New targets for the treatment of NASH (NAFLD) in 2012?

New targets for the treatment of NASH (NAFLD) in 2012? Dominique Larrey Service d Hépatogastroenterologie et transplantation Hôpital Saint Eloi CHU Montpellier INSERM 1040-IRB France Dom-larrey@chu-montpellier.fr

NASH Treatments Lifestyle - Nutrition - Physical exercice Drugs Bariatric surgery

Modify lifestyle?

Adapted physical activity?

Dr House advice?

Increase physical activity?

Change nutrition behavior?

NASH Regulation of nutrition and lifestyle - Reduction of steatosis by 20% within few days - Decrease/normalisation of transaminases - Improvement of glycaemia and lipidemia - Decrease of insulin-resistance - But. Long term maintenance is very difficult

Take care to avoid too difficult objectives

NASH Treatments Lifestyle - Nutrition - Physical exercice Drugs Bariatric surgery

Class of medications which have been evaluated on ALT, steatosis, inflammation and fibrosis Insulin sensitizing agents : glitazones, metformin Lipid lowering agents: statins, fibrates, gemfibrozil, PUVA omega 3 Drugs improving blood flow : pentoxifylline Anti-oxidants : UDCA, Vitamin E, betaine Weigth loss agents : cannabinoid modulators like CB1 antagonists : rimonabant

Thiazolidines-diones or glitazones anti-diabetics Agonists of PPARgs nuclear receptors Troglitazone withdrawn because hepatotoxicity. Rosiglitazone Pioglitazone

Glitazones Effects on transaminases Normalisation ALT/AST % transa. decrease Tetri 2003 Rosi 8 mg n=25 1 yr? 55% Ratziu 2008 Rosi 8 mg n=32 Placebo n=32 6 mon 38 % 7 % 30 % 10 % Promrat 2004 Pio 30 mg n=18 1 yr 72% 60% Sanyal 2004 Pio 30 mg+vit E n=10 vit E n=10 Belfort 2006 Pio 45 mg n=26 Placebo n=26 6 mon 6 mon 40 % 21 % 58 % 34 % Aithal 2008 Pio 30 mg n=37 Placebo n=37 1 yr 40 % 8 % After Ratziu 2009

Glitazones Histological results Steatosis Hépatocyte Inflammation Fibrosis Ballooning Tetri 2003 Rosi 50% of pts _ Ratziu 2008 Rosi - - - Promrat 2004 Pio? Sanyal 2004 Pio -? - Belfort 2006 PIo - Arthal 2008 Pio - - After Ratziu 2009

Pioglitazone or vitamin E x 96 weeks in NASH TT (247nondiabetic pts) PIVENS TRIAL Primary objective : decrease by at least 2 points of NAS score Limit of significance : p < 0,025 with decrease by at least one point of hepatocyte ballooning without aggravation of fibrosis Only vitamin E reached primary objective 50 p < 0,001 p < 0,04 Proportion de patients (%) 40 30 20 10 36 /84 NAT = 4,4 16/83 26/80 NAT = 6,6 0 Vit. E Placebo Ploglitazone NAT : number of patients to treat to obtain the primary criteria in a patient Sanyal AJ et al NEJM 2010;362:1675

Pioglitazone or vitamin E in NASH treament Vitamine E and pioglitazone improved lobular inflammation Vitamine E and pioglitazone improved hepatocyte ballooning 95 Proportion de patients (%) Aggravation Amélioration 80 60 40 20 0-20 -40 Vit. E p < 0,01 grade 0,6 grade 0,2 p < 0,001 grade 0,7 Placebo Ploglitazone Proportion de patients (%) Aggravation Amélioration 80 60 40 20 0-20 -40 grade 0,5 Vit. E p < 0,02 grade 0,2 Placebo p < 0,02 grade 0,4 Ploglitazone Proportion de patients (%) Vitamine E and pioglitazone did not improved fibrosis score Aggravation Amélioration 60 40 20 0-20 -40-60 grade 0,3 grade 0,1 Vit. E n.s. Placebo n.s. grade 0,4 Ploglitazone Sanyal et al. NEJM 2010;363:1675

PIVENS Study transaminase improvement Sanyal et al. N E J Med 2010; 362:1675

PIVENS Study insulin resistance improvement Sanyal et al. N E J Med 2010; 362:1675

Limitation of PIVENS study Missing follow-up biopsy: - 11 in placebo group - 4 in vitamin E group - 10 in pioglitazone group

Limitation of glitazone efficacy/tolerance ratio - Weight gain 4-5 kg within the first 6 months of treatment - Risk of cardiac decompensation with rosiglitazone - Risk of bladder carcinoma with pioglitazone - Bone loss and fractures in women

NASH treatment - Metformine Experimental background Controlled clinical trials - Uygun 2004 CS n=17 - Schwimmer 2005 CS n=10 - Bugiasini 2005 CS n=55 - Duseja 2007 CS n=7 - Nar 2008 CS n=34 - Idilman 2008 CS n=74 - Haukeland 2009 CS n=48 - Schields 2009 CS n=19 Decrease in transaminases Meta-analysis :No significant histological effects Musso et al Hepatology 2010; 52:79-104

Class of medications which have been evaluated on ALT, steatosis, inflammation and fibrosis Insulin sensitizing agents : glitazones, metformin Lipid lowering agents: statins, fibrates, gemfibrozil, PUVA omega 3 Drugs improving blood flow : pentoxifylline Anti-oxidants : UDCA, Vitamin E, betaine Weigth loss agents : cannabinoid modulators like CB1 antagonists : rimonabant

Effect of omega 3 PUFA on steatosis Meta-analysis Parker et al. J Hepatol 2012;56:944

Effect of omega 3 PUFA on ALT Meta-analysis Parker et al. J Hepatol 2012;56:944

Treatment by omega 3 PUFA Meta-analysis Parker et al. J Hepatol 2012;56:944 - Decrease of steatosis - Optimal dosage unknown but > 0,83 g/day - Requirement of well-designed controlled studies

Protecting effects of ursodesoxycholic acid (UDCA) in steatohepatitis Rodrigues, JCI 1998 Qiao, Hepatology 2002 Oxidative Stress TNF a Neuman, JGH 2002 Apoptosis UDCA Endotoxinemia Dysfunction NKT cells Nishigaki, DDS 1996 Necrosis Induced by Biliary acids Kobak, Gastro 2002 A Schwarzenberg, Pediatr Res 1996

UDCA controlled trials Dose (mg/kg) Duration (month) Biopsy Weight ALT Steatosis Inflam Fibrosis Lindor 13-15 24 Pre-post = - - Dufour 13-15 ± vit E 12 Pre-post = + + (UDCA + vit E) + (UDCA + vit E) - UrsoNash 27-30 12 Pré = ++?? ± Ulrich 25 12 Pré = -

Metabolic response at M12 UDCA % PLACEBO % p Glycaemia -2.2 [20] 3.8 [24] 0,002 Insuline -19 [39] 0 [60] 0,038 HOMA -20 [58] 6 [83] 0,009 Significant decrease of HbA1c (p<0,001) in UDCA group No effect on HDLc, triglycerides, cholesterol and LDLc % decrease compared to basal level, median [IQR]

NASH Pharmacological treatments New targets More than 25 drugs in Phase1 and 2 trials - Phosphodiesterase inhibitor PDE4 - Adipokine modulators ( adiponectin, leptin, resistin) - Inhibitors of pro-inflammatory cytokines - Modulators of cannabinoid receptors (rimonabant),other CR1B without central effects, CR2B - Cysteamine - Gliptines - PPAR alpha, PPAR delta agonists - Inhibitors of angiotensine I receptor ( sartans : telmisartan, valsartan, losartan) - Pro-biotics (intestin liver axis) (microbiome) - Agents suppressing fat in the liver

Phosphodiesterase PDE4 Concept Basis PDE are enzymes responsible for hydrolysis of cyclic nucleotides,including AMPc and GMPc PDE Inhibitors are able to decrease inflammatory response and to decrease the production of inflammation mediators, including cytokines such as TNF-alpha

Phosphodiesterase PDE4 Concept Basis PDE are enzymes responsible for hydrolysis of cyclic nucleotides,including AMPc and GMPc PDE Inhibitors are able to decrease inflammatory response and to decrease the production of inflammation mediators, including cytokines such as TNF-alpha Phase 2 studies provide no results vs placebo on ALT!!!

Anti-apoptotic agents Concept Basis Aptotosis leads to inflammation by activation of nuclear factor kappab and by inducing adhesion molecules,chemokines These apoptosis pathways are activated in NASH Hepatocyte apoptosis is increased in NASH GS-9450 is a caspase inhibitor against caspase 1,8,9 Caspase 8 is a key molecule for apoptosis induction

Effect of GS-9450 on apoptotis-mediated liver injury in NASH (phase 2 study) Design 124 patients With NASH ( biopsy) Randomized, double-blind trial GS-9450 QD 1,5,10,40 mg/day, 4 weeks vs placebo Results In the 40 mg group: CK-18 fragment decreased (NS) ALT decreased by 47 IU vs 2 IU in placebo group (P<0.0001)

Effect of GS-9450 on apoptotis-mediated liver injury in NASH (phase 2 study) Randomized, double-blind trial 124 pts with NASH Normalisation of ALT at week 4

Aramchol New synthetic lipidic molecule associating a mixture of cholic acid and saturated fatty acids susceptible to reduce hepatic fat. Aramchol partially inhibits SCD1 (Stearoyl-CoA desaturase 1), a regulator of lipid metabolism In rat, Fatty acid bile acid conjugates (FABAC) treatment prevented the occurrence steatosis in animals with high lipid diet (1). In mice, aramchol was shown to decrease adiposity and to increase energy stipend (2). 1.Gilat T et al. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology. 2003;38:436-42. 2. Gonen A et al. Fatty acid bile acid conjugates inhibit atherosclerosis in the C57BL/6 mouse model. Pathobiology. 2002-2003;70:215-8.

126 Effect of Aramchol in NASH Phase 2 randomised double-blind trial versus placebo 60 patients with NASH (biopsy) Aramchol : 300 mg versus 100 mg versus placebo for 3 months Evaluation of steatosis course by magnetic nuclear resonance spectroscopy 20 Evolution relative de la stéatose par SRMN (%) 15 10 5 0-5 -10-15 6,4 % p = 0,35 p = 0,02-2,9 % -12,6 % -20 Placebo (n = 20) Aramchol 100 mg/j (n = 20) Aramchol 300 mg/j (n = 20) Oren R, EASL 2012, Abs. 1418

Bariatric surgery Vertical-banded Gastroplasty Banding Gastric By-pass

Bariatric surgery and NASH success within the first year 890 severly obese patients with clinical, biological, histological evaluation before and one and et 5 years after bariatric surgery Course after one year after surgery in patients NASH (NAS > 5) Kg/m² % 60 50 40 30 20 20 0 80 70 60 50 40 30 20 10 0 BMI * Avant chirurgie Steatosis Hepatic lesions Fibrosis * * * Avant chirurgie 1 an 1 an UI/ml 70 60 50 40 30 20 10 0 1,5 0,5 As soon as 1 Yr after bariatric surgery liver lesions decrease 1 0 ALT * Avant chirurgie Avant chirurgie 1 an 1 an Inflammation Ballonisation 1/QUICKI Insuline-resistance 4 3 2 1 0 2 1,5 1 0,5 0 Avant chirurgie Avant chirurgie * 1 an 1 an * p < 0,05 124 Lassailly G, EASL 2012, Abs. 6

Bariatric surgery and NASH success within the first year 125 Clinical, biological, histological evolution between one and 5 years after surgery in patients with NASH (NAS > 5) Kg/m² 60 50 40 30 20 20 0 BMI p = 0,8 1 an 5 ans UI/ml 70 60 50 40 30 20 10 0 ALT p = 0,9 1 an 5 ans 1/QUICKI Insuline-resistance 4 p = 0,65 3 2 1 0 1 an 5 ans % 80 70 60 50 40 30 20 10 0 Steatosis Liver lesions Fibrosis p = 0,015 1 an 5 ans 0,8 0,6 0,4 0,2 0 Inflammation p = 0,9 p = 0,78 1 an 5 ans Ballonisation 2 1,5 1 0,5 0 p = 0,24 1 an 5 ans Beyond one year post surgery, there is no further improvement of fibrosis Lassailly G, EASL 2012, Abs. 6

NASH treatment Conclusion Pharmacological treatment necessary but: Therapeutic results still very limited Most tested drugs improve/normalise transaminases Effects on histological lesions much less documented: - decrease of steatosis : yes - decrease of inflammation : variable - decrease of fibrosis : unclear Many questions on indications, type, duration of TT and evaluation criteria -

Pharmacologic treatment of NASH Questions - What are the best targets? - What the adequate short mean - long term criteria evaluation (3-12 months? ) to assess efficacy/response ratio and strategy? - What is the adequate duration of treatment? Is there any possibility to stop it? - Interest of associated treatments (anti-ir, anti-oxidants, antiinflammatory agents, anti-fibrosing agents?) Who to treat? With which degree of lesions?