Antifibrotic therapy: between hopes and reality. Fabio Marra Dipartimento di Medicina Sperimentale e Clinica University of Florence, Italy

Transcription

1 Antifibrotic therapy: between hopes and reality Fabio Marra Dipartimento di Medicina Sperimentale e Clinica University of Florence, Italy

2 Disclosures Abbvie: consultant fees AstraZeneca: consultant fees Bayer: speaker honoraria, consultant fees, travel grants Gilead: speaker honoraria ViiV Healthcare: speaker honoraria, research support

3 Talk outline Significance and pathogenesis of fibrosis Targets for antifibrotic therapy Antifibrotic trials in clinical practice

4 Significance and pathogenesis of fibrosis

5 What is the meaning of hepatic fibrosis? A dynamic, multicellular, integrated, (partially) reversible chronic wound healing process Injury Inflammation Repair Regeneration

6 Pellicoro et al., Nat Rev Immunol 2014

7 The impact of etiology on chronic liver diseases Different pathogenic mechanisms Different rates of fibrogenesis and fibrolysis Different patterns of fibrosis development

8 Different mechanisms of fibrogenesis in chronic liver diseases Viral, Autoimmune Inflammation ASH, NASH Cholestatic Morphogens

9 Targets for antifibrotic therapy

10 Main sites of action of antifibrotic therapy Fibrolysis Damage Fibrogenesis Myofibroblast activation

11 Main sites of action of antifibrotic therapy Etiologic treatment Damage Hepatoprotectants Caspase inhibitors FXR ligands Antioxidants UDCA Anti-inflammatory agents Chemokine antagonists Inflammasome antag. TLR antagonists Corticosteroids Modulators of inflammation Macrophage polarization

12 Regression of fibrosis (and cirrhosis?) after Hep B therapy Marcellin et al., Lancet 2013; 381:486

13 Nuclear receptors as targets of therapy in NASH FLINT Trial (FXR - Obeticholic acid) Neuschwander-Tetri et al., Lancet 2015 GOLDEN505 Trial (PPARa/d Elafibranor) Ratziu et al., Gastro 2016 PIVENS Trial (PPARg - Pioglitazone) Sanyal et al., NEJM 2010 Fuchs et al., Semin Liver Dis 2016

14 Cenicriviroc (CCR2/CCR5 antagonist) Modified from Marra & Tacke, Gastroenterology, 2014

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16 Intestinal microbiota and fibrosis Obesity, alcohol Inflammasome activation Modified from Bieghs and Trautwein, HBSN 2014

17 Genetic and epigenetic factors, dietary factors, obesity Nutrients FFA Adipokine imbalance Cytokines Insulin resistance Adipose tissue Intestine PAMPs Increased permeability Lipotoxic factors Inflammatory balance ER stress Autophagy Nuclear receptors ROS Apoptosis Hypoxia Hepatocyte injury Inflammation HSC activation NASH±FIBROSIS Caligiuri et al., Int J Mol Sci 2016

18 Main sites of action of antifibrotic therapy Revertants of activation PPAR agonists Blockers of perpetuation Cannabinoid antagonists TK inhibitors NO donors Chemokine antagonists ACE-I, ARBs Myofibroblast activation

19 Matrix changes and signaling in the HPC niche Williams et al., Gastroenterology 2013

20 The time for elucidation of mechanisms

21 MerTK regulates HSC biology Petta et al., J Hepatol 2015

22 The TAM family of tyrosine kinase receptors

23 Main sites of action of antifibrotic therapy Limitation of matrix deposition TGF-b antagonists Antagonists of fibrogenic cytokines (CTGF, leptin, HH) Matrix crosslinking Lysyl oxidase blockers Cytoskeletal modifiers Fibrogenesis

24 Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis Palumbo-Zerr et al., Nat Med 2015

25 Mehal et al., Nat Med 2011 Searching for core pathways Common to at least 2 organs and species Evolutionary conserved Essential for fibrosis

26 Main sites of action of antifibrotic therapy Inducers of MFB apoptosis Sulfasalazine Gliotoxin Inducers of matrix degradation Lysyl oxidase blockers TIMPs antagonists Fibrolysis

27 Fate of stellate cells during resolution of fibrosis Henderson & Iredale, Gastroenterology 2014

28 Dual role of macrophages in fibrosis Pellicoro et al., Nat Rev Immunol 2014

29 Dual role of VEGF in liver repair Bataller & Iredale, Gastroenterology 2014

30 Ho et al., Nat Rev Rheumatol 2014

31 Antifibrotic trials in clinical practice

32 Progression of Chronic Liver Disease Rosselli et al., Gut 2013

33 Examples of areas where antifibrotics are needed NASH ALD PSC Cirrhotic patients, even after removal of the cause ( accelerate fibrolysis)

34 Problems with trials of antifibrotic drugs Requirement for liver biopsy Replace or associate with noninvasive tests Clinical benefit requires a long period of time Develop surrogate markers of clinical outcome (e.g.function tests, HVPG) Efficacy may not be assessed by a simple test which allows short pilot trials Develop tests that dynamically measure matrix turnover (e.g. imaging tests)

35 Need for a dynamic test (biomarker?) to assess therapy in clinical practice 1. Not for cross-sectional staging or diagnosis 2. Sensitive to rapid changes in fibrogenesis and/or fibrolysis 3. Possibly related to ECM turnover 4. Providing indication if the behavior of the whole organ 5. Linked to pathogenesis 6. Minimally or non-invasive

36 The example of pulmonary fibrosis

37 Targeted Imaging of Fibrogenesis and Fibrosis Schuppan et al., J Hepatol 2012

38 Big data as a source of targets and biomarkers Zhang et al., Gut 2016

39 Exogenous synthetic peptides as a source of biomarkers Kwong et al., Nat Biotech, 2013

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41 Functional tests in the liver HVPG (correlates with prognosis) Quantitative tests IGC Galactose elimination capacity Methacetin breath test Methionine breath test

42 Patient stratification in antifibrotic trials 1. Variable rates of fibrosis progression confound intepretation of response 2. Fibrosis progression is non-linear 3. Homogeneous groups would reduce trial duration and clarify outcomes 4. Serum biomarkers necessary to identify fast progressors

43 Stratification may be based on: 1. Disease stage Histology (including CPA) Stiffness Imaging Serum markers or scores Test of liver function HVPG 2. Risk of progression Genetic markers Environmental factors

44 How to improve antifibrotic drug testing Validate potential targets in reliable animal models and in human tissue (precision-cut liver slices?) Develop biomarkers of disease progression/regression Drug repurposing

45 Antifibrotic drugs already in clinical use Colchicine Pentoxifylline Canrenone Statins COX inhibitors N-acetyl-L-cysteine (NAC) NO donors Thiazolidinediones Angiotenin receptor blockers

46 Targeting fibrosis: agenda Greater clarification of at-risk populations to identify patients suitable for clinical trials Standardization of all elements of drug discovery and testing/validation of biomarkers: murine models (suboptimal) early human translation (PCLS) Clinical trials must be standardized, and explore possible toxicity Accelerated development of improved noninvasive Markers

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