NASDAQ:CNAT
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. September 24, 2015 Portal Hypertension 2
Cirrhosis of the Liver Cirrhosis is scarring of the liver in response to a variety of insults (viral infection, alcohol, obesity, etc.) There are no approved drugs that prevent progression to cirrhosis if the insult persists Liver cirrhosis kills 32,000 Americans each year The only “cure” is a transplant Portal hypertension is a severe and almost unavoidable complication of cirrhosis Responsible for the main clinical consequences including variceal bleeding, decreased liver function, ascites, and encephalopathy September 24, 2015 Portal Hypertension 3
As Cirrhosis Progresses, Symptoms Worsen Spectrum of Liver Disease Portal hypertension September 24, 2015 Portal Hypertension 4
Key Advances for Emricasan Based on results from exploratory Phase 2 Portal Hypertension trial Emricasan: A drug candidate with potential to achieve long-term resolution of fibrosis and cirrhosis Latest trial results: Demonstrated emricasan’s ability to induce a rapid and clinically meaningful reduction of severe portal hypertension Set the stage for longer term, mixed etiology, Phase 2b studies Support the rationale for using HVPG as a registration endpoint September 24, 2015 Portal Hypertension 5
Exploratory Phase 2 Portal Hypertension Trial Initiated September 2014 Open-label, multicenter (9 U.S. sites) pilot study 23 patients enrolled (22 evaluable) Early stage cirrhosis patients Portal hypertension confirmed by HVPG (>5 mmHg) at baseline Mixed etiology of liver disease – most NASH or HCV (active or SVR) 28 day dosing at 25 mg emricasan twice daily Change from baseline in HVPG and cCK18 as primary endpoints Two specified subgroups Patients with baseline HVPG <12 mmHg Patients with baseline HVPG ≥12 mmHg All sites trained on standardized HVPG measurement procedure All HVPG tracings evaluated by single independent expert reader Top-line data announced September 2015 September 24, 2015 Portal Hypertension 6
Phase 2 Portal Hypertension Pilot Study Top-line Results Rapid, statistically significant and clinically meaningful reductions in severe portal pressure Patient Group Mean Baseline HVPG Mean Change in HVPG HVPG ≥12 mmHg (N=12) ‒ 3.7 mmHg 20.6 mmHg (p<0.003) HVPG <12 mmHg (N=10) 8.1 mmHg + 1.9 mmHg (p=0.12) ‒ 1.1 mmHg Total (N=22) 15.2 mmHg (p=0.26) In severe PH patient group with baseline HVPG ≥12 mmHg: 8 of 12 achieved ≥10% reduction in HVPG 4 of 12 achieved ≥20% reduction in HVPG 2 of 12 achieved HVPG reductions to <12 mmHg Reducing HVPG by ≥10% or ≥20%, or to <12 mmHg is strongly associated with clinical benefit In total evaluable patient population cCK18 reduction was statistically significant (p<0.03) September 24, 2015 Portal Hypertension 7
Normal Liver – Minimal Resistance to Blood Flow Liver functions: Hepatic • Process nutrients vein • Produce essential substances • Remove toxins Sinusoid Normal Liver Coronary vein Portal Splenic vein Gut vasculature: vein Drains blood containing materials to be processed by the liver from the GI Total blood flow into the liver: organs into the portal vein Averages about 1350ml/min or 27% of resting cardiac output September 24, 2015 Portal Hypertension 9
Cirrhotic Liver Hepatic vein Varices Sinusoid Cirrhotic Liver Coronary vein Portal Splenic vein vein Splenomegaly Accumulating damage in the liver leads to Portal Hypertension (increased resistance to blood flow coming from the portal vein) and damage to the vessels that feed blood to the liver September 24, 2015 Portal Hypertension 10
Portal Hypertension Both resistance to blood flow in the cirrhotic liver and vasodilation in GI blood vessels outside the liver lead to increased portal pressure Hepatic ↑ Resistance vasoconstriction ↑ Flow GI vasodilation September 24, 2015 Portal Hypertension 11
Hepatic Venous Pressure Gradient (HVPG) HVPG is the measurement of the difference in pressure inside a hepatic vein with a balloon catheter inflated vs. deflated. This measurement provides a good estimate of the elevation in pressure inside the portal vein vs. the pressure in unrestricted blood vessels. HVPG has been identified by the FDA as a validated, objective measure that may be acceptable as a surrogate endpoint for clinical trials of patients with liver cirrhosis. Bosch, J et al. Nat Rev Gastroenterol Hepatol. 2009 Oct;6(10):573-82. September 24, 2015 Portal Hypertension 12
Portal Hypertension and Cirrhosis Portal hypertension HVPG ≥10 mm Hg defines clinically significant portal hypertension. Monitoring is indicated. HVPG ≥12 mm Hg defines severe portal hypertension with increased risk of blood vessel rupture. Treatment is indicated. Causes Fibrosis, restriction of blood flow (vasoconstriction) within the liver Vasodilation in the blood vessels feeding the liver caused in part by apoptotic microparticles derived from dying hepatocytes Treatment No current treatment addresses the vasoconstriction in the liver Beta blockers lower portal pressure through a systemic effect outside the liver to reduce blood flow into the liver Associated with increased cardiovascular risks September 24, 2015 Portal Hypertension 13
Emricasan A novel treatment for cirrhosis First-in-class, orally active, pan-caspase inhibitor Suppresses apoptosis and inflammation Addresses all etiologies of cirrhosis Pharmacodynamic effects Inhibits the activation of stellate cells and decreases fibrosis Reduces apoptosis of hepatocytes which decreases the formation of vasoactive microparticles Safe and well tolerated in fifteen clinical trials involving over 600 subjects No dose-limiting toxicities or drug-related serious adverse events Initial registration strategy to focus on cirrhosis September 24, 2015 Portal Hypertension 15
Emricasan Addresses Two Main Drivers of Liver Damage Common Across Multiple Etiologies APOPTOTIC INFLAMMATORY CASPASE ACTIVATION CASPASE ACTIVATION Various Insults • Infections: HCV / HBV ACTIVATED CASPASES ACTIVATED CASPASES • Obesity: NASH / NAFLD 2 | 3 | 6 | 7 | 8 | 9 | 10 1 | 4 | 5 • Alcohol-related conditions • Autoimmune disorders EMRICASAN Excessive Apoptosis Rapid and sustained reductions Plus Excessive Inflammation in elevated biomarkers of apoptosis and inflammation Key biomarkers: Key biomarkers: Caspase 3/7 ALT cCK18 (M30) flCK18 (M65) September 24, 2015 Portal Hypertension 16
cCK18: A Measure of Microparticles Apoptosis results in the release of pro-inflammatory, vasoactive microparticles cCK18 is embedded in the microparticles Increased inflammation exacerbates insult to liver and increases apoptosis Greater severity of liver disease correlates with higher cCK18 levels Emricasan reduces apoptosis, microparticle production, and related inflammation Reductions in cCK18 levels confirm emricasan’s on target activity Emricasan X X Hepatocytes undergoing apoptosis cCK18 is a direct X measure of microparticles David McCarthy, Gut May 2008 57 (5) September 24, 2015 Portal Hypertension 17
Microparticles: Significance in Liver Disease Important modulators of cell-to-cell communication in disease Often associated with severity of disease stage Biologically active substances are carried both on and in these particles Contents and particle surface mirror the parent cell Actively engulfed by Kupffer cells, stellate cells, endothelial cells Excessive microparticle production overwhelms engulfment capacity Caspase inhibition reduces the production of microparticles Barteneva, N et al. Circulating microparticles: square the circle. BMC Cell Biology 2013; 14:23 September 24, 2015 Portal Hypertension 18
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