepatology, Angers University Hospital, Angers, France
| | - Salvatorre Petta
- Section of Gastroenterology and Hepatology, Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza, Department, University of Palermo, Palermo, Italy
| | | | | | - Yu Chen
- Lilly Research Laboratories, Eli Lilly and Company Ltd (LLY), Indianapolis, Indiana, USA
| | | | - Andreas Geier
- Division of Hepatology, Department of Medicine II, Wurzburg University Hospital, Wurzburg, Germany
| | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, and Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Belgium
| | - Kristy Wonders
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Department of Pathology, Aretaieion Hospital, national and Kapodistrian University of Athens, Athens, Greece
| | - Pierre Bedossa
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Mike Allison
- Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University NHS Foundation Trust, CB2 0QQ, Cambridge, UK
| | - Georgios Papatheodoridis
- Gastroenterology Department, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Raluca Pais
- Assistance Publique-Hôpitaux de Paris, hôpital Pitié Salpêtrière, Sorbonne University, ICAN (Institute of Cardiometabolism and Nutrition), Paris, France
| | - Jean-Francois Dufour
- Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | | | - Stephen Harrison
- Department of Gastroenterology and Hepatology, Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
| | - Jeremy Cobbold
- Department of Gastroenterology and Hepatology, Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
| | - Adriaan G Holleboom
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centres, location AMC, Amsterdam, the Netherlands
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Javier Crespo
- Department of Gastroenterology and Hepatology, University Hospital Marques de Valdecilla. Research Institute Valdecilla-IDIVAL, Santander, Spain
| | - Mattias Ekstedt
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, School of Medicine, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Manuel Romero-Gomez
- UCM Digestive Diseases, ciberehd, Virgen del Rocio University Hospital. Institute of Biomedicine of Seville (CSIC/HUVR/US), Department of Medicine, University of Seville, Seville, Spain
| | - Richard Torstenson
- Cardiovascular, Renal and Metabolism Regulatory Affairs, AstraZeneca, Mölndal, Sweden
| | | | - Carla Yunis
- Internal Medicine and Hospital, Global Product Development, Pfizer, Inc, New York, New York, USA
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center Mainz, Mainz, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Vlad Ratziu
- Assistance Publique-Hôpitaux de Paris, hôpital Pitié Salpêtrière, Sorbonne University, ICAN (Institute of Cardiometabolism and Nutrition), Paris, France
| | - Clifford Brass
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
| | - Kevin Duffin
- Lilly Research Laboratories, Eli Lilly and Company Ltd (LLY), Indianapolis, Indiana, USA
| | - Koos Zwinderman
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
| | | | - Quentin M Anstee
- Department of Gastroenterology Hepatology, Antwerp University Hospital, and Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Belgium
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Patrick M Bossuyt
- Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, the Netherlands
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19
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Goodman ZD. Role of Liver Biopsy in Clinical Trials and Clinical Management of Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2023; 27:353-362. [PMID: 37024212 DOI: 10.1016/j.cld.2023.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis constitute a spectrum of histologic lesions characterized by varying degrees of hepatocellular injury and fat accumulation with inflammation and scarring. Fibrosis associated with this disease may progress to cirrhosis and its complications. As there are no approved therapies, clinical trials to assess potential forms of drug therapy are conducted to assess drugs for efficacy and safety before submission to regulatory review. Liver biopsies are performed and evaluated to confirm the diagnosis of nonalcoholic steatohepatitis and to assess fibrosis stage for inclusion in trials.
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Affiliation(s)
- Zachary D Goodman
- Center of Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA.
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20
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Francque S, Ratziu V. Future Treatment Options and Regimens for Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2023; 27:429-449. [PMID: 37024217 DOI: 10.1016/j.cld.2023.01.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Recent progress in our understanding of the pathogenic mechanisms that drive progression of nonalcoholic steatohepatitis as well as lessons learned from several clinical trials that have been conducted over the past 15 years guide our current regulatory framework and trial design. Targeting the metabolic drivers should probably be the backbone of therapy in most of the patients, with some requiring more specific intrahepatic antiinflammatory and antifibrotic actions to achieve success. New and innovative targets and approaches as well as combination therapies are currently explored, while awaiting a better understanding of disease heterogeneity that should allow for future individualized medicine.
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Affiliation(s)
- Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics (LEMP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; InflaMed Centre of Excellence, University of Antwerp, Antwerp, Belgium; Translational Sciences in Inflammation and Immunology, University of Antwerp, Antwerp, Belgium; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Antwerp University Hospital, Drie Eikenstraat 665, Edegem B-2650, Belgium.
| | - Vlad Ratziu
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, Paris Cedex 13 75651, France; INSERM UMRS 1138 CRC, Paris, France.
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21
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Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N. Challenges and opportunities in NASH drug development. Nat Med 2023; 29:562-573. [PMID: 36894650 DOI: 10.1038/s41591-023-02242-6] [Citation(s) in RCA: 149] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/20/2022] [Indexed: 03/11/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD-NASH trials and potential mitigating strategies to move the field forward.
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Affiliation(s)
| | - Alina M Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA
| | | | | | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Chandler, AZ, USA
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22
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Jacobson IM, Wong VWS, Castera L, Anstee QM, Noureddin M, Cusi K, Harrison SA, Bugianesi E, Younossi ZM. Expert Panel Consensus on Clinical Assertion Statements Describing Noninvasive Tools for Diagnosing Nonalcoholic Steatohepatitis. J Clin Gastroenterol 2023; 57:253-264. [PMID: 36251413 PMCID: PMC9911115 DOI: 10.1097/mcg.0000000000001780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
GOALS AND BACKGROUND A panel of 9 experts in nonalcoholic steatohepatitis gathered to assess multiple components of the diagnostic process. MATERIALS AND METHODS The Clinical Assertion Statements covered screening of patients with type 2 diabetes for high-risk nonalcoholic fatty liver disease, which-if any-noninvasive tests could determine whether to delay or defer biopsy, whether primary care providers and endocrinologists should routinely calculate Fibrosis-4 (FIB-4) scores in patients with nonalcoholic fatty liver disease or those at risk for it, optimal noninvasive tests to stage fibrosis, the need to consider fibrosis in patients with normal transaminase levels, periodic monitoring for progressive fibrosis, whether patients should undergo biopsy before pharmacotherapy, and the clinical utility of genetic testing. RESULTS AND CONCLUSIONS Evidence was presented to support or refute each Clinical Assertion Statement; the panel voted on the nature of the evidence, level of support, and level of agreement with each Statement. Panel level of agreement and rationale of each Clinical Assertion Statement are reported here.
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Affiliation(s)
- Ira M. Jacobson
- Department of Medicine and Therapeutics, NYU Langone Health, New York, NY
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Laurent Castera
- Department of Hepatology, Hôpital Beaujon (Beaujon Hospital), Assistance Publique-Hôpitaux de Paris, Clichy
- Department of Hepatology, University of Paris, Paris, France
| | - Quentin M. Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne
| | - Mazen Noureddin
- Fatty Liver Program, Karsh Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida
- Malcom Randall VAMC, Gainesville, FL
| | | | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, Torino, Italy
| | - Zobair M. Younossi
- Inova Medicine, Inova Health System
- Department of Medicine, Center for Liver Diseases, Inova Fairfax Medical Campus, Falls Church, VA
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23
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Harrison SA, Thang C, Bolze S, Dewitt S, Hallakou-Bozec S, Dubourg J, Bedossa P, Cusi K, Ratziu V, Grouin JM, Moller DE, Fouqueray P. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol 2023; 78:914-925. [PMID: 36804402 DOI: 10.1016/j.jhep.2023.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/19/2023] [Accepted: 02/01/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND & AIMS Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH. METHODS Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed. RESULTS One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to (-25% LFC, p = 0.008-0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure. IMPACT AND IMPLICATIONS Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease. CONCLUSIONS PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein. IMPACT AND IMPLICATIONS Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease.
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Affiliation(s)
| | | | | | | | | | | | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Vlad Ratziu
- Sorbonne Université, ICAN, Hospital Pitié-Salpêtrière, INSERM UMRS 1138 CRC, Paris, France
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24
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Noureddin M, Goodman Z, Tai D, Chng ELK, Ren Y, Boudes P, Shlevin H, Garcia-Tsao G, Harrison SA, Chalasani NP. Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis. Aliment Pharmacol Ther 2023; 57:409-417. [PMID: 36647687 PMCID: PMC10107331 DOI: 10.1111/apt.17363] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/07/2022] [Accepted: 12/07/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS In cirrhotic nonalcoholic steatohepatitis (NASH) clinical trials, primary efficacy endpoints have been hepatic venous pressure gradient (HVPG), liver histology and clinical liver outcomes. Important histologic features, such as septa thickness, nodules features and fibrosis area have not been included in the histologic assessment and may have important clinical relevance. We assessed these features with a machine learning (ML) model. METHODS NASH patients with compensated cirrhosis and HVPG ≥6 mm Hg (n = 143) from the Belapectin phase 2b trial were studied. Liver biopsies, HVPG measurements and upper endoscopies were performed at baseline and at end of treatment (EOT). A second harmonic generation/two-photon excitation fluorescence provided an automated quantitative assessment of septa, nodules and fibrosis (SNOF). We created ML scores and tested their association with HVPG, clinically significant HVPG (≥10 mm Hg) and the presence of varices (SNOF-V). RESULTS We derived 448 histologic variables (243 related to septa, 21 related to nodules and 184 related to fibrosis). The SNOF score (≥11.78) reliably distinguished CSPH at baseline and in the validation cohort (baseline + EOT) [AUC = 0.85 and 0.74, respectively]. The SNOF-V score (≥0.57) distinguished the presence of varices at baseline and in the same validation cohort [AUC = 0.86 and 0.73, respectively]. Finally, the SNOF-C score differentiated those who had >20% change in HVPG against those who did not, with an AUROC of 0.89. CONCLUSION The ML algorithm accurately predicted HVPG, CSPH, the development of varices and HVPG changes in patients with NASH cirrhosis. The use of ML histology model in NASH cirrhosis trials may improve the assessment of key outcome changes.
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Affiliation(s)
- Mazen Noureddin
- Houston Methodist Hospital and Houston Research Institute, Houston, Texas, USA
| | | | - Dean Tai
- HistoIndex Pte. Ltd., Singapore, Singapore
| | | | - Yayun Ren
- HistoIndex Pte. Ltd., Singapore, Singapore
| | - Pol Boudes
- Galectin Therapeutics Inc., Norcross, USA
| | | | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University and CT-VA Healthcare System, New Haven, Connecticut, USA
| | | | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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25
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Singh SP, Anirvan P. NAFLD in Indians: A Myopic Yet Alarming Perspective. J Clin Exp Hepatol 2023; 13:7-9. [PMID: 36647401 PMCID: PMC9840069 DOI: 10.1016/j.jceh.2022.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 11/30/2022] [Indexed: 01/18/2023] Open
Key Words
- CC, compensated cirrhosis
- DC, decompensated cirrhosis
- ESLD, end stage liver disease
- GI, Gastro-Intestinal
- HCC, hepatocellular carcinoma
- HE, hepatic encephalopathy
- LRE, liver-related events
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NC, non-cirrhosis
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Affiliation(s)
- Shivaram P. Singh
- Kalinga Gastroenterology Foundation, Bajrakabati Road, Cuttack, 753007, India
| | - Prajna Anirvan
- Kalinga Gastroenterology Foundation, Bajrakabati Road, Cuttack, 753007, India
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26
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Noureddin M, Harrison SA. NASH cirrhosis trials and major adverse liver outcomes: Big data needed. J Hepatol 2023; 78:5-7. [PMID: 36328331 DOI: 10.1016/j.jhep.2022.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/18/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
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27
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Updated S2k Clinical Practice Guideline on Non-alcoholic Fatty Liver Disease (NAFLD) issued by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) - April 2022 - AWMF Registration No.: 021-025. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e733-e801. [PMID: 36100201 DOI: 10.1055/a-1880-2388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
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28
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Roeb E, Canbay A, Bantel H, Bojunga J, de Laffolie J, Demir M, Denzer UW, Geier A, Hofmann WP, Hudert C, Karlas T, Krawczyk M, Longerich T, Luedde T, Roden M, Schattenberg J, Sterneck M, Tannapfel A, Lorenz P, Tacke F. Aktualisierte S2k-Leitlinie nicht-alkoholische Fettlebererkrankung der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – April 2022 – AWMF-Registernummer: 021–025. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1346-1421. [PMID: 36100202 DOI: 10.1055/a-1880-2283] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- E Roeb
- Gastroenterologie, Medizinische Klinik II, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - A Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - H Bantel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - J Bojunga
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin., Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - J de Laffolie
- Allgemeinpädiatrie und Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - M Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
| | - U W Denzer
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Marburg, Deutschland
| | - A Geier
- Medizinische Klinik und Poliklinik II, Schwerpunkt Hepatologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz - Medizinisches Versorgungszentrum, Berlin, Deutschland
| | - C Hudert
- Klinik für Pädiatrie m. S. Gastroenterologie, Nephrologie und Stoffwechselmedizin, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - T Karlas
- Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - M Krawczyk
- Klinik für Innere Medizin II, Gastroent., Hepat., Endokrin., Diabet., Ern.med., Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - T Longerich
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - T Luedde
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - M Roden
- Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - J Schattenberg
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - M Sterneck
- Klinik für Hepatobiliäre Chirurgie und Transplantationschirurgie, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - A Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - P Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - F Tacke
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
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29
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Pais R, Aron-Wisnewsky J, Bedossa P, Ponnaiah M, Oppert JM, Siksik JM, Genser L, Charlotte F, Thabut D, Clement K, Ratziu V. Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Hepatology 2022; 76:456-468. [PMID: 35076966 DOI: 10.1002/hep.32358] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 12/26/2021] [Accepted: 01/03/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS It remains unclear to what extent and which components of advanced liver disease improve after bariatric surgery. We herein describe the histological outcome in patients with advanced NASH and its relationship with weight loss and metabolic improvement. APPROACH AND RESULTS One hundred ninety-six patients with advanced NASH underwent bariatric surgery, 66 of whom agreed to a follow-up liver biopsy at 6 ± 3 years (36 with advanced fibrosis [AF] and 30 with high activity [HA] grade without AF). Liver biopsies LBs were centrally read and histological response was defined as the disappearance of AF or HA. Bariatric surgery induced major histological improvement: 29% of patients had normal histology at follow-up biopsy; 74% had NASH resolution without fibrosis progression; and 70% had ≥1 stage fibrosis regression. However, AF persisted in 47% of patients despite NASH resolution and some degree of fibrosis reversal, only evidenced by the EPoS seven-tier staging classification. These patients had lower weight loss and reduced hypertension or diabetes remission rates. Older age and sleeve gastrectomy were the only independent predictors for persistent AF after adjustment for duration of follow-up. All HA patients had major histological improvement: 50% normal histology, 80% NASH resolution, and 86% a ≥1 grade steatosis reduction. Patients with normal liver at follow-up had the largest weight loss and metabolic improvement. Independent predictors of normal liver were amount of weight loss, high histological activity, and the absence of AF before surgery. CONCLUSIONS Although bariatric surgery successfully reverses active steatohepatitis, AF can persist for many years and is associated with lesser weight loss and metabolic improvement. Weight loss alone may not be sufficient to reverse AF.
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Affiliation(s)
- Raluca Pais
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France.,Institute of Cardiometabolism and Nutrition, Paris, France.,Centre de Recherche Saint Antoine, INSERM UMRS_938, Paris, France
| | - Judith Aron-Wisnewsky
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France.,CRNH Ile de France, INSERM, UMRS U1269, Nutrition and Obesities Systemic Approaches (NutriOmics), Paris, France
| | - Pierre Bedossa
- INSERM UMRS 1138 CRC, Paris, France.,LiverPat, Paris, France
| | | | - Jean-Michel Oppert
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France
| | - Jean-Michel Siksik
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France
| | - Laurent Genser
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France.,CRNH Ile de France, INSERM, UMRS U1269, Nutrition and Obesities Systemic Approaches (NutriOmics), Paris, France
| | - Frederic Charlotte
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France
| | - Dominique Thabut
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France.,Centre de Recherche Saint Antoine, INSERM UMRS_938, Paris, France
| | - Karine Clement
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France.,CRNH Ile de France, INSERM, UMRS U1269, Nutrition and Obesities Systemic Approaches (NutriOmics), Paris, France
| | - Vlad Ratziu
- Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France.,Sorbonne Université, Paris, France.,Institute of Cardiometabolism and Nutrition, Paris, France.,INSERM UMRS 1138 CRC, Paris, France
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30
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Abstract
Initially a condition that received limited recognition and whose clinical impact was controversial, non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease. Although there are no approved therapies, major breakthroughs, which will be reviewed here, have paved the way for future therapeutic successes. The unmet medical need in NASH is no longer disputed, and progress in the understanding of its pathogenesis has resulted in the identification of many pharmacological targets. Key surrogate outcomes for therapeutic trials are now accepted by regulatory agencies, thus creating a path for drug registration. A set of non-invasive measurements enabled early-stage trials to be conducted expeditiously, thus providing early indications on the biological and possibly clinical actions of therapeutic candidates. This generated efficacy results for a number of highly promising compounds that are now in late-stage development. Intense research aimed at further improving the assessment of histological endpoints and in developing non-invasive predictive biomarkers is underway. This will help improve the design and feasibility of successful trials, ultimately providing patients with therapeutic options that can change the course of the disease.
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Tong XF, Wang QY, Zhao XY, Sun YM, Wu XN, Yang LL, Lu ZZ, Ou XJ, Jia JD, You H. Histological assessment based on liver biopsy: the value and challenges in NASH drug development. Acta Pharmacol Sin 2022; 43:1200-1209. [PMID: 35165400 PMCID: PMC9061806 DOI: 10.1038/s41401-022-00874-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 01/18/2022] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is increasingly recognized as a serious disease that can lead to cirrhosis, hepatocellular carcinoma (HCC), and death. However, there is no effective drug to thwart the progression of the disease. Development of new drugs for NASH is an urgent clinical need. Liver biopsy plays a key role in the development of new NASH drugs. Histological findings based on liver biopsy are currently used as the main inclusion criteria and the primary therapeutic endpoint in NASH clinical trials. However, there are inherent challenges in the use of liver biopsy in clinical trials, such as evaluation reliability, sampling error, and invasive nature of the procedure. In this article, we review the advantages and value of liver histopathology based on liver biopsy in clinical trials of new NASH drugs. We also discuss the challenges and limitations of liver biopsy and identify future drug development directions.
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Affiliation(s)
- Xiao-Fei Tong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Qian-Yi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Xin-Yan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Ya-Meng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Xiao-Ning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Li-Ling Yang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Zheng-Zhao Lu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Xiao-Juan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Beijing, 100050, China.
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Harvey BE. NASH: regulatory considerations for clinical drug development and U.S. FDA approval. Acta Pharmacol Sin 2022; 43:1210-1214. [PMID: 35110697 PMCID: PMC9061714 DOI: 10.1038/s41401-021-00832-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/23/2021] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease is a growing public health crisis, with phenotypes from nonalcoholic fatty liver to nonalcoholic steatohepatitis, currently known as NASH, which can progress to liver fibrosis and end stage cirrhosis. NASH is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus. There are still no U.S. FDA approved drugs or biological treatments for NASH or related liver diseases. Despite official agency guidance, the regulatory pathway to ultimate product approval is unclear, due to both the extra-hepatic factors that contribute to NASH, as well as the organizational structure of FDA, with its traditional separation of therapeutic indications within discrete review divisions. There is hope that continued evolution of the regulatory process will lead to the ability for clinical trial endpoints supporting NASH treatment approval to include both liver-based and traditional metabolic measures, independent of specific FDA division review.
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Affiliation(s)
- Brian E Harvey
- Brian E Harvey LLC, "Cooperation, Partnership & Friendship", Maryland, MD, USA.
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Lee SH. The Phase 2 Study to Evaluate Efficacy and Safety of Lanifibranor in Patients with Nonalcoholic Steatohepatitis: Back in the Spotlight? THE KOREAN JOURNAL OF GASTROENTEROLOGY 2022. [DOI: 10.4166/kjg.2022.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Sae Hwan Lee
- Division of Gastroenterology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
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34
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Garbuzenko DV. Drug Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Fibrosis. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022. [DOI: 10.22416/1382-4376-2021-31-5-16-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Aim. An overview of current pharmacotherapy for non-alcoholic steatohepatitis (NASH)-associated liver fibrosis.Key points. In current clinical recommendations, therapeutic measures in non-alcoholic fatty liver disease should include lifestyle change, body weight normalisation, NASH-associated liver fibrosis-specific drug therapy and treatment for metabolic syndrome-related diseases. Given a lack of approved antifibrotic therapies in NASH, several drugs have nevertheless demonstrated an adequate efficacy and safety in phase 3 clinical trials, also in compensated cirrhosis, which allows their practical validation in phase 4.Conclusion. The understanding of liver fibrosis as an adverse natural consequence of non-alcoholic fatty liver disease clearly attests for an early introduction and wide use of antifibrotic therapy to improve NASH outcomes and avoid associated complications.
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Affiliation(s)
- Guadalupe Garcia-Tsao
- From the Digestive Diseases Section, Yale University School of Medicine, New Haven, and the Digestive Diseases Section, Veterans Affairs Connecticut Healthcare System, West Haven - both in Connecticut
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Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, Arrese M, Fracanzani AL, Ben Bashat D, Lackner K, Gorfine T, Kadosh S, Oren R, Halperin M, Hayardeny L, Loomba R, Friedman S, Sanyal AJ. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med 2021; 27:1825-1835. [PMID: 34621052 DOI: 10.1038/s41591-021-01495-3] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 08/09/2021] [Indexed: 02/08/2023]
Abstract
Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.
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Affiliation(s)
- V Ratziu
- Sorbonne Université, Institute for Cardiometabolism and Nutrition and Hôpital Pitié- Salpêtrière, INSERM UMRS 1138 CRC, Paris, France.
| | - L de Guevara
- Hospital Ángeles Clínica Londres, Mexico City, Mexico
| | - R Safadi
- Hadassah Medical Organization, Hadassah Hebrew University Medical Center, Jerusalem. The Holy Family Hospital, Nazareth, Israel
| | - F Poordad
- Texas Liver Institute/UT Health San Antonio San Antonio, San Antonio, TX, USA
| | - F Fuster
- Centro de Investigaciones Clinicas Viña del Mar, Viña del Mar, Chile
| | | | - M Arrese
- Departamento de Gastroenterología Facultad de Medicina Pontificia Universidad Católica de Chile Santiago Chile and Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Anna L Fracanzani
- Department of Internal Medicine, Ca' Granda IRCCS Foundation, Policlinico Maggiore Hospital, University of Milan, Milan, Italy
| | - D Ben Bashat
- Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine & Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - K Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - T Gorfine
- Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel
| | - S Kadosh
- Statexcellence Ltd, Tel-Aviv, Israel
| | - R Oren
- Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel
| | - M Halperin
- Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel
| | - L Hayardeny
- Galmed Pharmaceuticals Ltd, Tel-Aviv, Israel
| | - R Loomba
- NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA
| | - S Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Arun J Sanyal
- Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA
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Shi YW, Yang RX, Fan JG. Chronic hepatitis B infection with concomitant hepatic steatosis: Current evidence and opinion. World J Gastroenterol 2021; 27:3971-3983. [PMID: 34326608 PMCID: PMC8311534 DOI: 10.3748/wjg.v27.i26.3971] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/28/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
With the increasing incidence of obesity and metabolic syndrome worldwide, concomitant nonalcoholic fatty liver disease (NAFLD) in patients with chronic hepatitis B (CHB) has become highly prevalent. The risk of dual etiologies, outcome, and mechanism of CHB with concomitant NAFLD have not been fully characterized. In this review, we assessed the overlapping prevalence of metabolic disorders and CHB, assessed the risk of advanced fibrosis/hepatocellular carcinoma in CHB patients concomitant with NAFLD, and discussed the remaining clinical issues to be addressed in the outcome of such patients. We also explored the possible roles of hepatitis B virus in the development of steatosis and discussed difficultiesof histological evaluation. For CHB patients, it is important to address concomitant NAFLD through lifestyle management and disease screening to achieve better prognoses. The assessment of progressive changes and novel therapies for CHB patients concomitant with NAFLD deserve further research.
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Affiliation(s)
- Yi-Wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Rui-Xu Yang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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