Welcome and Introduction
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1 Welcome and Introduction Henry C. Bodenheimer, Jr, MD Professor of Medicine Albert Einstein College of Medicine Chairman, Department of Medicine Beth Israel Medical Center New York, New York
2 Introduction PBC, PSC, and NASH are significant causes of liver disease morbidity and mortality PBC, PSC, and NASH impose a significant burden on patients and healthcare resources Despite advances in treatment of these diseases, there are still significant unmet patient care needs An increasing focus on the role of bile acids, and specifically the role of nuclear receptors, has identified potential promising therapy for these conditions Abbreviations: NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
3 Key Topics for Discussion Today Our understanding of PBC and its therapeutic options have evolved A significant proportion of patients with PBC have incomplete or no response to available treatment, emphasizing the need for new therapies Treatment response criteria and prognostic indicators have been identified and provide an opportunity to individualize disease management Abbreviations: PBC, primary biliary cirrhosis.
4 Key Topics for Discussion Today Lack of effective therapy for PSC is a significant unmet need The identification of targets for therapy (such as nuclear receptors, gut microbiota, etc) offers promise for control of the disease Recognition of the striking prevalence of NASH demands effective therapies be developed Multiple factors (such as insulin resistance, oxidative stress, and abnormal lipid metabolism) have a role in NASH, and are targets for evolving therapy Abbreviations: NASH, nonalcoholic steatohepatitis; PSC, primary sclerosing cholangitis.
5 Tracing the Evolution of PBC: What We Learned, What We Still Need to Know Henry C. Bodenheimer, Jr, MD Professor of Medicine Albert Einstein College of Medicine Chairman, Department of Medicine Beth Israel Medical Center New York, New York
6 Recognition of the Syndrome of Primary Biliary Cirrhosis Addison T, Gull W. Guys Hosp Rep. 1851;7: Slide courtesy of Dr. Henry Bodenheimer.
7 Primary Biliary Cirrhosis Autoimmune Mediated Disease Elevated IgM; Antimitochondrial antibody Associated autoimmune disorders Pathogenesis Lymphocytic destruction of biliary duct epithelium expressing PDC-E2 with resulting cholestasis, Inflammation and fibrosis Disease is increasingly recognized Comprehensive biochemical testing is common Dramatic growth in number of Hepatology practitioners Treatment of PBC available
8 Anatomy of the Canal of Hering Abbreviations: BD, bile duct; THV, terminal hepatic vein. Slide courtesy of Neil Theise, MD.
9 Canals of Hering in PBC CK 19 HLA-DR Abbreviations: BD, bile duct; PBC, primary biliary cirrhosis. With permission from Saxena R, et al. Hum Pathol. 2002;33:
10 Absence of Canals of Hering in Early PBC Abbreviation: PBC, primary biliary cirrhosis. With permission from Khan FM, et al. Hepatology. 2013;57:
11 Selected Drugs Evaluated in PBC Agent Efficacy Safety References D-penicillamine Removes copper Dysgeusia, thrombocytopenia Bodenheimer HC Jr, et al. Hepatology. 1985;5: Azathioprine Possible survival Chlorambucil Biochemical Bone marrow suppression Prednisolone Cyclosporine Histologic Survival Osteoporosis, Cushing s syndrome Renal function and hypertension Colchicine Biochemical Diarrhea Methotrexate Mycophenolate mofetil Ursodeoxycholic acid None None Bone marrow suppression, fatigue, pulmonary fibrosis Gastrointestinal toxicity, headache Only FDA-approved therapy to treat PBC Christensen E, et al. Gastroenterology. 1985;89: Hoofnagle JH, et al. Gastroenterology. 1986;91: Leuschner M, et al. J Hepatol. 1996;25: Wiesner RH, et al. N Engl J Med. 1990;322: Lombard M, et al. Gastroenterology. 1993;104: Bodenheimer H Jr, et al. Gastroenterology. 1988;95: Bach N, et al. Am J Gastroenterol. 2003;98: Combes B, et al. Hepatology. 2005;42: Talawalkar JA, et al. J Clin Gastroenterol. 2005;39: Poupon R, et al. Lancet. 1987;1: Poupon RE, et al. Gastroenterology. 1997;113: Slide courtesy of Henry Bodenheimer, MD.
12 Efficacy of Ursodeoxycholic Acid in Primary Biliary Cirrhosis Improved serum alkaline phosphatase and bilirubin values Rudic JS, et al. Cochrane Database Syst Rev. 2012;12:CD Delays histologic progression in early-stage disease Poupon RE, et al. J Hepatol. 2003;39:12-16 Pares A, et al. J Hepatol. 2000;32: Corpechot C, et al. Hepatology. 2000;32: Reduces risk of development of esophageal varices Lindor KD, et al. Mayo Clin Proc. 1997;72: Likely improves transplant-free survival in early-stage disease Corpechot C, et al. Gastroenterology. 2005;128: ter Borg PC, et al. Am J Gastroenterol. 2006;101:
13 Liver Transplants for PBC Analysis of liver transplantation trends in PBC over 12-year period (Jan 1995 Dec 2006) Absolute number of liver transplantations in United States increased approximately 249 transplants/year Absolute number of patients added to transplant waitlist increased 265 patients/year Absolute number of liver transplants for PBC decreased approximately 5.4 cases/year Absolute number of PBC patients added to transplant waitlist decreased 12.1 patients/year Lee J, et al. Clin Gastroenterol Hepatol. 2007;5:
14 PBC Prognosis by Stage on Ursodeoxycholic Acid With permission from Corpechot C, et al. Gastroenterology. 2005;128:
15 Drugs Under Evaluation for PBC Rituximab (B-cell depletion) Fibrates (PPAR-α agonists) Obeticholic acid (6-ethyl chenodeoxycholic acid, FXR agonist) Nor-ursodeoxycholic acid (bicarbonate umbrella, anti-inflammatory, anti-fibrotic) Abbreviations: FXR, farnesoid x receptor; PBC, primary biliary cirrhosis; PPAR, peroxisome proliferator-activated receptor.
16 Biochemical Effects of Rituximab in Patients with PBC and an Incomplete Response to UDCA Open-label study of rituximab treatment in patients with PBC and incomplete responses to UDCA (n = 6) Rituximab was well tolerated and associated with reductions in serum immunoglobulins (IgA; IgM) and antimitochondrial antibodies Significant reductions in serum ALP levels were observed up to 36 weeks following rituximab treatment Abbreviations: ALP, alkaline phosphatase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Tsuda M, et al. Hepatology. 2012;55:
17 Fenofibrate Improves Liver Biochemistry Values in PBC Patients Peroxisome proliferator-activated receptor (PPAR)-α agonist, fibric acid derivative Commonly used as a lipid-lowering agent Regulates immune response and cell proliferation PPAR-α activity Regulation of bile acid synthesis and detoxification Modulates phospholipid secretion, which helps protect bile duct epithelium by formation of micelles Package insert: contraindicated in active liver disease and PBC Levy C, et al. Hepatology. 2009;50(suppl 4):995A-996A. Zollner G, Trauner M. Br J Pharmacol. 2009;156:7-27.
18 Alkaline Phosphatase Levels During and After Fenofibrate Trial Open-label study to evaluate efficacy and safety of fenofibrate in patients with PBC and incomplete response to UDCA (n = 20) Alkaline phosphatase (ALP) levels decreased significantly ( IU/L) over course of study Rebound in ALP levels occurred following fenofibrate discontinuation Heartburn was the most frequent adverse event Levy C, et al. Aliment Pharmacol Ther. 2011;33:
19 Bile Acids From Simple Detergents to Pleiotropic Homeostatic Regulators Detergents in gut: solubilize fats in intestine absorption FXR: Liver, bile ducts, gut, fat OCA FXR Agonist Bile acid homeostasis: Nuclear receptor for bile acid signaling (intracellular bile acid sensor) Natural ligand: chenodeoxycholic acid (OCA = modified cheno) Bile acid synthesis and uptake Regulation of bile acid conjugation and excretion Metabolic effects: Hepatic triglyceride, VLDL synthesis Hepatic regeneration, intestinal bacterial overgrowth/translocation protection Modulation of insulin sensitivity and adiposity Anti-inflammatory/antifibrotic activity Abbreviations: FXR, farnesoid X receptor; OCA, obeticholic acid; VLDL, very low density lipoprotein. Makishima M, et al. Science. 1999;284: Watanabe M, et al. J Clin Invest. 2004;113: Cariou B, et al. J Biol Chem. 2006;281:
20 Dose Response Study Design OCA Addition to UDCA in PBC UDCA n = 35/group Baseline Placebo Obeticholic acid 10 mg Obeticholic acid 25 mg Obeticholic acid 50 mg Follow-up Screening Baseline 1 4 wk Predose Double-Blind Phase 12 wk Follow-Up Phase 2 wk Abbreviations: OCA, obeticholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
21 UDCA/Obeticholic Acid in PBC Alkaline Phosphatase Response Placebo 10 mg (n=37) 25 mg (n=42) 50 mg (n=25) AP (U/L) Baseline Follow- up Day of Visit Day 85- EOS p< all doses Abbreviations: AP, alkaline phosphatase; EOS, end of study; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
22 Pruritus Frequency and Severity Mild Moderate Severe % Placebo 10mg 25mg 50mg With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
23 Obeticholic Acid Monotherapy in PBC No UDCA use for 3 months N = 59 Placebo Baseline Obeticholic acid 10 mg Follow-Up Obeticholic acid 50 mg Screening Baseline 1-4 wk Predose Double-Blind Phase 12 wk Follow-Up Phase 2 wk With permission from Kowdley KV, et al. Hepatology. 2011;54(suppl S1):416A.
24 Obeticholic Acid Monotherapy in PBC Alkaline Phosphatase Response x ULN 4x ULN Mean values ± SEM 450 Placebo (n=23) x ULN 10 mg (n=20) 50 mg (n=16) AP (U/L) x ULN 2.25 x ULN 250 2x ULN Day x ULN Day 85- EOS All vs placebo P < Abbreviations: AP, alkaline phosphatase; EOS, end of study; SEM, standard error of the mean; PBC, primary biliary cirrhosis. With permission from Kowdley KV, et al. Hepatology. 2011;54(suppl S1):416A.
25 Primary Biliary Cirrhosis Unmet Therapeutic Need Alkaline phosphatase remains abnormal in most patients on ursodeoxycholic acid (UDCA), with 40% showing partial or no response Histology progresses in patients with incomplete response on UDCA, especially in stage 3/4 disease Elevated bilirubin, male gender, and younger age are predictors of poor response to UDCA
26 Filling PBC Treatment Gaps: New Insights, Emerging Targeted Therapies David E. J. Jones, MD, PhD Professor of Liver Immunology & Dean of Research Faculty of Medical Sciences Newcastle University Newcastle upon Tyne, United Kingdom
27 Survival Is Still Significantly Impaired in PBC in the UDCA Era Transplant-free survival of all NE1-25 cohort PBC patients vs case controls Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Jones DE, et al. J Hepatol. 2010;53:
28 Suboptimal Therapy in PBC What Are the Potential Causes? Drugs are not as effective as we think they are and/or our biomarkers of response don t accurately predict real response Effectiveness may not be as universal as we think it is Drugs are effective but we aren t using them optimally Drugs are effective but aren t actually getting to people Some combination of the above
29 Suboptimal Therapy in PBC What Are the Potential Causes? In UK-PBC national cohort, 20% of PBC patients are not treated with ursodeoxycholic acid (UDCA) Significant percentage of patients are treated with doses in 10- to 12-mg/kg range Some issues with adherence (weight gain, nausea, hair loss?) Simple and consistent message is needed about UDCA Urso Universally
30 UDCA Is an Effective Therapy in PBC Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Poupon RE, et al. Gastroenterology. 1997;113:
31 Criteria for Response to UDCA in PBC Paris Criteria Bilirubin <1 x ULN + ALT <2 x ULN +ALP <3 x ULN after 12/12 UDCA at mg/kg Responder: 96% survival vs 99% control population at 5 years Nonresponder: 69% survival vs 68% Mayo Predicted Survival Barcelona Criteria ALP decrease by 40% or normalized After 12/12 UDCA at mg/kg Issues Reciprocity Virtual controls (the 65-year-old woman paradox) Generalizability Dichotomizes a continuous variable Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Corpechot C, et al. Hepatology. 2008;48:
32 Criteria for Response to UDCA in PBC Early Stage Patients Patients (%) Rate of biochemical response Adverse outcome in responders 20 Barcelona Paris I Paris II Rotterdam Toronto Adverse outcome in nonresponders Early stage defined as normal albumin and bilirubin Paris II criteria: ALT and ALP 1.5 x ULN after medical therapy P = NS for Barcelona, Paris I, Rotterdam, and Toronto; P <0.05 for Paris II. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ULN, upper limit of normal. Corpechot C, et al. J Hepatol. 2011;55:
33 Criteria for Response to UDCA in PBC What About Normal LFT? Patients (%) Rate of biochemical response Adverse outcome in responders Paris IIa Paris IIb Paris IIc 16 Adverse outcome in nonresponders Paris IIc criteria: are normal ALP and ALT at end of UDCA P <0.001 for Paris IIa and Paris IIb; P <0.05 for Paris IIc. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; LFT, liver function test. Corpechot C, et al. J Hepatol. 2011;55:
34 UDCA-Response Criteria in the UK-PBC Patient Cohort Independent Validation RESULTS: Log- rank test for time free from LT for PBC, PBC- related death or Bilirubin 100µmol/L Criteria Chi- square statistic P- value Barcelona E- 03 Paris I 106 <1E- 16 Toronto E- 07 Paris II E- 11 Abbreviations: LT, liver transplant; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Carbone M, et al. Gastroenterology. 2013;144: e7.
35 Factors Predicting Outcome in PBC in the UK-PBC Patient Cohort Cox Proportionate Hazards Model: Time-to-Event Analysis Mul$variate $me- to- event analysis (baseline variables only) Variable Es$mate SE HR L95 U95 P Baseline Sodium Crea7nine LN Bilirubin <2e- 16 LN (AST or ALT ra7o) LN ALP Platelets Mul$variate $me- to- event analysis (including "Paris I response" at 12 months) Variable Es$mate SE HR L95 U95 P Baseline Sodium LN Bilirubin <2e- 16 LN (AST or ALT ra7o) Platelets months Treatment failure E- 12 Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HR, hazard ratio; LN, natural log; SE, standard error. Carbone M, et al. J Hepatol. 2013;58:S43-S44. Abstract 99. Slide courtesy of David E. J. Jones, MD.
36 BUT Just How Effective Is UDCA in PBC? The Conventional Model 79.7% of UDCA-treated patients are UDCAresponsive (Paris I) 797 beneficiaries per 1000 patients in UK-PBC cohort UDCA is highly effective! Significant proportion of patients meet response criteria before therapy is commenced
37 Just How Effective Is UDCA in PBC? 1000 patients 80% 20% 20% 800 UDCA-treated 200 UDCA-untreated 80% 160 nonresponders 640 responders 74% 166 true responders 474 respond without therapy UDCA has a beneficial effect in 166/1000 patients with PBC in the UK-PBC cohort For every 100 genuine responders, there are 96 genuine nonresponders Slide courtesy of David Jones, MD.
38 Treatment Failure in the UK-PBC Patient Cohort >50% of patients in the UK-PBC patient cohort who presented before the age of 50 have failed primary therapy (in a state of UDCA nonresponse or already transplanted) by the time of study With permission from Pells G, et al. J Hepatol. 2013;59:67-73.
39 UDCA Therapy in the UK-PBC Patient Cohort * UDCA Nonresponse is Asymmetrical in its Impact Female Male Gender Biochemistry *2315 full clinical data sets. With permission from Carbone M, et al. Gastroenterology. 2013;144: e7.
40 Potential Mechanisms for UDCA Nonresponse in PBC and Possible Options for Therapeutic Advance Different severity or nature of immune response Targeted immunosuppression (biologics) Different bile pool/microbiota Second-line bile acid therapies Different biliary epithelial response Biliary epithelial protectant agents Pre-existing fibrosis/cirrhosis Earlier diagnosis allowing treatment window for UDCA! Antifibrotics
41 FXR-Agonism as a Therapeutic Option in PBC Properties of Obeticholic Acid Shared Properties with Ursodeoxycholic Acid (UDCA) Choleresis Antiapoptosis Antioxidant Additional Direct Properties Induced bile acid detoxification Induced bile acid conjugation Suppressed bile acid synthesis Modified bile acid transport ( ABCB11, ABCB4; NTCP, OATBP3/8) Additional Indirect Properties (via GI release of FGF-19) Suppressed bile acid synthesis Could UDCA nonresponse addressed by OCA be a manifestation of indirect actions? Abbreviations: FCF-19, fibroblast growth factor 19; FXR, farnesoid X receptor.
42 FXR-Agonism as a Therapeutic Option in PBC Obeticholic Acid (INT-747) Phase II Data Day 85/ET p < p = Patients % Subjects Responding (%) % 44% 0% Placebo OCA mg mg OCA mg mg Dose Dose Placebo OCA 10 mg OCA 50 mg Placebo 10 mg 50 mg Abbreviations: ET, end of treatment; FXR, farnesoid X receptor; OCA, obeticholic acid. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
43 FXR-Agonism as a Therapeutic Option in PBC Obeticholic Acid (INT-747) Phase II Data 50 Placebo OCA 10mg10 mg OCA 50mg50 mg Patients Withdrawing Due to Pruritus % (%) Placebo OCA 10mg mg OCA 50mg mg With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
44 Challenges for Trial Design for Second-Line Therapy in PBC Definition of the at-risk population requiring second-line therapy Outcome measures (do UDCA response criteria apply to other therapies?) Lack of relevant biomarkers Impossibility of carrying out a hard endpoints trial due to prolonged disease (value of fibroscan?) Difficulty in performing a histology-based trial (acceptability and lack of scoring systems)
45 Overall Health Status and Quality of Life Are Also Impaired in PBC, UK-PBC Cohort Data (n = 2300) 35% of PBC patients report perceived QOL impairment vs 6% of healthy controls (P <.0001) 46% of PBC patients rated their perceived health status as fair or poor vs 15% of healthy controls (P <.0001) In terms of change over time, 49% of PBC patients reported their health as worse compared with the previous year vs 14% of healthy controls (P <.0001) Mells GF, et al. Hepatology. 2013;58:
46 Individual Symptom Domain Impacts UK-PBC Cohort Data (n = 2300) Fatigue is important symptom with significant impact on patients with the greatest impact on perceived QOL when accompanied by symptoms of social dysfunction Critical issue is how patients adapt and cope with fatigue as this will ultimately affect impact of fatigue on QOL Disease management should ultimately target both the underlying biology of the disease as well as symptoms Mells GF, et al. Hepatology. 2013;58:
47 Conclusions UDCA is safe, (relatively) cheap, and provides clear benefit; should be used universally An important minority of patients respond incompletely and are at significantly increased risk of death or need for transplant Best practice is to identify nonresponders and triage them for enhanced surveillance and consideration for trials Endpoints are a major challenge in second-line therapy evaluation Symptoms remain a major clinical challenge and an important endpoint for evolving therapies
48 Medical Management of PSC: Evolving Solutions to Ongoing Challenges Michael Trauner, MD Professor of Medicine Chair, Division of Gastroenterology and Hepatology Department of Internal Medicine III Medical University of Vienna Vienna, Austria
49 Liver Clinical Diagnosis of PSC Small Duct PSC 5-10% 20%/10y Gut-primed T-cells LPS MRC Obliterative fibrosis of bile ducts ERC Colitis PSC-IBD (~75%) Oligo-symptomatic Rectal sparing Right-sided domin. Backwash ileitis CRC (5x >UC) Loftus EV, et al., Gut. 2005;54: Common bile duct Duodenum Abbreviations: CRC, colorectal carcinoma; IBD, inflammatory bowel disease; ERC, endoscopic retrograde cholangiography; LPS, lipopolysaccharide; MRC, magnetic resonance cholangiography; PSC, primary sclerosing cholangitis. Diagram and images courtesy of Professors Gustav Paumgartner and Michael Trauner, Medical University of Vienna
50 Ongoing Challenges in Medical Management of PSC Early and correct diagnosis is it PSC? Exclusion of secondary causes (eg, IgG4) Mixed bag ; prognostic subgroups; overlap? Malignancy risk (CCA 10-15%, CRC) surveillance PSC = premalignant condition (cancer ~50% of deaths) Therapy limited options Lack of effective/established medical therapy Endoscopic therapy (dominant stenoses ~50%) Liver transplantation (70% 80% survival/10 years) Abbreviations: CCA, cholangiocarcinoma; CRC, colorectal carcinoma; IgG4, immunoglobulin G4. Trauner M, et al. Dig Dis. 2012;30(suppl 1): Eaton JE, et al. Gastroenterology. 2013;145: Hirschfield GM, et al. Lancet. 2013;pii:S (13) doi: /s (13) [Epub ahead of print]
51 Molecular Pathogenesis of PSC Potential Implications for Targeted Therapies Pathogenesis poorly understood Main reason for lack of effective medical therapy Immune-mediated disease? Immunosuppressants ineffective (exc.: IgG4, AIH overlap) Gut-derived factors (LPS, lymphocytes)? No firm correlation with IBD activity (liver transplantation?) Antibiotics, microbiome, new biologicals? Ischemia? (Abnormal) bile composition - biliary toxicity? UDCA disappointing, but novel bile acid therapies Abbreviations: IBD, inflammatory bowel disease; LPS, lipopolysaccharide, UDCA, ursodeoxycholic acid. Eaton JE, et al. Gastroenterology. 2013;145: Karlsen TH, Boberg KM. J Hepatol. 2013;59: Pollheimer M. et al. Best Pract Res Clin Gastroenterol. 2011;25:
52 Bile Acid-Based Therapeutics in PSC Current Practice and Future Directions UDCA as traditional bile acid-based therapy Role in slowing disease progression unclear Low-dose is safe, but efficacy not proven High-dose (28 30 mg/kg/d) is harmful Limited information to support UDCA as a chemopreventive drug (high-dose risk) AASLD guidelines against use; EASL more open Novel bile acid-based therapies on horizon Modified UDCA (norudca) and CDCA (OCA) Abbreviations: CDCA, chenodeoxycholic acid; OCA, obeticholic acid; UDCA, ursodeoxycholic acid. Wiencke K, et al. Clin Res Hepatol Gastroenterol. 2011;35: Chapman R, et al. Hepatology. 2010;51: European Association for the Study of the Liver. J Hepatol. 2009;51: Trauner M, et al. Dig Dis. 2012;30(suppl 1):39-47.
53 H & E norudca Reverses Sclerosing Cholangitis in Mdr2 (Abcb4) -/- (KO) Mice bd pv bd pv bd pv bd pv bd WT (+/+) KO (-/-) KO+UDCA KO+norUDCA * Months Rx UDCA norudca Conjugation Top images with permission from Fickert P, et al. Gastroenterology. 2006;130: Image of plastination of bile ducts and histograph image used with permission from Fickert P, et al. Gastroenterology. 2002;123: Halilbasic E, et al. Hepatology. 2009;49:
54 norudca Mechanisms of Action in Mdr2 (Abcb4) -/- Model of Sclerosing Cholangitis Clinical Development Phase I 2011 Phase II 2012 Phase III 2014 norudca PL x Anti-lipotoxic, bile acid detoxification and alternative export Mrp3 (Abcc3) Mrp4 (Abcc4) HO OH COO - Anti-proliferative Bile Acid Cholehepatic Shunting Anti-fibrotic Patent EP 2005 / Patent EP 2007 / Anti-inflammatory HCO 3 - With permission from Trauner M, et al. Dig Dis. 2012;30(suppl 1): Fickert P, et al. Gastroenterology. 2006;130: Halilbasic E, et al. Hepatology. 2009;49: Moustafa T, et al. Gastroenterology. 2012;142: e12. Fickert P, et al. J Hepatol. 2013;58:
55 Cellular Bile Acid Receptors as Therapeutic Targets - TGR5 and FXR TGR5 SNPs in Primary Sclerosing Cholangitis and Ulcerative Colitis Membrane receptor TGR5 Membrane transport Target cell Protein kinases FXR Nuclear receptors Protein targeting and function Gene transcription Inflammation, Metabolism Abbreviation: FXR, farnesoid X receptor. Karlsen TH, et al. Gastroenterology. 2010;138: Hov JR, et al. PLoS One. 2010;5:e Trauner M, et al. Gastroenterology. 2011;140: e1-12.
56 Stimulation of FXR by INT 767 Reverses Sclerosing Cholangitis in Mdr2 (Abcb4)-/- Mice Untreated 0 Obeticholic acid (INT-747) CO2H (FXR) HO refs OH EC50 FXR = 0.2 µm EC50TGR5 = 20 µm INT-767 INT-777 INT INT-777 OH (TGR5) HO Rx 3 Months INT-767 CO2H OH (Dual) HO EC50 FXR = 175 µm EC50TGR5 = 0.9 µm With permission from Baghdasaryan A, et al. Hepatology. 2011;54: OSO3H OH EC50 FXR = µm EC50TGR5 = 0.67 µm
57 Mechanisms of Action of FXR Ligands and Other Therapeutics Counteracting Biliary Toxicity FXR Bile Acids UDCA BSEP MDR3 FXR (UDCA) (Fibrates) Phospholipids Hepatocyte Abbreviations: BSEP, bile salt export pump; FXR, farnesoid X receptor; UDCA, ursodeoxycholic acid. Bile ducts (cholangiocytes) Inflammation HCO 3 - Bicarbonate Umbrella FXR norudca (UDCA) (Budesonide) Modified after: Slide courtesy of Professor Gustav Paumgartner, Beuers U, et al. Hepatology. 2010;52:
58 Nuclear Receptor Agonists in Fibrosing Cholangiopathies - Status for PSC Nuclear Receptor Therapeutic Ligand Rationale, Mechanism Status FXR Obeticholic acid (INT-747), INT-767 BA homeostasis, HCO 3 - umbrella, inflammation (IBD?) PPARα Fibrates BA/PL homeostasis, inflammation (IBD?) (déjà vu: PBC) PPARγ Curcumin (glitazones) Fibrosis, inflammation VDR Vitamin D Fibrosis, inflammation (cathelicidin?) RAR Retinoic acid (atra) BA homeostasis, fibrosis Preclinical (Mdr2 -/- ); phase II planned? (phase III in PBC) Single cases/small series; phase II completed Preclinical (Mdr2 -/- ); dosage issue Preclinical (Mdr2 -/- ) Preclinical (CBDL); open-label study recruiting Abbreviations: BA, bile acid; CBDL, common bile duct ligation; FXR, farnesoid-x receptor; IBD, inflammatory bowel disease; PPAR, peroxisome proliferator-activated receptor; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; RAR, retinoic acid receptor; VDR, vitamin D receptor. Halilbasic E, et al. Clin Liver Dis. 2013;17: (Review). Mizuno S, et al. J Gastroenterol. 2010;45: Baghdasaryan A, et al. Hepatology. 2011;54: Baghdasaryan et al, Gut Apr; 59(4): Hochrath K, et al Bone. 2013;55: He H, et al. Hepatology. 2011;53:
59 Fibrosing Cholangiopathies Current and Future Therapies Gut-primed T-cells LPS Colitis (~75%) FXR Primary biliary cirrhosis (PBC) UDCA, norudca?? FXR, PPAR?, GR? Primary sclerosing cholangitis (PSC) norudca? FXR??, PPAR?? FXR Common bile duct Microbiota Duodenum Liver image courtesy of Professor Gustav Paumgartner. Endoscopic image and slide courtesy of Michael Trauner, MD.
60 Microbiome Antibiotics Other Novel Therapeutics Immunotherapy and Beyond Limited effects (recommended for endoscopic retrograde cholangiography [ERC] prophylaxis, bacterial cholangitis) Minocycline, metronidazole, vancomycin? Gut-focused therapies Immunosuppressants disappointing (including TNF) New biologicals and TKIs (integrins, janus kinase)? Antifibrotics (simtuzumab, lysyl oxidase homolog 2) Eaton JE, et al. Gastroenterology. 2013;145: Hirschfield GM, et al. Lancet. 2013;pii:S (13) doi: /s (13) [Epub ahead of print]
61 A1 B1 C2 B1 A1 C2 Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in PSC Summary No established medical therapy UDCA (15 20 mg/kg/d), avoid higher dose Endoscopic therapy (ERC) of dominant strictures Liver transplant (end-stage liver disease; recurring bacterial cholangitis, pruritus, biliary dysplasia) UDCA: chemoprevention of CRC questionable (CCA??); g surveillance (colonoscopy, MR + CA 19-9)! Future: norudca, nuclear receptor-ligands (farnesoid X receptor), microbiota, new biologicals? Abbreviations: CCA, cholangiocarcinoma; CRC, colorectal carcinoma ERC, endoscopic retrograde cholangiography. Eaton JE, et al. Gastroenterology. 2013;145: Chapman R, et al. Hepatology. 2010;51: European Association for the Study of the Liver. J Hepatol. 2009;51:
62 Novel Therapeutics for the Management of NASH Arun J. Sanyal, MD Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition Executive Director, Education Core Center for Clinical and Translational Research Virginia Commonwealth University Richmond, Virginia
63 Defining the Need for Therapy CIRRHOSIS NASH + ADVANCED FIBROSIS More predictable NASH FATTY LIVER Less predictable Abbreviation: NASH, nonalcoholic steatohepatitis.
64 Who to Treat Features Associated with Progression to Bridging Fibrosis or Cirrhosis Multiple features of metabolic syndrome Weight gain Persistent elevation of alanine transaminase Ballooning Mallory bodies
65 What Are the Potential Targets for Therapeutics for NASH? Insulin sensitizers Insulin resistance FFA + insulin + cytokines Steatosis + metabolic dysregulation ER stress Oxidative stress Mitochondrial injury Antioxidants Inflammatory signaling Apoptosis Cell death Stellate cell activation Fibrosis Abbreviations: ER, endoplasmic reticulum; FFA, free fatty acids; NASH, nonalcoholic steatohepatitis. Slide courtesy of Arun Sanyal, MD.
66 External Validity of Efficacy of Vitamin E Authors N Dose Comparators Histology Arendt IU/d Placebo Improved* Sanyal IU/d Pioglitazone, placebo Improved Lavine IU/d Metformin, placebo Improved Harrison IU/d Placebo Improved Sanyal IU/d Vitamin E + pioglitazone Improved Dufour IU/d UDCA + placebo, placebo Improved *CT scan assessment of steatosis only. All histologic parameters excluding fibrosis. Steatohepatitis and ballooning. Fibrosis improvement. Sanyal AJ, et al. N Engl J Med. 2010;362: Lavine JE, et al. JAMA. 2011;305: Harrison SA, et al. Am J Gastroenterol. 2003;98: Sanyal AJ, et al. Clin Gastroenterol Hepatol. 2004;2: Dufour J-F, et al. Clin Gastroenterol Hepatol. 2006;4:
67 Beneficial Effects of Glitazones on NASH Systematic review and meta-analysis of thiazolidinedione effects on histologic and biochemical variables in NASH 7 randomized trials (n = 489) with histologic outcomes; 4 trials were placebo-controlled (n = 355) Primary outcome was histologic improvement (fibrosis, steatosis, inflammation, hepatocellular ballooning) Treated participants showed improvements in Fibrosis: RR 1.38, 95% CI 1.01 to 1.89 Steatosis: RR 2.03, 95% CI 1.57 to 2.62 Inflammation: RR 1.71, 95% CI 1.32 to 2.21 Hepatocellular ballooning: RR 1.62, 95% CI 1.15 to 2.28 Mahady SE, et al. J Hepatol. 2011;55:
68 Comparison of Vitamin E and Pioglitazone Vitamin E Pioglitazone Phase IIb/III trial data (better than) Placebo, pioglitazone Placebo Weight gain None Yes, continuous Improvement in insulin resistance None Yes Fracture risk None Yes Congestive heart failure None Yes All-cause mortality?? Slight increase??
69 What s New and Evolving?
70 There Is a Paucity of Therapeutic Development for NASH Number of actively recruiting phase II trials for treatment of NASH Available at:
71 Drugs in Development for NASH Phase III pivotal trials None Phase IIb studies Pentoxifylline (NASH CRN) Ethyl-eicosapentaenoic acid (EPA-E) (Mochida) Obeticholic acid (OCA) (Intercept) GFT-505 (Genfit) S-adenosylmethionine (Abbott) Anti-lysyl oxidase monoclonal antibody (Gilead)
72 Pentoxifylline for NASH proportion of subjects (%) NAS drop of 2 PTX placebo P p< < primary Primary endpoint Endpoint (n = 26) (n = 29) Zein CO, et al. Hepatology. 2011;54: Slide courtesy of Arun Sanyal, MD.
73 Pentoxifylline for NASH change in grade PTX placebo (n (n=2 = 26) 6) (n = 29) fat LI CB Abbreviations: CB, cytologic ballooning; LI, lobular inflammation; NASH, nonalcoholic steatohepatitis. Zein CO, et al. Hepatology. 2011;54: Slide courtesy of Arun Sanyal, MD.
74 Effects of n3 PUFA on NASH Patients with ALT Above ULN (%) P =.0001 Baseline Month 12 Control (n = 14) PUFA (n = 42) Abbreviations: ALT, alanine aminotransferase; NASH, nonalcoholic steatohepatitis; PUFA, polyunsaturated fatty acid; ULN, upper limit of normal. Capanni M, et al. Alimentary Pharmacol Ther. 2006:23; Slide courtesy of Arun Sanyal, MD.
75 6α-Ethyl Chenodeoxycholic Acid Obeticholic Acid (INT-747) Semisynthetic Derivative of CDCA Obeticholic Acid (INT-747) 6a-ethyl chenodeoxycholic acid CDCA Chenodeoxycholic acid FXR EC 50 (agonist) mm 8.66 mm ~ 2 log h FXR agonism Abbreviations: CDCA, chenodeoxycholic acid; FXR, farnesoid X receptor. Reprinted with permission from Pelliciari R, et al. 6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity J Med Chem. 2002;45: Copyright 2013, American Chemical Society.
76 FXR Effects on Lipid Metabolism Regulation of Lipid Homeostasis by Hepatic FXR Abbreviations: ANGTPL3, angiopoietin-like 3; apoc-ii, apolipoprotein C2; apo-c-iii, apolipoprotein C3; FA, fatty acid; FFA, free fatty acid; FXR, farnesoid X receptor; HDL-C, high-density lipoprotein cholesterol; hpparα, human peroxisome proliferator-activated receptor alpha; LPL, lipoprotein lipase; SHP, small heterodimer partner; SR-BI, scavenger receptor type I B-1; SREBP-1c, sterol regulatory element binding protein-1c; TG, triglyceride; VLDLR, very low density lipoprotein receptor. With permission from Zhang Y, Edwards PA. FXR Signaling in Metabolic Disease. FEBS Lett. 2008;582:
77 Type 2 Diabetes and NAFLD Exploratory Study Placebo Baseline Obeticholic acid (INT-747) 25 mg Obeticholic acid (INT-747) 50 mg Euglycemic Clamp - 2 Stage Baseline 2 weeks Double-Blind Phase 0 6 weeks 6 NAFLD, nonalcoholic fatty liver disease. Mudaliar S, et al. Gastroenterology. 2013;145:
78 Enrichment of Obeticholic Acid (INT-747) of Serum Bile Acids Day Bile acids other than INT- 747 INT Conjugates Total bile acids ( µ mol/l) Bile acids other than OCA (INT-747) OCA (INT-747) + Conjugates 0.0 Placebo 25 mg 50 mg Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
79 Endogenous Bile Acid After Obeticholic Acid (OCA) Administration % Change from Baseline to Day 43/End of Treatment E n d o g e n o u s B ile A c id s (% D fro m b a s e lin e ) * * * * * * P la c e b o O C A 2 5 m g O C A 5 0 m g N = 2 3 N = 2 0 N = 2 1 * * * p , **p 0.0 1,**p Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
80 Glucose Disposal Rate Low-Dose Insulin Clamp 60 mu x m 2 Body Surface Area/Min 5.0 G D R (m g /k g /m in ) D a y 0 D a y 4 3 P = 0.04 Placebo b o (N = 117) 7 ) OCA 25 mg (N = 15) O C A 2 5 m g (N = 1 5 ) OCA 50 mg (N = 12) O C A 5 0 m g (N = 1 2 ) Combined doses vs placebo: P = Abbreviations: GDR, glucose disposal rate; OCA, obeticholic acid. Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
81 Glucose Disposal Rate High-Dose Insulin 120 mu x m 2 Body Surface Area/Min 8.5 G D R (m g /k g /m in ) D a y 0 D a y 4 3 P = Placebo (N = 117) 7 ) O C A 2 5 m g (N = 1 5 ) Combined doses vs placebo: P = OCA 25 mg (N = 15) OCA C mmg g (N = 112) 2 ) Abbreviations: GDR, glucose disposal rate; OCA, obeticholic acid. Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
82 Percentage Weight Change All Patients 0 Placebo kg* OCA 25 mg kg* OCA 50 mg kg* -1 Weight Change - % -2-3 p = * Day 0 weight (mean) Placebo 25 mg 50 mg N=21 N=20 N=18 Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
83 Changes in Aminotransferases After OCA Administration 6 0 A L T 6 0 A S T U L N ra n g e : 4 5 to 5 2 U /L U L N ra n g e : 3 0 to 5 2 U /L A L T (U /L ) 4 0 A S T (U /L ) p = T re a tm e n t D a y T re a tm e n t D a y Placebo (N=23) OCA 25 mg (N=20) OCA 50 mg (N=18-21) P la c e b o (N = 2 3 ) 2 5 m g (N = 2 0 ) 5 0 m g (N = ) Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
84 OCA Affects Circulating Lipids OCA 25 mg (N=20) OCA 50 mg (N=18-21) Abbreviations: HDL, high density lipoprotein; LDL, low density lipoprotein; LLN, lower limit of normal; OCA, obeticholic acid; ULN, upper limit of normal. Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
85 Change in ELF Test Score After OCA Day Mean Change in ELF Score p = Placebo (N = 23) OCA 25 mg 25 (N mg = (N=20) OCA 50 mg 50 (N mg = (N=20) 25mg vs Placebo Hyaluronic acid p=0.05 P3NP p=0.01 TIMP1 p=0.03 Abbreviations: ELF, enhanced liver fibrosis; OCA, obeticholic acid; P3NP, procollagen-3 N-terminal peptide; TIMP1, tissue inhibitor of metalloproteinase 1. Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
86 Clinical AEs in >1 Patient and Significant AEs Placebo OCA 25 mg OCA 50 mg n = 23 n = 20 n = 21 N % N % N % Any AE 14 61% 9 45% 16 76% Constipation 5 24% Headache 1 4% 1 5% 3 14% Pruritus 2 9% 1 5% 2 10% Diarrhea 2 9% Pyrexia 2 9% Nasopharyngitis 2 9% URTI 2 9% 1 5% ALT/AST Increase* 1 4% 1 5% *Only severe AE; all others mild or moderate. Abbreviations: ALT, alanine aminotransferase; AST; aspartate aminotransferase; OCA, obeticholic acid; URTI, upper respiratory tract infection. Mudaliar S, et al. Gastroenterology. 2013;145: Slide courtesy of Arun Sanyal, MD.
87 PPAR-α/δ Agonist (GFT 505) Improve hepatic insulin resistance Decrease triglycerides Decrease LDL cholesterol Decrease gamma-glutamyl transferase, ALT No induction of PPAR-driven genes in skeletal muscle Cariou B, et al. Diabetes Care. 2013;36:
88 What is the Best Approach for the Patient with Advanced Fibrosis? Natural history more predictable Steatohepatitis Stage 1 2 Stage 3 4 Disease progression OUTCOMES Goals of Therapy Reduced mortality Reduced liver outcomes Improved functionality Improved quality of life Reduced healthcare resource utilization
89 NAFLD Fibrosis Score (NFS) Predicts Mortality Analysis to evaluate long-term effect of NAFLD on mortality, using data from NHANES Patients with high NFS had 69% increase in mortality (HR: 1.69; 95% CI: 1.09 to 2.63) Patients with intermediate NFS had 26% increase in mortality (HR: 1.26; 95% CI: ) Abbreviations: APRI, aspartate aminotransferase to platelet ratio index; HR, hazard ratio; CI, confidence interval; NHANES, National Health and Nutrition Examination Survey. Kim D, et al. Hepatology. 2013;57:
90 Studies to Reverse Cirrhosis tropocollagen strand lysine residue Anti-Lysl oxidase-mab lysyl oxidase carbonyl group (allysine) cross-linkage (aldol condensation) Abbreviation: mab, monoclonal antibody.
91 Summary and Conclusions Drug therapy of NASH must be provided in those with documented and established NASH with activity and some fibrosis, especially if multiple features of metabolic syndrome and elevated ALT are present Metformin does not work and has no role in the treatment of NASH Pioglitazone has beneficial effects on NASH but adverse effects limit its widespread utility Vitamin E improves NASH in adults and children without obvious serious adverse events in clinical trials; its longterm safety and generalizability of benefits remain to be established Several new agents are under study and appear to be promising tools to prevent NASH-related morbidity and mortality
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