NASH in 2017 and beyond. Raluca Pais, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France

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1 NASH in 2017 and beyond Raluca Pais, Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France

2 NAFLD-NASH definition NAFLD 90% NASH 24-98% NAFLD =macrovesicular steatosis > 5% of hepatocytes. NASH=steatosis+ ballooning + lobular inflammatory infiltration Cohen et al, science 2011; Sanyal et al, Hepatol 2011

3 Epidémiologie

4 Prevalence of NAFLD 25% to 35% worldwide Israel USA Prevalence of NAFLD China Italy Taiwan Japan Mexico Korea India Prevalence of obesity Lazo et al. Semin. Liver Dis. 2008

5 Prevalence of NASH within NAFLD % steatosis % NASH Ekstedt N=129 Tertiary CYTOL 2002 N=248 Tertiary,multicentric Soderbergh N=118 Tertiary care NASH CRN N=679 Tertiary,multicentric Campos N=125 Bariatric surgery 45 55

6 VA Corporate Data Warehouse Recognition of ALT increase Diagnosis of NAFLD/NASH Lifestyle modifications Referral specialist evaluation Blais, Am J Gastroenterol 2014 Structured Chart Review NAFLD case definition RECEIPT OF NAFLD CARE Persistently increased ALT No viral hepatitis No excessive alcohol (2 yrs prior) Metabolic Sd BMI >30 kg/m²

7 NAFLD : an underrecognizeddisease 39.4% recognition of ALT increase 21.5% diagnosis of NAFLD/NASH 15% lifestyle modifications 10.5% referral specialist evaluation 60.6% NO NAFLD CARE Only the magnitude and proportion of ALT elevation were predictive of receiving NAFLD care Blais, Am J Gastroenterol 2014

8 Pathogenèse

9 Lipogenèse de novo Lipolyse du tissu adipeux Fructose + Glucose Acetyl CoA ACC FAS SCD SREBP-1c ChREBP Acides gras libres Dysfonction du tissue adipeux: - Hypertrophie des adipocytes - Infiltration macrophagique - Hypoxie - Fibrose - sensibilité à l insuline - adiponectine - cytokines proinflammatoires Lipides lipotoxiques - Acide palmitique - Lysophosphatidilcholine - Céramides - Cholestérol libre MOGAT2 DGAT2 Triglycérides Necroinflammation Stéatose Carnitine CPT1 CPT2 PNPLA3 Aminoacides Choline/PC VLDL Hypertriglycéridémie NASH Fibrose CHC Beta oxydation mitochondriale

10 Diagnostic

11 Usualdiagnostic circumstancesfor NAFLD LFTs+ Ultrasound Cirrhosis X NASH Increased ferritin LFTs+ Metabolic RF Metabolic RF + Normal ALT Key points : presence of steatosis (ultrasound, markers) presence of metabolic risk factors

12 Marqueurs sériques non-invasifs disponibles FIBROSE STEATOSE STEATOHEPATITE FibroTest ELF Panel Fibromètre Angulo SteatoTest Kotronen FLI NASHTest CK 18? NASH Dg (CK18, adiponectin, resistin) Ratziu, BioMedCentral Gastro 2006 Guha, Hepatology 2008 Angulo, Hepatology 2007 Cales, Hepatology 2005 Rosenberg, Gastroenterology 2004 Poynard, Comp Hepatol 2005 Poynard, BMC Gastro 2006 Wieckowska, Hepatology 2006

13 NAFLD fibrosis score NAFLD fibrosis score 0,037 * age + 0,094 * BMI + 1,13 * IFG/diabetes + 0,99 * AST/ALT 0,013 * platelets 0.66 * albumin + 1,675 Angulo, Hepatology 2007; Boursier, Current Opin Med Diag 2012; Shah, Clin Gastroenterol Hepatol 2009

14 NAFLD fibrosis score F0-2 F3/4 1, ,9 0,8 0,7 0,72 0,78 0, % AUROC 0,6 0,5 0, % 66.9% 0,3 30 0,2 20 0,1 10 0,0 F 2 F 3 F < Grey zone < Xiao, Hepatology 2017

15 NFS: a good fibrosis test in diabetics? 1693 US diabetics (code ICD-9 from 09/11 to 11/15) Negative 1018 without NASH 675 probable NASH (AST or ALT 30 (M) ou 19 (W), T2DM, no other cause, no alcohol) 0,037*age + 0,094*BMI + 1,13*IFG/diabete + 0,99*AST/ALT 0,013*platelets 0.66*albumin + 1,675 Intermediate Positive Joshi, ILC2016-RS-4095

16 Tests sanguins de fibrose FIB4 : attention à l âge! 3754 patients, hépatopathie chronique prouvée histologiquement Chez les patients 60 ans, le tauxde faux positifsétaitde 82.0% Boursier, J Hepatol 2017

17 Transient Elastography

18 Factors influencing liver stiffness Steatosis De Ledinghen, Expert Med Rev Devices 2010 Boursier, J Gastroenterol 2014

19 CAP pour interpréter le Fibroscan Petta, Hepatology 2016

20 Fibroscan manufacturer recommendations M probe if skin liverdistance capsula <25mm, XL probe if 25mm Manufacturer recommendations Adjustment Boursier, AASLD 2017

21 Combination blood tests + Fibroscan F0-2 F3/4 Fibroscan + NAFLD fibrosis score % 70 FS < 7,9 kpa NFS < -1,455 Autres FS 9,6 kpa NFS > 0, % 100% F0/2 Biopsy F3/ FS < 7,9 kpa NFS < -1,455 Biopsy FS 9,6 kpa NFS > 0,676 Petta, Liver Int 2015

22

23 When to perform liver biopsy on an individual basis? Metabolically stable? Attempt diet and lifestyle change Failure (s) previous attempts? Never tried No change Improvement weight, IR, ALT N Comorbidities Patient motivation Trials Fibrosis risk FT/FS (or clinical) +/+ +/- -/- MONITORING LB

24 Liver Biopsy prone to sampling error: 1 stage: 41%; 2 stages: 12% interobservervariability: 1 stage discordance 24% NAS Score = Steatosis(0-3) + Inflammation (0-3) + Ballooning(0-2) SAF Classification: Diagnos( c** No*NAFLD* NAFLD* NAFLD* NAFLD* NAFLD* NASH* NASH* Ratziu, Gastroenterology2005 Bedossa, Hepatology2012 NAFLD* NASH* NASH*

25 Histoire Naturelle EXTRAHEPATIC COMPLICATIONS Fibrosis progression HCC ESLD Liver Transplantation

26 NASH CRN N = 396 pts Sanyal, AASLD 2016

27

28 Bedside risk factors for severe fibrosis in NASH Age > yrs Diabetes BMI > 27 kg/m² Arterial HTN Hypertriglyceridemia(TG > 1.7 mmol/l) ALT>2N AST/ALT > 1 Angulo, Hepatology 1999 Ratziu, Gastroenterology 2000 Dixon, Gastroenterology 2001

29 Fibrosis progression in patients with NAFLD Metaanalysis of 11 studies of patients with NAFLD and paired liver biopsies (N = 411 pts) Fibrosis progression rate: NAFL: 1 stage over 14 years NASH: 1 stage over 7 years Singh et al., Clin Gastroenterology and Hepatology 2015

30 Causes of death in NASH cirrhosis Same as in any other cause of cirrhosis Same prognostic value of MELD, Child-Pugh, N=152 NASH-cirrhosis 8 yrs f/u 29 Deaths Competitive risk Cardiovascular N=8 Other N=2 Sepsis Liver failure N=19 Variceal hemorrhage HCC Sanyal, Hepatology 2006

31 Progression to liver-relateddeath N=152 NASH-cirrhosis& 150 HCV-cirrhosis Child A Child B Child C Sanyal, Hepatology 2006

32 NAFLD and HCC In Europe Over the pastdecade ALD: 28% NAFLD: 22% No CLD: 20% Dyson, J Hepatol 2013

33 NAFLD and HCC GHPS experience N = 323 patients undergoing liver resection Pais et al, unpublished

34 NAFLD and HCC GHPS experience HCC distribu on according to the e ology of chronic liver disease and fibrosis stages Recurrence-free survival according to the e ology of chronic liver disease. Pais et al, unpublished

35 Characteristics of NAFLD and HCC US, retrospective: 1500 HCC VA Hospital ( ) 8% NAFLD related HCC Europe (Italy), prospective : 145 NAFLD-HCC and 611 HCV-HCC Particularities of patients with NAFLD-related HCC : - Older - Higher prevalence of metabolic comorbidities - Absence of cirrhosis (42%) - No HCC screening (57%) - Less eligible for HCC specific therapy (comorbidities, advanced tumors) Mittal, CGH 2015 Bellentani, Hepatology 2015 in press

36 NAFLD liver transplantation NAFLD 2 nd etiologyof livertransplantation in US Wong, Gatroenterology2015

37 NAFLD Center stage of the metabolic syndrome? Hypertension Cardiovascular Prevalence essential HTN NAFLD Endothelial& coronary dysfunction Carotid plaques Impairedventricularfctand metabolism CV events Incident diabetes Insulin requirements Diabetes OSA

38 NAFLD and early ATS transversal studies NAFLD and C-IMT NAFLD and CAC > 100 Sookoian, J Hepatol 2008 Jaruvongvanich, Dig Liv Dis, 2016

39 NAFLD is an independent predictor for the occurrence of early ATS -Longitudinal studies C-IMT 1872 subjects FU = 8 ±4 years Coronary Calcium Score 4731 subjects FU = 4 years Pais, J Hepatol 2016 Sinn, Gut 2016

40 NAFLD is additive to established MRF in increasing the risk of incidentt2dm N = subjectsfroma South Koreanoccupationalcohort Risk factors OR, 95% CI IR alone 3.66 ( ) Overweight/obesity 1.29 ( ) NAFLD 2.73 ( ) IR + overweight/obesity 6.16 ( ) IR + NAFLD 6.73 ( ) Overweight/obesity + NAFLD 3.23( ) IR + overweight/obesity + NAFLD ( ) Adjusted for age, sex, alcohol, smoking status, exercise, educational status, TG, and ALT Sung, Diabetes Care 2012

41 Severityof NAFLD and incidentt2dm Chang, Am J Gastroenterol 2013

42 NAFLD and type 2 diabetes bidirectional relationship Worsening of histological features and fibrosis progression Type 2 diabetes In patients with T2DM, the presence of NAFLD should be looked for irrespective of liver enzyme levels, since T2DM patients are at high risk of disease progression (A2) In persons with NAFLD, screening for diabetes is mandatory, by fasting or random blood glucose or HbA1c (A1) NAFLD Increased risk of incident type 2 diabetes

43 NAFLD and chronic kidney disease Cumulative incidence of CKD N = pts Combinded kidney-liver transplantation Viral hepatitis Alcohol + biliary CLD NASH + CC Sinn, J Hepatol 2017 Singal, Transplantation 2016

44 NASH fibrose et SAS N= 101 Obese patients ODI=3 Normal liver ODI=20 Steatosis and fibrosis >>>> Hypoxia severity is significantly associated with NAS score even after adjustment for confounding metabolic factors >>>> Hypoxia severity is an independent factor of more severe liver fibrosis Aron-wisnewsky, C Minville et al, J Hepatol 2012;

45 Work-up in patients withnafld: a multiorganapproach NAFLD Extrahepatic comorbidities? Liver condition Type 2 diabetes Sleep apnea Evaluate CV risk Dyslipidemia Cofactors of fibrosis Pathological form Stage Prognosis

46 NAFLD Non pharmacological treatment

47 Life style modifications 1. Histological improvement 293 patients; 89% with paired liver biopsy F/u: 52 weeks Low-fat hypocaloric diet (- 750 kcal) Vilar Gomez, Gastroenterology 2015

48 2. Fibrosis Life style modifications Patients, % N = 73 N = 16 N = 8 N = 16 Vilar Gomez, Gastroenterology 2015

49 Life style modifications physical activity Higher energy consumption Reduces body weight Fatigue, discomfort =>poor long-term compliance. Increase muscular strength, mass and bone density; less weight loss Improves dyslipidemia, HBP, IR Less energy consumption Improvement in 50% of cases without weight loss Hashida, J Hepatol 2017

50 Weight loss correlates with the frequency of medical visits Dudekula, PlosOne (11)

51 3% -5% weight loss to improve steatosis 7% -10% for NASH resolution > 10% for fibrosis regression Negative predictors of response: - Older age - Type 2 diabetes - More severe NASH activity Weight loss is difficult to maintain in reallife settings : - Maximum at 6 month - 6% of initial body weight at 1 year - 50% of initial weight loss is regained in 3 years Dansinger, Ann Int Med, 2007

52 N = 381 patients BARIATRIC SURGERY 95.7% of patients had a fibrosis score F % of patients regressed or remained at the same stage of fibrosis. 94/381 (24%) patients had T2DM in this cohort Mathurin, Gastroenterology 2009

53 BARIATRIC SURGERY Distribution of NAS Distribution of Fibrosis NASH disappeared in 85.4% of cases Fibrosis improved in 46%. The rate of disappearance of NASH was higher in patients with mild NASH than in those with moderate or severe NASH 14.6% of patients had persistent NASH 1 year after bariatric surgery. These patients had significantly lower weight loss, higher NAS and refractory IR profile

54 Bariatric surgery in cirrhosis ,1 Nationwide Inpatient Sample, In-hospital mortality(%) ,3 0,9 Mortality 16,3 2,2 1 Adjuted Odd ratio No cirrhosis (n= ) Compensated cirrhosis (n=3 888) Decompensated cirrhosis (n=62) Mosk, Clin Gastroenterol Hepatol 2011

55 When should drug treatment be implemented? Naive: 4-6 mo of diet/lifestyle Treat if no effect and metabolically stable Counseling experienced: (Reinforce counseling prefessionally?) Treat if metabolically stable

56 A requiem for Metformin FIBROSIS INFLAMMATION STEATOSIS Musso, Hepatology 2010

57 ) Glitazones -Biochemical Response RCT OPEN-LABEL EXTENSION TRIAL 1,4 1,2 PLB -RSG RSG -RSG ALT (fold baseline) 1,0 0,8 0,6 0,4 PLB -RSG RSG -RSG 0,2 0,0 M0 M16 M40 31 paltm4 paltm8p100altmp100altm paltm20 paltm24 paltm28 paltm32 paltm36 paltm40 31/28* /25* 21 Ratziu, Hepatology 2010

58 Glitazones - Histological Improvement Trial Drug (mg/d) Type STEATOSIS BALLOONING INFLAMMATION Belfort 2006 Pio/45 RCT/PLB YES YES YES FLIRT 2008 Rosi/8 RCT/PLB YES NO NO Tetri 2003 Promrat 2004 Rosi/8 Open label Pio/30 Open label YES YES YES YES YES YES Sanyal 2004 Pio/30 +Vit E RCT/Vit E YES NO* NO Aithal 2008 Sanyal 2010 Pio/30 Pio/30 RCT/PLB RCT/PLB NO YES YES YES NO* YES

59 Glitazones - Histological Improvement Trial Drug (duration) Type IMPROVEMENT IN FIBROSIS Belfort 2006 Pio/6mo RCT/PLB NO A vs. B FLIRT 2008 Rosi/12mo RCT/PLB NO Tetri 2003 Promrat 2004 Rosi/12mo Open label Pio/12mo Open label NO YES Sanyal 2004 Pio/6mo +Vit E RCT/Vit E NO Drug A Drug B Aithal 2008 Sanyal 2010 Pio/30 RCT/PLB YES Pio/30 RCT/PLB NO

60 Histological improvement in VitE RCTs Steatosis Inflammation Ballooning NASH resolution Fibrosis Harrison/1yr PIVENS/2yrs Nobili/2yrs TONIC/2yrs denotes improvement; vs. placebo

61 Results of large UDCA RCTs Study Duration Dose Lindor 2 yrs Low ALT vs PLB No Histological improvement No Leuschner 2 yrs Medium No No* URSONASH 1 yr High Yes Lindor, Hepatology 2004; Leuschner, Hepatology 2010; Ratziu, J Hepatol 2011

62 OCA ARAMCHOL Insulin resistance NAFLD IMM 124E LIRAGLUTIDE Obesity Proinflammatory Pathways NGM282 BMS Dyslipidemia Oxidative stress NASH GS SIMTUZUMAB FIBROSIS ELAFIBRANOR GR-MD-02 Liver related events CENICRIVIROC

63 ELAFIBRANOR Phase IIb GOLDEN trial Dual PPAR α/δ 274 adult patients with histological evidence of NASH ; International RCT (Europe, US) Elafibranor80 mg Elafibranor120 mg Placebo 1 year 1 Endpoint: Resolution of NASH with no worsening of fibrosis 2 nd Endpoint: Change in NAS, fibrosis, liver enzymes, lipids, metabolic markers, safety Ratziu, Gastroenterology2016

64 GOLDEN 505 Primary Endpoint in ITT Population Resolution of NASH without worsening of fibrosis Protocol defined (resolution of any of: steatosisor ballooning or lobular inflammation) Modified definition (no ballooning, none or mild lobular inflammation) 30 P = P = Placebo ELF 80 ELF Placebo ELF 80 ELF 120 Ratziu, Gastroenterology2016

65 NAS 2-point reduction according to Baseline NAS severity in the ITT Population (n 274) Placebo Elafibranor 80 mg Elafibranor 120 mg Mild (3) Moderate (4-5) Severe (6-8) Ratziu, Gastroenterology2016

66 Beneficial on NASH components and fibrosis improvement in Responders to Elafibranor 120 mg 0,5 0 GFT mg Responders GFT mg Non responders -0,5 Change in Score -1-1,5-2 -7,96 p=0.06 *** -25,45 ** *** -2,5-3 *** NAS Steatosis Ballooning Inflammation Fibrosis 5% NASH components ** : p<0.01 *** : p<0.001

67 ELAFIBRANOR Pleiotropic effects Fibrogenesis (TGFβ1, αsma, Col1α1) Oxidative stress (CAT, SOD) Inflammation(MCP-1, IL-6, TNFα) steatosis ( lipid utilization) Oxidative stress (CAT, SOD) ALT, GGT, ALP Hepatic hemodynamics LIVER DYSFUNCTION FIBROSIS CVD RISK Atherogenic lipid profile Endothelial dysf. (ET-1, RGS5, Nox) Vessel Ox stress (CAT, GPx1, HO1) Vessel inflam (ICAM1, MCP1) Triglyceride clearance (APOC3) VLDL-APOB & LDL-APOB sd-ldl cholesterol level HDL cholesterol level (APOA1/A2) NEFA utilization (ACOX, CPT1, EHHADH) NEFA level (lipolysis, β-oxidation) LIPID METABOLISM PPARα/δ GLUCOSE HOMEOSTASIS INFLAMMATION NF-κB, TLRs TNFα, IL-1β IL-6, CRP, SAA, HG, fibrinogen Kupffer cell activation (BCL6) Insulin sensitivity (Fgf21) Hepatic glucose output (PEPCK, FAS, ACC, PDG, G6PDH) insulin

68 Glycemic parameters in diabetics Effect size GFT mg vs placebo (relative change %) 0 FPG Fasting Insulin Fructosamin C-peptide FFA -5 Relative Change (%) ,03 * -10,11 ** ELAFIBRANOR effects on glucose homeostasis and lipids metabolism ,8-26,34-30 p=0,06 * -31,3-35 ** Effect size GFT mg vs placebo (Absolute change - mmol/l) Relative Change (%) * : p<0.05 ** : p<0.01 ** 0,11-0,24 *** -0,17 *** -0,43-0,55 *** *** TG CHOL HDL-C LDL-C VLDL-C ** : p<0.01 *** : p<0.001

69 FLINT Phase 2 Trial Design The Farnesoid X Receptor Ligand Obeticholic Acid (OCA) in NASH Treatment NASH CRN Interim Analysis when 50% of patients completed treatment and had an endof-treatment liver biopsy N=283 Patients w/ Histological Evidence of NASH Placebo QD OCA 25 mg QD Follow up Follow up Screening (Biopsy) 72 week Treatment Period 24 week off-drug Primary endpoint: Histological improvement defined as: No worsening in fibrosis; and Decrease in NAS of 2 points Tetri, Lancet 2014

70 Top-line resultsof the FLINT trial OCA Placebo NAS 2 pt reduction 46% (N:110) 21% (N:109) <0.001 Resolution of NASH 22% 13% 0.09 Improvement in fibrosis (>1 stage) 35% 13% 0.01 Change in fibrosis All individual components of NAS improved Tetri, Lancet 2014

71 FLINT Improved Secondary Histologic Outcomes at Week Patients with Improvement (%) P < P= P< Placebo (n = 109) OCA 25 mg (n = 110) 35 P< Lobular inflammation Steatosis Hepatocellular ballooning Fibrosis Abbreviation: OCA, obeticholic acid. Neuschwander-TetriBA, et al. Lancet.2015;385:

72 Lipid Concentrations mg/dl mg/dl mg/dl mg/dl : Data from Tetriet al. The Lancet. Published online November 7, : All p-values compared to placebo. *p<0.05 3: Converted mean values using factor of 38.6 for cholesterol and 88.5 for triglycerides. Tetri, Lancet

73 LEAN Liraglutide s Efficacy & Action in NASH Control Group n = patients Randomised, Double-blinded (stratified: site, diabetes) Experimental Group n=25 Placebo 0.6mg OD (Days 1-7) Placebo 1.2mg OD (Days 8-14) Placebo 1.8mg OD (Days ) Inclusion criteria: Normal BMI at inclusion NASH Biopsy < 6mths Age T2DM or non-t2dm (HbA1c <9.0%; no insulin) Week 48 (visit 7) Liraglutide 0.6mg OD (Days 1 7) Liraglutide 1.2mg OD (Days 8 14) Liraglutide 1.8mg OD (Days ) Primary End-point: Resolution of NASH (disappearance of ballooning) without worsening of fibrosis Liver Biopsy Secondary End-points: Changes in NAS Safety; liver biomarkers; metabolic Armstrong, The Lancet, 2015

74 Liraglutide: primary end-point and evolution of histological lesions Disparition de NASH et absence d aggravation de fibrose Score de fibrose Kleiner Amélioration, n (%) Aggravation, n (%) Liraglutide (n = 23) Placebo (n = 22) 9 (39,1 %) 2 (9,1 %) < 0,05-0,2 6 (26,1 %) 2 (8,7 %) 0,2 3 (13,6 %) 8 (36,4 %) p ns ns < 0,05 Score NAS total -1,3-0,8 ns Ballonnisation Amélioration, n (%) -0,5 14 (60,9 %) -0,2 7 (31,8 %) Ns 0.05 Stéatose Amélioration, n (%) -0,7 19 (82,6 %) -0,4 10 (45,5 %) ns < 0,05 Inflammation lobulaire Amélioration, n (%) -0,1 11 (47,8 %) -0,2 12 (54,5 %) ns ns Armstrong, The Lancet, 2015

75 Liraglutide:effect on metabolic parameters and LFTs Liraglutide (n = 26) Placebo (n = 26) p Métabolique IMC (kg/m 2 ) Poids (kg) TA systolique (mmhg) HbA1c (%) Glycémie (mmol/l) HDL cholestérol (mmol/l) -1,84-5,25-5,0-0,49-1,04 0,07-0,27-0,58-3,0 0,04 0,73-0,04 0,005 0,003 ns 0,074 0,006 0,014 Tests hépatiques ALAT (UI/ml) ASAT (UI/ml) GGT (UI/ml) Cytokératine 18 (UI/ml) ELF test -26,6-15,8-33, ,25-10,2-8,6-7,2-92 0,09 ns ns 0,013 0,097 0,052 Armstrong, The Lancet, 2015

76 Liraglutide: histological benefit independent of weight loss, glycemic control or the presence of T2DM

77 Why is the response rate stuck between 40 50% Clinical Phenotypes COMPLEXITY OF NAFLD Histological Phenotypes Multiple pathogenetic pathways

78 Potential approach to solve the problem Nodal target of strategic importance Therapeutic choice Combination therapy Individual approaches to Individual patient

79 NAFLD : treatment options Lifestyle modification «non specific» pharmacological treatment Antioxidant(vit E) Hepato-protective (UDCA) Anti-inflammatory(pentoxyfylline) Bariatric surgery Probiotics Others(ARA2, PUFA ) Antidiabetics: Glitazones, GLP1 agonist «specific» pharmacological treatment FXR Agonist PPAR α/δ Agonist Cenicriviroc ASK-1 inhibitors Others Endoscopic treatement Endoscopic bypass Endoscopic sleeve Intragastric balloon Others