NAFLD 2017 Identifying and managing disease while waiting for a cure

NAFLD 2017 Identifying and managing disease while waiting for a cure A. Sidney Barritt IV, MD, MSCR Associate Professor of Medicine UNC Liver Center High Impact Hepatology 4 November 2017

Disclosures I may discuss off label use of some medications I have provided consulting for Target Pharmasolutions I participate in NASH clinical trials with: Intercept Pharmaceuticals Genfit Gilead BMS NuSirt Boehringer Ingelheim Cirrus Conatus

Learning Objectives By the conclusion of the lecture, the learner should be able to: Discuss the current therapies for non-alcoholic fatty liver disease in the United States Discuss mechanisms of action for potential new therapies for non-alcoholic fatty liver disease Discuss implications of the growing population of patients with non-alcoholic fatty liver disease

Is NAFLD a real disease? Societal Impact of NAFLD Finding Cases NAFLD 2017 Future Interventions Management Philosophy Currently Available Interventions

Is NAFLD a real disease?

Prevalence depends on population studied and method used to make diagnosis 1 in 3 American adults has simple steatosis Ultrasound data estimates prevalence ~50% NAFLD is common NHANES III estimates range from 8-24% Prevalence in bariatric surgery patients may be as high as 90%, up to 55% may have NASH and 12% with bridging fibrosis Global prevalence 24% Incidence of new NAFLD rising in step with increasing rates of obesity, diabetes and physical inactivity Harrison et al Clark et al AJG 2007 Younossi et al Hepatology 2016 www.cdc.gov accessed 2017

NAFLD is a progressive disease Who will progress? Risk Factors Central obesity Hypertension Dyslipidemia Type 2 Diabetes Metabolic syndrome Advancing age ALT is not an indicator of disease severity

Disease progression is associated with increased mortality All Cause mortality Liver related mortality Dulai et al Hepatology 2017

Finding Cases

What to do? Chalasani et al Hepatology 2017 AASLD guidance statement Screening for NAFLD in primary care, diabetes and obesity clinics There is an argument for systematic screening among those at high risk Markov model suggested not cost effective due to no treatment Experts call for vigilance for chronic liver disease in patients with type 2 DM Guidance Statements Routine Screening for NAFLD in high-risk groups attending primary care, diabetes, or obesity clinics is not advised at this time due to uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to long-term benefits and cost effectiveness of screening. There should be a high index of suspicion for NAFLD in patients with type 2 diabetes. Clinical decision aids such as NAFLD Fibrosis Score or FIB4 or transient elastography can be used to identify those at low or high risk for advanced fibrosis. My View Most of my referrals come from incidental LFT abnormalities or incidental finding of steatosis on imaging performed for another purpose Must admit that pure screening does not yet make sense from a WHO screening justification definition In any patient with facets of the metabolic syndrome, I think LFTs +/- ultrasound is not unreasonable Additive to patent motivation for lifestyle changes While pharmacologic management not yet available, I do have clinical trials

Diagnosis and Evaluation Algorithm Repeat LFTs Screening Tests and/or Imaging Viral Hepatitis Serologies Iron Overload (Ferritin and % saturation) Hepatic auto antibodies (ANA, AMA, ASMA) Others may be appropriate pending clinical situation (antitrypsin, ceruloplasm, etc..) ALT is not sensitive or specific for NAFLD! (+) Screening test Treat as appropriate FTD-PUTP H. Lesesne M.D. Call the pharmacy! Barritt et al, CGH 2010 (-) Screening Tests Normal U/S Follow? Refer? Biopsy? DILI? (-)Screening Tests Echogenic U/S NAFLD (biopsy?) Adapted from Dowman, APT, 2011

Evaluation and Treatment Algorithm NAFLD confirmed/ highly suspected NAFLD fibrosis score* (-1.455) Low Risk Reassure Repeat NFS in : = 1.675+ (0.037*age) + (0.094*BMI) + (1.13 if DM) + (0.99* AST/ALT)- (0.013*plt) (0.66*alb) Angulo, Hepatol 2007 >(-1.455) Indeterminate to High Risk Refer/further investigation 1 year 3-5 years Non-Invasive assessment of severity vs. liver biopsy** Simple Steatosis Return to Primary Care NASH/ NAFLD Cirrhosis Management of Disease Adapted from Dowman, APT, 2011

Non invasive assessment of disease Several clinical prediction scores for assessing severity of disease NFS = 1.675+ (0.037*age) + (0.094*BMI) + (1.13 if DM) + (0.99* AST/ALT)- (0.013*plt) (0.66*alb) Both are reasonable to use. NFS made with the apriori intent of assessing fibrosis in NASH vs FIB-4 in HCV Comparable AUROC scores Inexpensive On hand held devices Angulo, Hepatol 2007 FIB-4 Sterling, Hepatol 2006

Vibration Controlled Transient Elastography We believe that the accurate, noninvasive diagnosis of NAFLD, NASH, and advanced fibrosis is one of the most important unmet needs in the evaluation of a patient with suspected NAFLD. Rinella at al, Gastroenterology and Hepatology 2014

MRI Technology MRE for Fibrosis 2D and 3D MRE have AUROC >0.92 Multiple single center trials show MRE>VCTE MR-PDFF for steatosis MR-PDFF>CAP for fat quantification

Management Philosophy Currently Available Interventions

Consider the entire patient All Cause mortality in the general population 1. CVD 2. Cancer ~12. Liver disease All cause mortality in the patient with NASH 1. CVD 2. Cancer 3. Liver disease We can address these risks in a complementary manner with currently available medications Metabolic syndrome Obesity Liver Cancer risk

Lifestyle Modification Systematic review of 11 diet only studies 2 exercise only studies 7 combination studies In general interventions were relatively brief (1-6 months) Many lacked control group, only a few used histology Dietary interventions manipulated fat, carb content Thomaet al J Heptol 2012

It s never too late Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study. Weight loss might safely reduce portal pressure in obese cirrhotic patients with portal hypertension Spanish multicenter study of 60 obese patients with cirrhosis and HPVG >6mmHg who underwent a 16 week lifestyle intervention aimed at reducing body weight through diet and exercise Lifestyle intervention decreased body weight by 5.0±4.0 Kg; (p<0.0001 vs. baseline) associated with a significant decrease in waist circumference and percentage of body fat Berzigotti et al, Hepatology 2017

Ruhl, Gastro 2005, Ray, Nat Rev Gast Hepatol, 2013. Sinha, Hepatology, 2013. Barritt, AGA Perspectives, 2013 Coffee? >2.25 billion cups of coffee consumed worldwide daily Coffee has been credited in improving many liver diseases HCC, ETOH, HCV NAFLD Reduces intrahepatic fat via lysosomal autophogy How much is enough? Those who drink 2+ cups daily have ½ rate of chronic liver disease compared to those who drink <1cup daily 38% lower risk of HCC (any vs. none)

Pharmacologic management Lifestyle Intervention Diabetes management Dyslipidemia HTN Lifestyle intervention Metabolic syndrome Obesity Cancer Risk Liver Specific Statins? Coffee? Diabetes Obesity Vtiamin E Pioglitazone Liraglutide Adapted from Anstee, AASLD Postgraduate Course 2017

Future Interventions

Mechanisms of action in NASH therapy Adapted from Anstee, AASLD Postgraduate Course 2017

Elafibranor Peroxisome Proliferator-Activated Receptor PPAR agonists improve insulin resistance, lipid metabolism and glucose homeostasis anti-inflammatory

Elafibranor Elafibranor is a PPAR agonist which improves insulin sensitivity, glucose homeostasis, lipid metabolism and reduces inflammation Phase II clinical trial of patients with NASH Elafibranor 80mg n=93 Elafibranor 120 n=91 Placebo n=90 Study x 52 weeks, 1* outcome of resolution of NASH without fibrosis worsening Ratziu, Gastro 2016

Elafibranor Results ITT: no difference between drug and placebo NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; based on a post-hoc analysis for modified NASH definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score 4, elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11) Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution Drug well tolerated Secondary end points all showed improvement in elements of the metabolic syndrome Modified end points were sufficient to justify phase III clinical trial Ratziu, Gastro 2016

FXR agonist will decrease hepatic fat and may improve insulin resistance Significance of LDL unknown Obeticholic Acid Farsenoid X Receptor

FLINT trial/ obeticholic acid Background: The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor FXR activation decreases hepatic lipogenesis and decreases cholesterol conversion to bile acids Assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. Neuschwander-Tetri et al, Lancet 2015

FLINT trial- results 141:142 obeticholic acid vs. placebo. 45% improved liver histology compared with 21% in the placebo group (relative risk 1 9, 95% CI 1 3 to 2 8; p=0 0002). 23% of 141 patients in the obeticholic acid developed pruritus compared with 6% of 142 in the placebo group. OCA patients had inc. TC and LDL with dec. HDL Trial stopped early by DSMB due to clear effect Phase 3 trial on going Neuschwander-Tetri et al, Lancet 2015

Selonsertib ASK1 inhibitor (apoptosis) Activated in NASH and correlates with fibrosis stage Inhibition improves steatosis, inflammation and fibrosis in mice

Selonsertib Phase 2 RCT Selonsertib +/- simtuzumab for 24 weeks No placebo arm 1* end point was improved fibrosis 43% on SEL 18mg had improved histology Phase 3 trial on going Loomba Hepatology 2017 epub

Ceniciviroc Dual antagonist of C-C chemokine receptor types 2 and 5 (CCR2/CCR5) Antifibrotic effect Blockade of CCR2/5 inhibits stellate cell activation Anti-inflammatory effect Inhibts Kupffer cells and monocyte/macrophage recruitment

Ceniciviroc Phase 2 RCT 289 NASH patients w/wo DM Preliminary endpoint of improved histology not met, but appears to have an antifibrotic effect Antifibrotic effect justified phase 3 clinical trials Friedman et al Hepatology 2017 epub

Challenge of treating NASH will continue If/when there are successful FDA approved interventions for NASH, questions and challenges will remain Are these lifetime drugs? Interventions to pause disease while patients fix lifestyle problems CV risk Cancer risk Trial efficacy vs. real world effectiveness NASH patients appropriate for clinical trials NASH NAFLD

Real world observational trial Any patient with a clinical or biopsy proven diagnosis of NAFLD Includes patients with cirrhosis and those underrepresented in clinical trials Goal is to describe real world practice and natural history of disease with ability to perform phase 4 surveillance of new drugs once released. Target-NASH Barritt et al AASLD 2017 Barritt et al Contemp Clin Trials 2017

Societal Impact of NAFLD

Economic Burden of NAFLD In the United States, over 64 million people are projected to have NAFLD, with annual direct medical costs of about $103 billion ($1,613 per patient). Authors suggests a conservative underestimate Costs do not account for potential new drugs Indirect costs work productivity, etc. not included Costs are highest in patients aged 45-65. The burden is significantly higher when societal costs are included. Younossi et al Hepatology 2016

How has NASH changed the waitlist? The population of patients with end-stage liver disease is changing. Aging population Increasing prevalence of nonalcoholic steatohepatitis (NASH) Increasing comorbidites Highly effective treatments for hepatitis C (HCV) There is marked regional variation in liver transplant (LT) practices and waitlist characteristics. Policy planning for LT requires a deep understanding of national trends and regional variation in the waitlist. We aimed to describe LT waitlist trends and outcomes nationwide, and in one region with high MELD at transplant (Region 5) compared with lower MELD (Region 11). Yi et al, AASLD 2016

Waitlist Analysis-Results Patients listed for LT in the US are aging. The prevalence estimates of NASH and HCC are increasing while that of HCV is declining. Rise in NASH is greater in region 11 Yi et al, AASLD 2016

Liver Transplantation Over the next decade, NASH will become the leading disease etiology for liver transplantation Patents will be older and wait longer for transplant Risk of waitlist drop out will increase Year Male (%) Age>=60 (%) HCV (%) NASH (%) HCC (%) Expected Wait time for MELD 22-27, days waitlist drop out (%) Baseline Scenario 2015 64.7 35.9 29.6 18.2 16.5 82 41.3 2020 64.5 44.9 22.9 21.1 25.5 123 44.6 2025 64.5 47.1 21.0 21.9 28.5 182 45.8 Optimistic Scenario 2015 64.7 35.3 30.2 18.0 15.4 88 39.3 2020 64.3 36.5 30.2 19.5 13.0 70 33.4 2025 63.3 36.8 29.5 20.4 12.0 62 28.7 Pessimistic Scenario 2015 64.7 36.0 29.5 18.1 16.7 96 44.9 2020 64.7 45.3 22.2 20.5 27.7 205 59.8 2025 64.9 47.7 19.6 20.7 32.4 368 69.9 Yi et al AASLD 2016 abs # 1400, 1403

Liver Transplantation NAFLD and NASH will impact both the donor and recipient transplant population We examined waitlist trends by region and disease etiology and then simulated the waitlist characteristics over the next decade The liver transplant waitlist size will remain relatively static on a national level over the next decade. This balance will not be achieved by additional transplants but by waitlist dropout instead. Yi et al AASLD 2016 abs # 1400, 1403

NAFLD and Donor Organs As incidence and prevalence of NAFLD increases in our patient population, it is also increasing in the donor population Steatotic livers associated with increased PNF and decreased 2 year survival 30% steatosis cut-off, PNF 5% vs. 2% and survival 77% vs. 91% Microvesicular steatosis may not carry the same risk as macrovesicular steatosis PNF and survival similar In LDLT, most centers aim for less than 10% steatosis and are reluctant to use grafts with >30% steatosis

8,000 Forecasted LT Trends: 2010-2030 100% Number of Livers 7,000 6,000 5,000 4,000 3,000 2,000 1,000 90% 80% 70% 60% 50% 40% 30% 20% 10% Percent of Discard/Health Attribute # Livers Used # of Livers Donated Discard Rate % Obese % Diabetes % DCD - 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2030 2029 2028 2027 2026 2025 2024 2023 2022 2021 2020 0% Year Orman, et al, Liver Transplantation 2015

Implications Patients requiring liver transplantation will likely become older, bigger and sicker Could tying reimbursement to outcome metrics continue downward pressure on risk tolerance? Increased waitlist size, increase waitlist time, increased waitlist morbidity and mortality Transplant at higher MELD may change post transplant survival and hospital course

Summary 1. NAFLD is a real disease and can progress to cirrhosis and ESLD 2. Diet and exercise remain the backbone of NAFLD therapy 3. Pharmacologic management possible for the entire patient that addresses overall health risks 4. Specific pharmacologic interventions for NASH on the horizon but not ready yet 5. NAFLD is a significant health care burden 6. NAFLD will need to be addressed aggressively in the precirrhotic stage as transplant may not be a long term solution for this population

UNC Comprehensive NAFLD Clinic Hepatology Care Diagnostic evaluation Non invasive assessment of disease Liver biopsy Endoscopic procedures General cirrhosis care Management of end stage liver disease Transplant Evaluation Clinical trials 4 phase 3 clinical trials actively enrolling Several phase 2 trials in startup NASH Target observational trial Psychological Services Health Literacy Assessment Adherence Education Assessment of comorbid depression and anxiety Eating disorder management/education Nutrition Services Dietician Assessment Diabetic Diet Education Low sodium diet education Fluid restriction diet education

Questions? barritt@med.unc.edu