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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.
2 Jefferies Global Healthcare Conference June 2015
Why NASH Cirrhosis? Why Now?
Liver disease patients typically have no symptoms until they progress to cirrhosis
There are no approved drugs that prevent progression to cirrhosis
Liver cirrhosis kills 32,000 Americans each year The only “cure” is a transplant
By 2020, the leading cause of liver transplants is expected to be NASH
3 June 2015 Jefferies Global Healthcare Conference
Why Conatus? Why Now?
4 June 2015 Jefferies Global Healthcare Conference
First-in-class, small molecule, orally active, pan-caspase protease inhibitor Mechanism of action relevant regardless of etiology or disease severity Suppresses apoptosis and inflammation: two key drivers of liver disease
Activity confirmed by mechanism-specific biomarker cCK18 Baseline levels increase with disease severity Dose-related, rapid and sustained reductions even in severely ill patients
Safe and well tolerated in fourteen clinical trials involving over 550 subjects No dose-limiting toxicities or drug-related serious adverse events Important clinical trial readouts expected over next six months
Initial registration strategy to focus on NASH cirrhosis High medical need with large and growing patient population No current disease-modifying treatments Potential to access accelerated approval pathways Potential for registration strategy to include NASH fibrosis
5
Lead Compound: Emricasan (IDN-6556)
Potential to address the full spectrum of liver disease with initial focus on NASH cirrhosis
June 2015 Jefferies Global Healthcare Conference
Key Drivers of Focus on NASH Cirrhosis
Potent mechanism with demonstrated activity across the full spectrum of liver disease Explicit regulatory pathway and high unmet need in cirrhosis Stable and compliant patient population in NASH
6 June 2015 Jefferies Global Healthcare Conference
Liver Fibrosis Cirrhosis/Failure
Caspase Activation Drives Two Key Pathways
Various Insults • Infections: HCV / HBV • Obesity: NASH / NAFLD • Alcohol-related conditions • Autoimmune disorders
Jefferies Global Healthcare Conference 8 June 2015
Excessive Apoptosis Excessive Apoptosis Plus Excessive Inflammation
APOPTOTIC CASPASE ACTIVATION
ACTIVATED CASPASES
2 | 3 | 6 | 7 | 8 | 9 | 10
INFLAMMATORY CASPASE ACTIVATION
ACTIVATED CASPASES
1 | 4 | 5
Liver Fibrosis Cirrhosis/Failure
9
Interrupting the Pathways May Improve Outcome
Jefferies Global Healthcare Conference
Various Insults • Infections: HCV / HBV • Obesity: NASH / NAFLD • Alcohol-related conditions • Autoimmune disorders
EMRICASAN Excessive Apoptosis
Plus Excessive Inflammation Rapid and sustained reductions
in elevated biomarkers of apoptosis and inflammation
June 2015
APOPTOTIC CASPASE ACTIVATION
ACTIVATED CASPASES
2 | 3 | 6 | 7 | 8 | 9 | 10
INFLAMMATORY CASPASE ACTIVATION
ACTIVATED CASPASES
1 | 4 | 5
Key biomarkers: ALT
flCK18 (M65)
Key biomarkers: Caspase 3/7 cCK18 (M30)
Apoptosis results in the release of highly pro-inflammatory 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
10 Jefferies Global Healthcare Conference
David McCarthy, Gut May 2008 57 (5)
Hepatocytes undergoing apoptosis
Emricasan
X
X X
cCK18 is a direct measure of inflammatory microparticles
cCK18: A Biologically Plausible Marker of Improvement that is Objective, Measurable and Sensitive to Change*
June 2015
*Sanyal, AJ, et al. Hepatology 2015;61:1392-1405; doi: 10.1002/hep.27678
Eight Phase 1 trials conducted in the US, EU and Asia Healthy volunteers and patients with organ impairment Confirmed dosing for clinical studies
Six randomized, placebo-controlled Phase 2 trials conducted in the US and EU
Included patients with liver diseases due to a variety of causes Well tolerated, no drug-related serious adverse events
Biomarker results suggest disease-modifying potential
Levels of mechanism-specific biomarkers increase with disease severity Reproducible reductions in these biomarkers are achieved in patients across the full spectrum of liver disease
12
Emricasan Clinical Experience to Date
Studied in over 550 patients
June 2015 Jefferies Global Healthcare Conference
13
Three Dosing Trials in Organ-impaired Patients
Established appropriate dosing in patients with varying degrees of liver impairment
June 2015 Jefferies Global Healthcare Conference
● Moderate Hepatic Impairment
● Severe Hepatic Impairment
● Mild Hepatic Impairment
● Severe Hepatic Impairment + Acute Decompensation
● No Hepatic Impairment
DECOMPENSATED CIRRHOSIS
COMPENSATED CIRRHOSIS
LIVER FAILURE
ACLF Trial
Severe Renal Impairment Trial
Hepatic Impairment Trial
NORMAL
PK/PD data in five distinct patient populations has been evaluated in aggregate to inform dosing for future trials
Baseline biomarker data confirm MOA targeted by emricasan is highly engaged
Conclusions Safety
No dose-limiting toxicities or drug-related SAEs Drug Activity
Confirmed by reduction in elevated cCK18 levels Confirmed across all liver disease stages tested, even ACLF
Drug Exposure Systemic drug levels increased with severity of hepatic impairment Appropriate dosing confirmed across spectrum of hepatic impairment
38 patients with NAFLD/NASH and persistently elevated ALT 28-day double-blind, placebo-controlled Objectives
Confirm safety, dosing, and tolerability in target population
Efficacy variables - primary Change from Baseline in ALT
Efficacy variables - secondary Change from Baseline in cCK18, AST, caspase 3/7, flCK18 Change from Baseline in HOMA-IR
14
NAFLD/NASH Phase 2 Trial
Understanding dosing in patients with different etiologies
June 2015 Jefferies Global Healthcare Conference
Top-line results announced 1Q15 Detailed results presented at EASL in April
Screening Phase Treatment Phase
Emricasan: 25 mg BID N=19
Placebo BID N=19
Follow-Up Phase
Follow-Up
Screen
RANDOMIZATION Day 1 M1 / Day 28 M2
Met primary endpoint Statistically significant (p<0.05) reduction in ALT compared to placebo control ALT reduction of ~39% in treatment arm vs reduction of ~14% in placebo arm
Key secondary serum biomarkers – cCK18, AST, caspase 3/7, flCK18 Elevations at baseline confirm engagement of apoptosis and inflammation Statistically significant reductions from baseline confirm drug activity cCK18 reduction of ~30% in treatment arm vs increase of ~4% in placebo arm
Emricasan was safe and well tolerated No dose-limiting toxicities or drug-related serious adverse events No adverse effects on lipid levels or insulin sensitivity
Conclusions Confirmed that optimal dose of emricasan is consistent across etiologies Demonstrates that the mechanism is relevant in NASH Opened the door for more advanced studies in NASH
15
NAFLD/NASH Phase 2 Trial Results
Top-line results in March 2015; detailed results at EASL Annual Meeting in April 2015
June 2015 Jefferies Global Healthcare Conference
Comments on the Model for End-Stage Liver Disease (MELD) Objective measure, validated MELD score >10 linked to negative liver-related clinical outcome 2 point change in MELD score or lack of progression to MELD score of 15 as potential surrogate endpoints
Comments on the Child-Pugh-Turcotte (CPT) score Objective-subjective measure, validated 2 point change in CPT score or lack of progression from CPT-A to CPT-B potential surrogate endpoints
Comments on Hepatic Venus Pressure Gradient (HVPG) Objective measure, validated HVPG >10 mm Hg linked to negative liver-related clinical outcome Lowering to or lack of progression to HVPG >10 mm Hg potential surrogate endpoints
Comments on cCK18 utility Objective measure, sensitive to change Levels correspond to improvement in liver histology in NASH
17
Manuscript from AASLD/FDA Joint Workshop*
Published online December 2014
June 2015 Jefferies Global Healthcare Conference
*Sanyal, AJ, et al. Hepatology 2015;61:1392-1405; doi: 10.1002/hep.27678
Ongoing Phase 2 Portal Hypertension (PH) clinical trial ~20 patients, open-label pilot study
Early stage cirrhosis in patients with evidence of portal hypertension; mixed etiology of liver disease Most subjects HVPG baseline value expected to be >10 mm Hg Change in HVPG and cCK18 as endpoints One month dosing at 25 mg emricasan twice daily Top-line data expected 3Q15
Ongoing Phase 2 Liver Cirrhosis (LC) clinical trial ~80 patients, double-blind, placebo-controlled 1st phase + open-label 2nd phase
Cirrhosis with MELD score at entry from 11-18; mixed etiology of liver disease Changes in MELD score, CPT score and cCK18 as endpoints Three month dosing at 25 mg emricasan twice daily First stage top-line data expected 4Q15
18
Clinical Development in Cirrhosis On Target
Trials initiated September 2014
June 2015 Jefferies Global Healthcare Conference
Feedback on proposed registration trial patient populations and methods of measuring and analyzing validated surrogate endpoints of MELD, CPT, and HVPG in patients with NASH cirrhosis
Design details for registration trials to be finalized based on results from two ongoing cirrhosis trials and additional feedback from regulatory agencies
Evaluating opportunity to include a clinical trial in patients with NASH fibrosis as a component of overall registration strategy
19
Regulatory Clarity on Initial Registration Pathway
Met with FDA in May 2015
June 2015 Jefferies Global Healthcare Conference
Fibrosis Compensated Cirrhosis
Decompensated Cirrhosis Transplant
U.S. Patients (Diagnosed) 1,617K 1,077K 230K 6.5K
EU5 Patients (Diagnosed) 628K 617K 191K 5.3K
Cost per Patient (U.S.) <$5K $22K $66K $600K
Fibrosis Compensated Cirrhosis
Decompensated Cirrhosis Transplant
U.S. Patients (Diagnosed) 1,617K 1,077K 230K 6.5K
EU5 Patients (Diagnosed) 628K 617K 191K 5.3K
Cost per Patient (U.S.) <$5K $22K $66K $600K
As Liver Disease Progresses to Cirrhosis, Symptoms and Healthcare Costs Increase
21 June 2015 Jefferies Global Healthcare Conference
Sources: P Byass 2014, CPMC, and Conatus sponsored market analysis Cost per Patient figures are annual except for Transplant, which is one-time
Spectrum of Liver Disease
Uniquely Positioned to Address Both Medical Need and Efficiency of Development
22 June 2015 Jefferies Global Healthcare Conference
• Approved drugs address symptoms or complications of liver disease, not underlying mechanisms
• Medical need shifts from symptoms
to clinical outcomes with cirrhosis
• Validated clinical endpoints for advanced cirrhosis patient populations may allow more efficient drug development
• Conatus is initially targeting high medical need patients with cirrhosis for whom emricasan may modify the course of disease
Liver Failure
Decompensated Cirrhosis
Asymptomatic Symptomatic
Other Companies
Disease Severity
Relat
ive U
nmet
Nee
d
Relative Disease Prevalence Size (directional, not to scale) Sources: Clinicaltrials.gov; company websites
Fibrosis
Cirrhosis
Based on three factors: 1) understanding how to dose emricasan in patients
with different levels of liver impairment
2) understanding how to dose emricasan in patients with different etiologies of liver disease
3) regulatory clarity on endpoints suitable for registration trials, in particular those potentially useful in accelerated approval pathways
23
Emricasan Initial Registration Strategy
Focus on NASH cirrhosis supplemented with data in patients with NASH fibrosis
June 2015 Jefferies Global Healthcare Conference
1) addressed with results from three organ impairment trials announced in January 2015
2) addressed with results from NAFLD/NASH trial announced in March 2015
3) addressed in meeting with FDA in May 2015 with feedback on proposed patient populations and validated surrogate endpoints
Emricasan Initial Registration Status
Finalizing design details by year-end 2015 for registration trial in NASH-driven cirrhosis Evaluating opportunity to include NASH-driven fibrosis trial in overall registration strategy
24 June 2015 Jefferies Global Healthcare Conference
25
Emricasan: Clinical Milestones
Goals: Define dosing, broaden safety database, show activity against validated endpoints
June 2015 Jefferies Global Healthcare Conference
Post Liver Transplant HCV Clearance with Unresolved Fibrosis/Cirrhosis (POLT-HCV-SVR)
Phase 2b initial baseline data expected 2Q15
Liver Cirrhosis (LC)
Phase 2 first stage top-line data expected 4Q15
Portal Hypertension (PH)
Phase 2 top-line data expected 3Q15
Target Population Preclinical Phase 1 Phase 2 Importance Next Milestone
Long term safety with histology endpoints
Validated Surrogate endpoint
Validated Surrogate endpoint
Emricasan: Investment Highlights
Large market opportunity in cirrhosis with potential future opportunities in larger liver disease indications
Mechanism applies across the entire spectrum of liver disease, regardless of cause or stage of progression
Clinical data has shown consistent safety and statistically significant reductions in key biomarkers of liver cell death and inflammation
Near-term milestones with two cirrhosis trials measuring validated surrogate endpoints
Regulatory feedback confirmed opportunity in cirrhosis and provided clarity on analysis of surrogate endpoints in the context of potential accelerated approval
Inclusion of NASH fibrosis provides supplemental safety and could provide early entry into key area of liver disease spectrum
IP protection through 2028 (US) and 2027 (International), without extension
June 2015 Jefferies Global Healthcare Conference 26