Hepatic fibrosis: Concept to treatment.
Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases.
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
Christian
C
Trautwein
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Scott L
SL
Friedman
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Detlef
D
Schuppan
Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK. Electronic address: m.pinzani@ucl.ac.uk.
Massimo
M
Pinzani
D000818:Animals; D002986:Clinical Trials as Topic; D004359:Drug Therapy, Combination; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology; D008264:Macrophages / Q000502:physiology; D012107:Research Design
Antifibrotic; Fibrosis; Hepatic stellate cells; Liver