KOL Symposium on Portal Hypertension

Transcription

1 KOL Symposium on Portal Hypertension Striving to improve human health September 27 I 2018 NASDAQ CNAT

2 Forward-looking Statements This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, prospective products, product approvals, research and development costs, timing and likelihood of success, plans and objectives of management for future operations, and future results of current and anticipated products are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These known risks and uncertainties are described in detail in our filings made with the Securities and Exchange Commission from time to time. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and we undertake no obligation to revise or update this presentation to reflect events or circumstances after the date hereof. KOL Symposium on Portal Hypertension September 27,

3 Agenda Introductory Comments Steven J. Mento, Ph.D. President and CEO, Conatus Pharmaceuticals Inc. Clinical Importance of Portal Hypertension Guadalupe Garcia-Tsao, M.D. Professor of Medicine in the Section of Digestive Diseases at Yale School of Medicine Director of the Clinical and Translational Core at Yale Liver Center Chief of the Section of Digestive Diseases at the Veterans Administration-Connecticut Health Care System Pathophysiology of Portal Hypertension Jaime Bosch, M.D., Ph.D. Guest Professor of Hepatology at Inselspital, Bern University, Switzerland Emeritus Professor of Medicine in the Liver Unit at the Hospital Clínic-IDIBAPS, University of Barcelona Chairman of the Baveno Cooperation Q & A KOL Symposium on Portal Hypertension September 27,

4 Emricasan and Portal Hypertension Steven J. Mento, Ph.D. President and CEO

5 Portal Hypertension Is an Important, Significant Problem Severe portal hypertension (HVPG 12 mmhg) is the main driver of decompensation in cirrhosis including variceal bleeding, ascites, hepatic encephalopathy, and liver-related mortality* It is manifested through a combination of intrahepatic and extrahepatic pathology The emricasan mechanism of action has the potential to positively impact both HVPG is an objective measure of portal hypertension* Decreasing HVPG in patients with severe portal hypertension is predictive of clinical benefit HVPG may be an appropriate surrogate endpoint for accelerated approval in severe portal hypertension Emricasan has already demonstrated improvements in severe portal hypertension in patients with compensated cirrhosis All ~240 patients in ENCORE-PH presented with severe portal hypertension due to NASH at baseline The primary endpoint for the study is the mean change in HVPG after 6 months of dosing Positive results from ENCORE-PH would further demonstrate emricasan s potential to provide clinically meaningful benefit to NASH cirrhosis patients *Bosch J. et al. Nat. Rev. Gastroenterol. Hepatol. 6 (2009), KOL Symposium on Portal Hypertension September 27,

6 Emricasan Positioned for Success in NASH and Beyond Profile First-in-class pan-caspase inhibitor ideally suited to treat liver disease Efficacy Potent mechanism with multiple disease intervention points Safety Administered to ~700 subjects (~500 with liver disease) across 17 clinical trials Orally administered Actively transported into the liver Not metabolized in the liver Addresses all etiologies of cirrhosis Confirmed activity across broad spectrum of chronic liver disease Signal of anti-fibrotic treatment effect using a histology endpoint in HCV Clinically meaningful reductions in relevant cirrhosis endpoints Well tolerated with over 150 patientyears of exposure Serious adverse event and adverse event profiles similar in placebo and emricasan treated patients KOL Symposium on Portal Hypertension September 27,

7 Microparticles Trigger Activation of Effector Cells and Resulting Injury Effector Cells: Collagen Injury Contraction Stellate cells Caspase activation Proinflammatory cytokines Hepatocyte Hepatocyte damage (apoptosis) Biologically active microparticles Macrophage Vasoconstrictor production Endothelial cells Fenestration KOL Symposium on Portal Hypertension September 27,

8 Emricasan Reverses Effector Cell Activities to Facilitate Healing Effector Cells: Collagen Injury Emricasan Contraction Stellate cells Caspase activation Proinflammatory cytokines Hepatocyte Hepatocyte damage (apoptosis) Biologically active microparticles Macrophage Vasoconstrictor production Endothelial cells Fenestration KOL Symposium on Portal Hypertension September 27,

9 Accumulating Damage in the Cirrhotic Liver Leads to Increasing Portal Hypertension and Clinical Complications Blood pressure in the portal vein increases initially due to restriction of blood flow through the damaged liver As portal hypertension increases further, cardiac output increases and vasculature in the gut dilates to increase blood flow toward the liver Hepatic Vasoconstriction Resistance GI Vasodilation Flow Portal hypertension is largely responsible for decompensation and death in liver cirrhosis KOL Symposium on Portal Hypertension September 27,

10 Emricasan Can Modify the Course of Disease Progression Potentially Both Inside and Outside the Liver Proposed emricasan intrahepatic activity Reduce resistance to blood flow through the liver Reduce hepatocyte apoptosis and release of microparticles Reduce constriction of hepatic sinusoids by activated stellate cells Increase intrahepatic concentration of nitric oxide, a critical vasodilator in the liver that is reduced in cirrhosis Reduce collagen deposition and improve blood flow to sinusoids Reopen pores in sinusoids and allow better blood flow to and from hepatocytes Hepatic Vasoconstriction Resistance GI Vasodilation Flow Proposed emricasan extrahepatic activity Reduce increased blood flow into the liver Reduction of circulating microparticles from damaged liver cells may trigger reduction of GI vasodilation Garcia-Tsao, G et al. Late-breaking oral presentation (LB6) at AASLD November Emricasan interrupts key processes driving the disease progression cycle KOL Symposium on Portal Hypertension September 27,

11 Phase 2 Portal Hypertension Pilot Study: Top-line Results Emricasan Significantly Reduced Severe Portal Hypertension 22 cirrhotic subjects with portal hypertension 12 with baseline HVPG 12 mmhg (severe PH) 25 mg emricasan BID for 28 days Severe PH subgroup improved from baseline HVPG 17.2% mean change in HVPG 3.7±4.0 mmhg, p<0.003* Responders in severe PH subgroup 11/12 had a decrease in HVPG 8/12 had a 10% decrease 4/12 had a 20% decrease 2/12 decreased to < 12 mmhg Conclusion: Emricasan administered orally for 28 days was associated with a clinically meaningful decrease in portal pressure in patients with compensated cirrhosis and severe portal hypertension Subjects with baseline HVPG 12 mmhg (N=12) HVPG ±5.3 mmhg *p-value not adjusted for multiple testing 17.6±6.1 mmhg Baseline Day 28 Garcia-Tsao, G et al. Late-breaking oral presentation (LB6) at AASLD November KOL Symposium on Portal Hypertension September 27,

12 Phase 2b ENCORE-PH Trial Clearing a Path Forward in NASH Cirrhosis Patients with Severe Portal Hypertension EmricasaN, a Caspase inhibitor, for Evaluation in Portal Hypertension DESIGN Design ~240 patients at ~60 sites across US and EU. Randomized 1:1:1:1 to receive placebo or emricasan at 5mg, 25mg, or 50mg BID NASH cirrhosis and severe portal hypertension (HVPG 12 mmhg) Double-blind, placebo-controlled Primary Endpoint HVPG mean change from baseline at week 24 Strong basis for HVPG as a surrogate endpoint in patients with severe portal hypertension Extension 24-week treatment/placebo continuation Following for clinical outcomes Top-line HVPG results expected 4Q18 KOL Symposium on Portal Hypertension September 27,

13 Why Are We So Excited about ENCORE-PH? We believe Portal hypertension is a significant problem with a high medical need Emricasan has demonstrated impact on severe portal hypertension The ENCORE-PH patient population and trial design are optimized for success Success in ENCORE-PH would set the stage for a pivotal Phase 3 trial Portal hypertension could be the fastest pathway to approval in NASH cirrhosis KOL Symposium on Portal Hypertension September 27,

14 Emricasan: Robust NASH Clinical Pipeline Across the Spectrum of Liver Disease Target Population Preclinical Phase 1 Phase 2 Next Milestone ENCORE-PH (NASH Cirrhosis) ~240 patients at ~60 sites in the US and EU HVPG Endpoint Phase 2b top-line data expected 4Q18 ENCORE-NF (NASH Fibrosis) ~330 patients at ~90 sites in the US and EU Biopsy Endpoint Phase 2b top-line data expected 1H19 ENCORE-LF (NASH Cirrhosis) ~210 patients at ~90 sites in the US Clinical Endpoint Phase 2b top-line data expected 2H19 Three Phase 2b NASH clinical trials designed with endpoints tailored to each patient population provide multiple independent paths forward KOL Symposium on Portal Hypertension September 27,

15 Novartis Partnership Reduces Risk / Extends Market Reach Emricasan NASH Opportunity Established Pharma Partner Relevant Expertise Substantial Resources EMRICASAN Cirrhosis w/ Severe PH Fibrosis Decomp. cirrhosis Broad Market Reach Partnership fully funds emricasan development through market approval Partnership can target broader markets than Conatus could alone KOL Symposium on Portal Hypertension September 27,

16 NASH Cirrhosis Opens the Door to Broader Markets NASH cirrhosis represents ~25% of total cirrhosis patients Emricasan s MoA is etiology-indifferent and has the potential to benefit all cirrhosis patients 25% NASH Cirrhosis 75% Non-NASH Cirrhosis other drivers of cirrhosis e.g. HCV, ALD, etc. Estes C et al J Hepatol 2018 KOL Symposium on Portal Hypertension September 27,

17 KOL Symposium on Portal Hypertension Striving to improve human health September 27 I 2018 NASDAQ CNAT

18 Clinical Importance of Portal Hypertension Guadalupe Garcia-Tsao, M.D. Professor of Medicine in the Section of Digestive Diseases at Yale School of Medicine Director of the Clinical and Translational Core at Yale Liver Center Chief of the Section of Digestive Diseases at the Veterans Administration-Connecticut Health Care System KOL Symposium on Portal Hypertension September 27,

19 Clinical Importance of Portal Hypertension Guadalupe Garcia-Tsao, M.D. Disclosures: Consulting for: Biovie, Conatus, Cook, Enterome, Galectin, Intercept, Martin, Theravance I will be discussing the unapproved used of non-selective beta-blockers in the treatment of portal hypertension

20 Cirrhosis is the end stage of any chronic liver disease Cirrhotic liver Normal liver Chronic liver disease Cirrhosis Alcohol Hepatitis C / B NASH Cholestatic Autoimmune

21 Survival in Any Chronic Liver Disease Depends on the Presence (or Absence) of Cirrhosis Hepatitis C Non-alcoholic steatohepatitis Cumulative Survival No cirrhosis (n=696) Years Cirrhosis (n=141) Stage 1 Stage 2 Stage3 Cirrhosis (n=13) Stage Time, months No Cirrhosis (n=87) Niederau et al. Hepatology 1998, 28:1687. Younossi et al. Hepatology 2011, 53:1874.

22 Globally, deaths from cirrhosis have been rising Global Burden of Disease Study Lancet 2015; 385:

23 Cirrhosis is ranked higher among causes of global deaths Global Burden of Disease Study Lancet 2015; 385:

24 Cirrhosis is among the top 10 causes of years of life lost in developed countries and the 8 th in the USA Global Burden of Disease Study Lancet 2015; 385:

25 Prevalence of NAFLD in the U.S. population NAFLD: ~30% NASH: ~5 % NASH cirrhosis: ~1.25 % US population 320,000,000 NAFLD: 96,000,000 NASH 16,000,000 NASH cirrhosis 3,200,000

26 Cirrhosis consists of two main clinical stages Median survival >12 yrs Median survival ~ 2 yrs Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death D Amico, Garcia-Tsao, Pagliaro. J Hepatol 2006;44:217.

27 Compensated Diagnosis of cirrhosis Decompensated Making the diagnosis of cirrhosis in the compensated patient can be challenging Making the diagnosis of cirrhosis in the decompensated patient is not challenging

28 Portal hypertension is the main driver of decompensation Portal hypertension Chronic liver disease Compensated cirrhosis Long asymptomatic stage Decompensated cirrhosis Ascites Variceal hemorrhage Encephalopathy Jaundice Death D Amico, Garcia-Tsao, Pagliaro. J Hepatol 2006;44:217.

29 Hepatic Venous Pressure Gradient (HVPG) is the method used to measure portal pressure It is obtained through hepatic vein catheterization It is safe and reproducible HVPG 6 mmhg indicates portal hypertension HVPG >10-12 mmhg indicates clinically significant portal hypertension

30 ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE Clinically-significant portal hypertension is responsible for complications of cirrhosis that define decompensation Cirrhotic Liver Varices Variceal hemorrhage Ascites Encephalopathy Portal vein pressure Clinically significant PORTAL HYPERTENSION

31 ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE First line therapies for treating the complications of cirrhosis are mostly symptomatic Cirrhotic Liver Varices Variceal hemorrhage Ligation Ascites Diuretics Paracentesis Portal vein pressure Clinically significant PORTAL HYPERTENSION Encephalopathy Measures to decrease ammonia in gut

32 Main goals of therapy in cirrhosis are to prevent decompensation and death Chronic liver disease Treatment of etiology Compensated cirrhosis Decompensated cirrhosis Death Clinically significant portal hypertension persists despite elimination of the cause of cirrhosis More importantly, there is no etiological therapy for the most frequent etiology of cirrhosis (NASH)

33 Non-selective beta-blockers decrease portal pressure in both compensated and decompensated cirrhosis Portal hypertension NSBB (propranolol, nadolol, carvedilol) Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death Ascites Variceal hemorrhage Encephalopathy Jaundice D Amico, Garcia-Tsao, Pagliaro. J Hepatol 2006;44:217.

34 In compensated cirrhosis, decompensation* is significantly lower in patients on NSBB who are HVPG responders ** However, only ~50 % of compensated patients are HVPG responders N= 332 *Clinical events: ascites, variceal hemorrhage, or encephalopathy Turco et al. EASL **mostly defined as to <12 mmhg or >20% from baseline NSBB = non-selective beta-blockers

35 In a recent randomized trial, NSBB prevented decompensation in patients with compensated cirrhosis and clinically significant portal hypertension Rate of decompensation (3 yrs): Placebo: 27/101 (27%) NSBB: 16/100 (16%) Placebo p = NSBB (Graph kindly provided by Dr. Villanueva) Villanueva C et al. AASLD 2016 NSBB = non-selective beta-blockers (propranolol or carvedilol)

36 Non-selective beta-blockers decrease portal pressure in both compensated and decompensated cirrhosis Portal hypertension NSBB (propranolol, nadolol, carvedilol) Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death Ascites Variceal hemorrhage Encephalopathy Jaundice D Amico, Garcia-Tsao, Pagliaro. J Hepatol 2006;44:217.

37 In decompensated cirrhosis death/transplant is significantly decreased in patients in whom HVPG decreases with NSBB (HVPG responders *) However, only ~40 % of decompensated patients are HVPG responders bbbbbbbbbbbbbb N=280 Turco et al. EASL **mostly defined as to <12 mmhg or >20% from baseline

38 Summary and Unmet Needs Cirrhosis is a major cause of death in the world and in the USA and death rates are increasing Beyond etiological therapies, there is a need to decrease portal pressure in patients with cirrhosis as this decrease is associated with lower decompensation and lower mortality rates Beta-blockers reduce portal pressure in ~50% of patients with cirrhosis Drugs or combination drugs that decrease portal pressure in the majority of patients and improve liver perfusion (and liver function) are still needed

39 Pathophysiology of Portal Hypertension Jaime Bosch, M.D., Ph.D. Guest Professor of Hepatology at Inselspital, Bern University, Switzerland Emeritus Professor of Medicine in the Liver Unit at the Hospital Clínic-IDIBAPS, University of Barcelona Chairman of the Baveno Cooperation KOL Symposium on Portal Hypertension September 27,

40 PATHOPHYSIOLOGY OF PORTAL HYPERTENSION EFFECTS OF EMRIC ASAN Jaime Bosch, M.D., Ph.D. Disclosures Consultant for Conatus, Gilead, Actelion, BioVie, Brudylab, BLB and Exalenz Member of Advisory Boards for Conatus, Actelion and BLB Research grants from Conatus, Gilead and Exalenz

41 Cirrhosis The common end-stage of chronic liver disease of many different etiologies* Characterized by parenchimal remodelling, with extensive fibrotic septa (scars) surrounding regenerative nodules and by a hard, nodular surface Major and increasing cause of death in USA and worldwide

42 Fibrosis: liver scars caused by chronic liver damage Normal liver: no fibrosis Smooth, homogeneous perfusion Cirrhotic liver: fibrosis, septa and nodules Irregular, heterogeneous perfusion. Stiff. increased resistance & impaired flow portal hypertension liver failure

43 Fibrosis: liver scars caused by chronic liver damage Normal liver: no fibrosis Cirrhotic liver: fibrosis, septa and nodules Smooth, homogeneous perfusion Irregular, heterogeneous perfusion. Stiff. increased resistance & impaired flow portal hypertension liver failure

44 Pathophysiology of Portal Hypertension Hemodynamic factors P = Resistance Blood flow 1. Increased Liver Resistance Mechanical Architectural changes Fibrosis Vascular occlusion Early HVPG < 10 mmhg Dynamic Endothelial dysfunction Vascular tone 2. Collaterals and Varices 3. Increased Portal Inflow Splanchnic vasodilation Increased vasodilators Increased cardiac output Sodium retention portal pressure angiogenesis Increased Portal Pressure * Imbalance between insufficient vasodilators (NO) iiiand excessive vasoconstrictors (NE, TXA2, ET, A-II) Bleeding Ascites Encephalopathy Advanced HVPG 10 mmhg

45 Old drugs (NSBBs) act on the splanchnic vasodilation of advanced cirrhosis Response to Propranolol in Compensated Cirrhosis is negligible in patients with HVPG < 10 mmhg Decrease in HVPG (%) 8% 16% Decrease in HVPG (mmhg) P< P< HVPG < 10 mmhg (n=54) No hyperkinetic circulation HVPG 10 mmhg (n=194) Villanueva C Bosch J, Hepatology 2015

46 Mechanism of fibrosis progression in chronic liver injury Players & Roles 1) Hepatic stellate cells (HSC) Structural changes Vascular occlusion 2) Liver sinusoidal endothelial cells (LSEC) nn Dynamic component 3) Liver macrophages nn Biologic signal amplifier

47 Liver sinusoidal endothelial cells (LSEC) Highly differentiated endothelial cell, lack basement membrane and exhibit fenestrations in «sieve plates» LSEC de-differentiate in liver injury «Endothelial dysfunction»: a) increased hepatic vascular tone b) pro-angiogenic, prothrombotic, proinflammatory c) capillarization Braet and Wisse, 2002

48 Increased Hepatic Resistance: you need two for tango HSC activation and proliferation Fibrosis structural HSC Liver Injury Endothelial dysfunction Initial stage LSEC Increased Vascular Tone dynamic sinusoidal remodelling & AnGn septa & nodule formation vascular occlusion increased stiffness Impaired vasorelaxation NO vasoconstr Portal Hypertension Advanced stage splanchnic vasodilation and increased portal inflow

49 Increased Hepatic Resistance: you need two for tango HSC activation and proliferation Fibrosis structural HSC Liver Injury Endothelial dysfunction Initial stage LSEC Increased Vascular Tone dynamic sinusoidal remodelling & AnGn septa & nodule formation vascular occlusion increased stiffness Impaired vasorelaxation NO vasoconstr Portal Hypertension Advanced stage splanchnic vasodilation and increased portal inflow

50 Liver fibrosis is (spontaneously and slowly) reversible in rodents 12w CCl 4 Issa et al Gastro 2004 Lafoz & Garcia-Pagan 16w CCl 4 8w off CCl4

51 Fibrosis is (very slowly) reversible in human cirrhosis HBV-CLD treated long-term with Entecavir cirrhosis Chang et al Hepatology 2010

52 Targetting fibrosis regression LIVER INJURY CESSATION INSULT KC CHANGING INFLAMMATION TO RESTORATION IMPROVE HSC ECM DEGRADATION Pro-inflammatory signals MMPs TIMPs LSEC LOX / TG Courtesy of Dr J Gracia-Sancho

53 Targetting fibrosis regression LIVER INJURY CESSATION INSULT KC CHANGING INFLAMMATION TO RESTORATION IMPROVE HSC ECM DEGRADATION Pro-inflammatory signals MMPs TIMPs LSEC LOX / TG Removal of injury CCR2/CCR5 antagonists anticoagulants TIMP inh Emricasan Caspase inhibitors (emricasan, ASC1) Emricasan PPAR agonists MMPs antioxidants KLF2 inducers (statins) KLF2 inducers (statins) LOX inh? IGF-l inh FXR agonists FXR agonists Courtesy of Dr J Gracia-Sancho GLP1 analogs, JAK2 ant

54 Fibrosis regression in patients with ACLD Limiting Factors Physical/chemical properties of fibrotic scars Cross-linking Composition of ECM Pattern of fibrosis Role of matrikines in the progression/regression of CLD Duration of fibrosis Degree of disease progression Hypocellularity Lack of microvasculature may limit LSEC-dependent resolution and decrease the efficacy of therapeutic strategies Point of no return?

55 Improving ACLD trough the regulation of endothelial phenotype Role of the transcription factor KLF2 MR Statins Shear stress KLF2 gene transcription Dekker RJ et al., Blood Parmar KM et al., J Biol Chem 2005 Sen-Banerjee S et al., Circulation 2005 enos TM AP Endothelial phenotype maintenance Gracia-Sancho J. Bosch J., Gut Marrone G.Bosch., J Hepat anti-inflammatory anti-fibrotic anti-thrombotic Abraldes J Bosch J. Gastroenterology 2009 Abraldes J Bosch J. J Hepatol 2007 Zafra C Bosch J. Gastroenterology 2004

56 Effects of Simvastatin (SVT) Vs Placebo Double-blind RCTs in human cirrhosis SVT decreases HVPG SVT improves Survival* Simvastatin p=0.030 HR: (0.152 to 0.986) Placebo Abraldes J Bosch J. Gastroenterology 2009 Zafra C Bosch J. Gastroenterology 2004 Marrone et al. GUT 2012 Simvastatin associated to standard of care improves survival after variceal bleeding (BLEPS Study) Abraldes J, Villanueva C, Bosch J. Gastroenterology 2016

57 Targetting fibrosis regression Emricasan Reverse Activation of Effector Cells to Ameliorate Cirrhosis (exosomes)

58 Emricasan reduces hepatocyte apoptosis in cirrhosis (A) Protein expression of cleaved caspases in livers from cirrhotic rats treated with emricasan or vehicle (n=12 per group) (B) Top, representative images of hematoxylin and eosin staining. Bottom, representative images and quantification of hepatic cell death using TUNEL analysis

59 Emricasan reduces portal pressure by decreasing hepatic resistance and improving liver microvascular dysfunction (A) Portal pressure, portal blood flow, hepatic vascular resistance and mean arterial pressure measured in vivo in cirrhotic rats treated with emricasan or vehicle (n=12 per group). (B) Portal perfusion pressure (PPP) and liver vasorelaxation in response to acetylcholine

60 Emricasan for one week ameliorates liver fibrosis and HSC phenotype in cirrhotic rats Representative images and corresponding quantifications of Sirius Red staining, and α-sma and desmin immunohistochemistry in livers from cirrhotic rats treated with emricasan or vehicle (n=12 per group)

61 LSEC from cirrhotic rats: Emricasan improves fenestration, decreases capillarization and restores function

62 Hepatocytes isolated from cirrhotic livers Emricasan enhances the expression of transcription factors and cellular transporters (left), increases CYP450 activity (center) and protein synthesis (right) regain function

63 Emricasan improves the phenotype of non-parenchymal liver cells through paracrine mechanisms HSC LSEC Macrophages Effects of pre-conditioned media from vehicle (left bars) or emricasan treated (right bars) cirrhotic hepatocytes on HSC, LSEC and macrophages isolated from cirrhotic livers

64 Emricasan: Exosomes* from cultured cirrhotic rat hepatocytes treated with emricasan deactivate HSC *(but not microvesicle-enriched secretome sub-fraction) Dotted line: mrna expression in HSC incubated with secretome sub-fractions of vehicle-treated hepatocytes

65 Effects of Emricasan on hepatocytes isolated from human cirrhotic explants Expression of Transporters Protein Synthesis Toxicity biomarkers Emricasan treatment increased expression of transporters (left), albumin and urea synthesis (center) without cell damage (right)

66 Mechanisms of the effects of Emricasan on hepatic hemodynamics, hepatic cells phenotype, hepatocyte function and liver fibrosis Cirrhotic rats receiving emricasan for 7-days show significantly lower portal pressure than vehicle-treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement is associated with: 1) Significantly better liver function, 2) Reduced hepatic inflammation, 3) Improved liver cells phenotype (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages), 4) Reduced fibrosis In vitro experiments in liver cells from cirrhotic patients demonstrate that emricasan exerts its benefits by directly improving hepatocytes, and ameliorate other hepatic cells through an exosome-mediated paracrine mechanism.

67 Acknowledgements Emricasan ameliorates portal hypertension and liver fibrosis in cirrhotic rats through a hepatocyte-mediated paracrine mechanism* J Gracia-Sancho 1,2,3, N Manicardi 1, M Ortega Ribera 1, R Maeso-Díaz 1, S Guixé-Muntet 1,3, A Fernández-Iglesias 1,2, D Hide 1,2, H García-Calderó 1,2, Z Boyer-Díaz 4, PC Contreras 5, A Spada 5, J Bosch 1,2,3 1 Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute, Barcelona, Spain. 2 CIBERehd, Instituto de Salud Carlos III, Spain. 3 Hepatology, Department of Biomedical Research, Inselspital, University of Bern, Switzerland. 4 Barcelona Liver Bioservices, Barcelona, Spain. 5 Conatus Pharmaceuticals, San Diego, CA. USA. Submitted to Hepatology (2018)

68 questions to: KOL Symposium on Portal Hypertension Striving to improve human health September 27 I 2018 NASDAQ CNAT