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Treating NASH with Fibrosis

Vivek Saraswat Sanjay Gandhi Postgraduate Institute Lucknow India . Treating NASH with Fibrosis. Pharmacological Therapies for NASH. (Torres & Harrison, 2008). Pharmacological Therapies for NASH. Currently no effective therapy is available for treating or preventing fibrosis in NASH

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Treating NASH with Fibrosis

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  1. VivekSaraswat Sanjay Gandhi Postgraduate Institute Lucknow India Treating NASH with Fibrosis

  2. Pharmacological Therapies for NASH (Torres & Harrison, 2008)

  3. Pharmacological Therapies for NASH • Currently no effective therapy is available for treating or preventing fibrosis in NASH • Many drugs in the pipeline: phase 2/3 evaluation • Score-card in 2013: 32 studies in NASH-NAFLD • Result pending: 18 • Completed: 14 • Effective: 03 • Not effective: 06 • Not reported: 05

  4. Major studies with NASH-related liver fibrosis as primary endpoint

  5. Insulin Sensitisers - Metformin Sound theoretical basis Improves insulin sensitivity & promotes weight loss  Lipogenesis,  fat oxidation (Zhou, 2001)  Steatosis and ALT in ob/ob mouse (Lin, 2000) Contradictory pilot data (Marchesini, 2001; Tiikkainen, 2004; Nair, 2004; Bugianesi, 2005)

  6. Meta-AnalysisMetformin – No Effect on Inflammation Musso et al, 2010

  7. Sound theoretical basis – PPAR-λ agonists Anti-steatotic(Maeda, 2001; Mayerson, 2002) Anti-inflammatory (Jiang, 1998; Xu 2003) Anti-fibrotic (Galli, 2002) PPARAγ mutations associated with NASH (Savage, 2003) Early RCTs all encouraging (Sanyal, 2004; Belfort, 2006; Aithal, 2008; Ratziu, 2008) FLIRT/FLIRT 2 (63 patients Roziglitazonevs Placebo, 1 year + 2 years) Significant improvement in steatosis, ALT and insulin sensitivity No improvement in steatohepatitis or fibrosis Increased risk of cardiovascular complications Pioglitazonevs Placebo (74 non-diabetic patients, 1 year) Improvement in steatohepatitis and fibrosis Most Recent Large RCT (PIVENS) Sanyal, 2010 Insulin sensitizers: Glitazones

  8. ‘PIVENS’ Trial p = 0.001 NNT 4.2 • 247 non-diabetic adults with NASH • 30mg Pioglitazone • 800IU Vitamin E • Placebo • Liver biopsy at 96 Weeks • Primary Endpoint = 2-point NAS reduction (including reduced ballooning) without increasing fibrosis • Both agents improved steatosis & inflammation scores • Only Vitamin E reduced ballooning • Neither agent reduced fibrosis p = 0.04 NNT 6.9

  9. Steatosis Inflammation Fibrosis (Musso et al, 2010)

  10. Meta-AnalysisAntioxidants Inflammation Fibrosis Musso et al, 2010

  11. What’s on the Horizon…?

  12. Major studies with NASH-related liver fibrosis as primary endpoint

  13. Targeting the Renin-Angiotensin System (RAS) in NASH • Hepatic stellate cells have a RAS that prevents apoptosis • Drugs that induce hepatic stellatecell apoptosis will stimulate fibrosis reversion despite ongoing liver injury • Antifibrotic effect of Olmesartandemonstrated in rat model of MCD induced fibrosingsteatohepatitis (Hirose, 2007)

  14. A2RB Anti-Fibrotic Effects: Clinical Trials • Yokohama et al, 2004 • 7 NASH patients, Losartan 50 mg/day for 48 weeks. • Reduced serum markers of fibrosis • Colmenero et al, 2009 • 14 HCV Patients, Losartan 50 mg/day for 18 months. • Reduced fibrosis and altered gene expression. • Georgescu et al, 2009 • Telmisartan may have additional insulin sensitising benefits. Yokohama et al, 2004

  15. LOSARTAN 50 mg/day + STANDARD CARE FELINE Study Design PLACEBO + STANDARD CARE LIVER BIOPSY LIVER BIOPSY PATIENTS RANDOMISED ANALYSIS (24 months) WITHIN 6 MONTHS LIVER BIOPSY • Inclusion Criteria • NASH with Fibrosis (Kleiner F1-F3). • Age >18. • Liver Biopsy within 6 Months • No ACE-I or A2RB Therapy. • Follow-Up • Non-invasive markers at 0, 48 & 96 weeks. • Liver biopsy at 24 months. • Study visits: 1, 4, 24, 48, 72, 96 weeks • End Points • Primary: Change of Kleiner fibrosis score between baseline and trial end. • Secondary: Grade of steatohepatitis, Serological fibrosis markers, Mechanistic study of NFkBRel Ser536.

  16. FXR Agonists – Obeticholic Acid • Cross-talk between bile acid transport/ signaling and hepatic lipid metabolism

  17. SREBP-1c ChREBP SHP MTP SHP HNF4 SHP LPL + (Apo CII +, Apo CIII -) Cyp7a1 PPARa + Glc G6P Liver WAT Oxidation FFA TG (Storage) FA-CoA VLDL-TG FXR FXR (FXR) TGR5 BA Bsep Ntcp VLDL Chol Muscle Enterohepatic BA Circulation Bile 4-12 x/d BA (FXR) TGR5 Absorption WAT FXR Fibroblast Growth Factor 19 Glucagon-like Peptide-1 Intestine Adapted from Trauner, Hepatology 2007

  18. The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in NASH Treatment (FLINT) Trial NIDDK sponsored study (NCT01265498) 283 adult NASH patients randomized to either 25 mg OCA or placebo for 72 weeks. Biopsies at start and end of 72-week treatment period. Study stopped early due to a highly statistically significant improvement (p=0.0024 on an intention-to-treat [ITT] basis) in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score (NAS) of at least two points with no worsening of fibrosis, as compared to placebo. • 6-weeks treatment with 25/50mg/day OCA induced: • Evidence of FXR activation, • 24.5% Increased insulin sensitivity (p=0.011), • Reduced gGT and ALT levels, • Reduced markers of fibrosis, • Weight loss.

  19. GFT505 in NAFLD (‘GOLDEN-505’) • Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis (NASH) ClinicalTrials.govidentifier: NCT01694849 Sponsor: Genfit • Phase IIb, double-blind, randomized, placebo controlled study • Recruitment goal: 270 randomized patients (recruitment completed) : • 90 patients in placebo group • 90 patients in GFT505 80mg group • 90 patients in GFT505 120mg group

  20. Consensus Statements • 1. Currently no pharmacologic agent has proven efficacy for reversing fibrosis in NASH • 2. Insulin sensitizers and anti-oxidants benefit steatosis and inflammation but not fibrosis • 3. Several promising agents in phase2/3 studies; results expected soon • Losartan A2T1 RB • OCA FXRA • GFT 505 PPAR-αδ agonist • Simtuzumab LOXL2 inhibitor

  21. Thank you

  22. Hepatology 2007; 45: 1375-1381 Hirose et al, 2007

  23. Tested ‘Liver-directed’ Therapies Ursodeoxycholic Acid 13-15mg/kg - no benefit in large RCT (Lindor, 2004) Urso + Vit E: encouraging pilot data (Dufour, 2006) 28-35mg/kg may be beneficial ( ALT/Fibrotest)(Ratziu, 2010) Antioxidants Vitamin E: Benefit in recent RCT (Sanyal, 2009) Betaine: reduced ALT and histology (Abdelmalek, 2001) Probucol: reduced ALT in small RCT (Merat, 2003) Iron depletion(Facchini, 2002; Riquelme, 2004)

  24. Vitamin E: Implications for NASH Management • PIVENS & TONIC indicate that Vitamin E may be effective in some patients • Vitamin E is cheap so may have a placement in management of some patients • BUT Need for caution: • Increased all cause mortality risk at >400 IU/day (Miller, 2005; Bjelakovic, 2007) • Increased haemorrhagic stroke risk (although reduced embolic stroke risk) (Schwarts, 2010) • Increased Prostate carcinoma risk (Lippman, 2009; Klein, 2011)

  25. Meta-analysis of 4 studies examining HCC prevalence in cohorts of patients with T2DM. N=105,495 T2DM patients OR 0.3 (0.17-0.52), p<0.001

  26. 22,047 HCC patients with T2DM and matched controls. • Multivariate analysis adjusting for Age, Gender, HBV, HCV, Cirrhosis, Renal Function, Duration of T2DM, Diabetic control (HbA1c), Other diabetic meds. 7%  HCC risk/year Metformin Rx OR 0.93 (0.91-0.94), p<0.0001

  27. Metformin activates AMP-activated protein kinase signallingand reduces mTORpathway activity. • Leads to inhibition of HCC cell proliferation and induction of G0/G1 cell cycle arrest.

  28. Management Priorities • Ratziu et al, 2010 • Musso et al, 2010 • Anstee et al, 2013 Promrat et al, 2010 Thoma et al, 2012 Hallsworth et al, 2011 • Yokohama et al, 2004 • Colmenero et al, 2009 • Sanyal et al, 2010 • Musso et al, 2010 • Armstrong et al, 2012 Zhang et al, 2012 Chen et al, 2013 El-Serg et al, 2009 Singh et al, 2013

  29. Large, Ongoing, Phase IIb RCTs in NASH Ratziu, Nature GI & Hepatology Reviews 2013

  30. Untested ‘Liver-Directed’ Therapies • IKK inhibitors (e.g. Sulphasalazine) • Anti-inflammatory/anti-fibrotic (Oakley, 2005) • Improve NASH in experimental models (Beraza, 2008) • ER stress (chaperones) • TUDCA, 4-phenylbutyrate(Ozkan, Science 2006) • Peripheral CB1 blockade • Improves CHD and lipid metabolism (Jourdan, 2012) • FXR/TGR5 agonists (Zhang, 2009) • Combined PPARα/PPARδ agonist(Stales, 2013) • Probiotics(Li 2003, Vajro 2011, Aller 2011) • Enhancers of autophagy (Caffeine) (Sinah, 2013; Li, 2014)

  31. SAMe/AdeMet is a metabolically pleiotropic molecule. • SAMe is the main methyl-donor for methylation of nucleic acids, phospholipids, histones, biogenic amines and proteins. • Homocysteine lies on the intersection of the transmethylation and the trans-sulphurationpathway that leads to glutathione synthesis. SAMe

  32. SAMe Reduced transmethylation of methionine to SAMe ??due to ROS inhibition of MAT

  33. Mat1a knockout mice have low SAMe levels and show activation of lipogenesisand inhibition of TG release >>> Steatosis. • Gnmtknockout mice have high SAMe levelsbut also show >>> Steatosis. SAMe Overall, data suggests that both abnormally high or low levels of SAMe may promote NAFLD: maintaining a balance of metabolites may be important. Editorial: Jacobs et al, 2013

  34. S-Adenosyl-L-Methionine in NAFLD (‘EXPO’) • Study to Investigate the Effects of Different Doses of S-adenosyl-L-methionine (SAMe) in Subjects With Nonalcoholic Fatty Liver Disease and Non-treated Matched Healthy Volunteers as Control Group (EXPO) ClinicalTrails.gov identifier NCT01754714 Sponsor: Abbott • Open-label, Randomized, Parallel-Group, Exploratory Study to Investigate the Effects of Different Doses of S-adenosyl-L-methionine (SAMe) in Subjects With Nonalcoholic Steatohepatitis (NASH) and Non-treated Matched Healthy Volunteers as Control Group • 120 patients; currently recruiting: France, Germany & Poland (estimated end Sept 2014) • Endpoints: • Methionine elimination half-life measured in blood • Hepatic Panel (liver laboratory parameters) • Metabolic Panel (metabolic laboratory parameters) • Immunological/Anti-oxidant Panel (immunological and anti-oxidant laboratory parameters): cytokine profile (IL-6, IL-8, IL-10, TNFα), MCP-1, G-CSF, glutathione in erythrocytes, isoprostane level. • Fibrosis and Apoptosis Markers (fibrosis and apoptosis laboratory markers) : CK18, Hyaluronic acid, ActiTest/Fibrotest

  35. Targeting the Patient…Where Are We Now? WHO? Individual Risk Stratification WHERE? Clinical Setting Overweight, Metabolic Syndrome Age, etc * Steatosis vs. NASH * High Prevalence Groups; Hepatology Referrals HOW? Diagnostic Strategies WITH WHAT? Therapy Lifestyle: Diet & Exercise Insulin Resistance – Metformin/Glitazones* Anti-Oxidants – Vitamin E* Fibrosis – A2RB HCC – Metformin/Statins Staged Approach using non-invasive tools +/- Biopsy: - Steatosis vs. NASH; - Extent of Fibrosis.

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