Tricoci P, N Engl J Med 2012 Farb A, Circulation 2003

1. Safety and Tolerability of CSL112 in Patients with Stable Atherothrombotic Disease: Results from a Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study Pierluigi Tricoci, Denise M. D’Andrea, Paul A. Gurbel, Marina Cuchel, BrionM. Winston, Robert Schott, Robert J. Weiss, Henry E. Paez, Michael A. Blazing, Louis A. Cannon, Alison L. Bailey, Dominick J. Angiolillo, Penelope Dalitz, Shelley Myles-Di Mauro, Charles Shear, John H. Alexander

2. High Rate of Early Recurrent Atherothrombotic Events After ACS with Current Strategies • Thrombosis Rx • UFH/LMWH • Fondaparinux • Bivalirudin • GPI IIb/IIIa • Aspirin • Clopidogrel • Prasugrel • Ticagrelor • Rivaroxaban •  Thrombosis •  Bleeding • Lipid rich plaque Rx • Statin CV Death/MI/Stroke Tricoci P, N Engl J Med 2012 Farb A, Circulation 2003

3. Background—HDL and Atherosclerosis • HDL cholesterol levels are inversely correlated with the risk of atherosclerotic cardiovascular events. • Recent large-scale clinical drug trial experience has invalidated change in HDL cholesterol levels as a predictor of efficacy. • Increasing HDL anti-atherosclerotic function is now the focus of novel therapeutics. • HDL anti-atherosclerotic function is hypothesized to be largely driven through ApoA-I and the promotion of cholesterol efflux, the first step in reverse cholesterol transport. • ApoA-I most effectively mediates cholesterol efflux from plaque through interaction with the macrophage ATP-binding cassette transporter ABCA1.

4. Background—CSL112 • CSL112 is an ApoA-I, the chief protein component of HDL, purified from human plasma and reconstituted with phospholipids to form HDL particles suitable for IV infusion.1 • CSL112 is similar to native HDL3 in size, organization, and function.1 • A prototype formulation, CSL111 was shown to modify atherosclerotic plaque composition on IVUS but caused transient increases in transaminases.2 • CSL112 represents a reformulation of the prototype formula with changes in excipients and increased uniformity of the product. CSL112 1Diditchenko S, ArteriosclerThrombVascBiol 2013 2Tardif JC, JAMA 2007

5. CSL112 Development Program Hypothesis • A short course of treatment with CSL112 infusion(s) administered after an ACS will reduce early recurrent atherothrombotic cardiovascular events following ACS by: • Rapidly increasing cholesterol efflux capacity in serum. • Modifying the composition and stability of atherosclerotic plaques.

6. CSL112 Phase 2a Trial A phase 2a adaptive, multicenter, randomized, double-blind, placebo-controlled, single-ascending-dose clinical trial of CSL112 was designed to: • Assess safety in patients with stable atherothrombotic disease who were taking standard-of-care medications, including aspirin and either clopidogrel or prasugrel. • Further characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of CSL112 in this population.

7. Trial Design Double Blind Stable Atherothrombotic Disease (N≈40) CSL112 Dose group 1.7 g • Key inclusion criteria: • CAD or PVD • >1 month from acute events • On aspirin and clopidogrel/prasugrel • Key exclusion criteria: • CrCl <60 mL/min • Hepatobiliary disease • Poor clopidogrel metabolism (if on clopidogrel) • Change in Rx <1 month 3:1* Placebo CSL112 Dose group 3.4 g 3:1* Placebo CSL112 Dose group 6.8 g 3:1* Placebo *Stratification: CrCl>90 mL/min vs CrCl>60 to <90 mL/min

8. Study Periods and Follow-UpOverview

9. Study Endpoints Primary safety assessments • Frequency of study–product-related adverse events. • Frequency of clinically significant elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3x ULN). Secondary safety assessments • Changes from baseline in other clinical laboratory tests and assessments. • Platelet function test. Main PK/PD evaluations • Key PK parameters (AUC, Cmax, Tmax) of ApoA-I, cholate, and phosphatidylcholine. • Measures of reverse cholesterol transport and lipoprotein • Total and ABCA1-mediated cholesterol efflux potential (ex vivo). • Serum concentrations of preBeta1 HDL, esterified and un-esterified HDL, non-HDL cholesterol.

10. Subject Disposition Patients randomized: 45 Patients treated: 44 Completed study: 44

11. Baseline Characteristics Data presented as n (%) or median (IQR).

12. Primary- Endpoint - Adverse Events (Active Treatment Period) *Occurring within 72 hrs of infusion or considered related by investigator (independent of time). †Includes IV infusion site ecchymosis/hematoma, erythema, coldness, phlebitis. ‡CTCAE v.4 grade at any timepoint.

13. Primary Endpoint - Liver Safety (change from baseline during active treatment period)

14. Other Selected Clinical Laboratory (change from baseline during active treatment period) • Continuous variables shown as mean (SD).

15. PK of ApoA-I Mean Plasma Concentrations with Different Doses of CSL112 • Dose-proportional PK observed • All parameters comparable to those seen in healthy subjects

16. Changes in Mean Global Cholesterol Efflux by Time and CSL112 Dose

17. Summary of Main Biomarker and Platelet Aggregation Data • Reverse cholesterol efflux and lipids: • Increase global and ABCA1-dependent cholesterol efflux. • Increase preBeta1 HDL (HDL-VS) and cholesterol esterification. • No change observed in triglycerides, apo-B, non-HDL-C, Lp(a). • Full data to be presented by Andreas Gilles et al. Tuesday, November 19 at 10:45 AM, Room C143. • Platelet aggregometry: • No significant antiplatelet effect. • Full data to be presented by Paul A. Gurbel et al. Wednesday, November 20 at 9:30 AM, Poster Hall, Core 2.

18. Conclusion • In this phase 2a trial among patients with stable atherothrombotic disease, a single infusion of CSL112 : • Did not show evidence of liver toxicity. • Had an overall favorable safety profile on adverse events. • Did not cause significant changes in other clinical laboratory parameters. • Produces a predictable, rapid, and dose-dependent increase in ApoA-I plasma concentration • Was associated with a dose-dependent increase in key markers of reverse cholesterol transport. • These results on the safety and biological mechanisms of potential clinical efficacy support continued development of CSL112.

19. CSL112 Clinical Development Progression • Global phase 2b trial of CSL112 in patients post-ACS to start in early 2014 • Study objectives: • Assess safety and tolerability of CSL112 immediately following ACS. • Examine effect of CSL112 on occurrence of major adverse cardiac events (MACE).

20. Investigators Dominick J. Angiolillo, MD, PhD - Jacksonville, FL Alison L. Bailey, MD - Lexington, KY Michael A. Blazing, MD - Durham, NC Louis A. Cannon, MD - Petoskey, MI Marina Cuchel, MD, PhD - Philadelphia, PA Paul A. Gurbel, MD- Baltimore, MD Jonathan A. Mosley, DO - Madisonville, KY Henry E. Paez, MD - Miami, FL Robert Schott, MD - Chula Vista, CA Robert J. Weiss, MD - Auburn, ME BrionM. Winston, MD, MPH- Rapid City, SD