1. Potential Utility of rNAPC2 in ACS: Phase 2 Heparin Replacement Trial Evaluating RNAPc2 In Acute Coronary Syndromes Potential Utility of rNAPC2 in ACS: Phase 2 Heparin Replacement Trial Evaluating RNAPc2 In Acute Coronary Syndromes Robert P. Giugliano, MD, SM, Associate Physician, Cardiovascular Division Brigham and Women's Hospital Assistant Professor in Medicine Harvard Medical School Boston, MA

2. Novel Tissue Factor / Factor VIIa Inhibitor Reduces Ischemia in Patients with NSTE-ACS: Results of the Dose- Ranging and Heparin De-Escalation Phases of the ANTHEM-TIMI 32 Trial RP Giugliano 1, SD Wiviott 1, DI Simon 2, MJ Schweiger 3, MA Leesar 4, PH Stone 1, R Bach 5, A Skene 6, SR Deitcher 7, E Braunwald 1 on behalf of the ANTHEM-TIMI 32 Investigators (1) Brigham & Women’s Hospital, Boston, MA. (2) University Hospitals – Case Medical Center, Cleveland, OH. (3) Baystate Medical Center, Springfield, MA. (4)U of Louisville, Louisville, KY. (5) Washington U School of Medicine, St. Louis, MO. (6) Nottingham Clinical Research Limited, Nottingham, UK. (7) Nuvelo, Inc., San Carlos, USA

3. Disclosures Accumetrics, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals Baxter Bayer Healthcare LLC Beckman Coulter, Inc. Biosite Incorporated Bristol-Myers Squibb CardioKinetix CV Therapeutics, Inc. Eli Lilly and Company FoldRx GlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corp Accumetrics, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals Baxter Bayer Healthcare LLC Beckman Coulter, Inc. Biosite Incorporated Bristol-Myers Squibb CardioKinetix CV Therapeutics, Inc. Eli Lilly and Company FoldRx GlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corp Integrated Therapeutics Corp KAI Pharmaceuticals Merck & Co., Inc. Millennium Pharmaceuticals, Inc. Novartis Pharmaceuticals Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics Corporation Roche Diagnostics GmbH Sanofi-Aventis Sanofi-Synthelabo Recherche Schering-Plough St Jude Medical The National Institutes of Health Integrated Therapeutics Corp KAI Pharmaceuticals Merck & Co., Inc. Millennium Pharmaceuticals, Inc. Novartis Pharmaceuticals Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics Corporation Roche Diagnostics GmbH Sanofi-Aventis Sanofi-Synthelabo Recherche Schering-Plough St Jude Medical The National Institutes of Health The TIMI Study Group received research/grant support in the last 2 yrs through Brigham & Women’s Hospital from (alphabetical order): MJ Schweiger, MA Leesar, R Bach, and A Skene received research grant support from Nuvelo; SR Deitcher is an employee of Nuvelo

4. Background l Exposure of tissue factor (TF) initiates coagulation at sites of vascular injury (plaque rupture, PCI) l rNAPc2 is a recombinant, modified version of NAPc2 (derived from the hookworm) that provides potent factor X(a)-dependent inhibition of the TF/fVIIa complex l rNAPc2 prevented new thrombin generation in a dose- dependent manner in phase 2 studies of elective knee surgery and elective PTCA l Ischemia during continuous ECG monitoring identifies patients with ACS at high risk of adverse cardiac events l Enoxaparin was associated with less ischemia based on continuous ECG and better clinical outcomes than UFH, suggesting more proximal inhibition may be more effective than distal inhibition of the coagulation cascade

5. Trial Design: Dose Ranging nSTE ACS -> Early Catheterization rNAPc2 (n=163) IV bolus q 48h 8 escalating doses (1.5, 2, 3, 4, 5, 7.5, 10 † mcg/kg) Placebo IV q 48h n = 40 ASA, Enox or UFH, GP IIb/IIIa*, clopidogrel* PK, PD: pre-dose, 2-6h, 48h, d7, d42 Continuous ECG x 7 days Clinical f/u to 6 months Major Endpoints Safety Major/Minor Bleed Efficacy F1+2, PT, PK Holter Ischemia * Encouraged per current practice guidelines † 10 mcg/kg dose panel repeated Blinded Randomized 4:1

6. nSTE ACS Early Cath nSTE ACS Early Cath Heparin De-Escalation (HDE) Design (n=52) ASA GP IIb/IIIa* clopidogrel* ASA GP IIb/IIIa* clopidogrel* * Encouraged per current practice guidelines † 30 U/kg bolus (max 2500 U); 6 U/kg/h (max 600 U/h) ‡ Defined as use of open-label anticoagulant to manage a thrombotic complication rNAPc2 10 mcg/kg rNAPc2 10 mcg/kg ½ Std † UFH (n=26) No UFH (n=26) 2 Sequential Panels Unblinded PK, PD, Cont ECG, 6 mth clinical Angiograms reviewed by Core Lab Thrombosis monitored by Investigators Endpoints Major/Minor Bleed Thrombotic Bailout ‡ F1+2, PT, PK Holter Ischemia 1 2

7. Entry Criteria and Study Schema rNAPc2/ placebo (rNAPc2/ placebo) Angio +/- PCI IV GP IIb/IIIa (encouraged) 144h 048h96h R in hospital 192h(8d) Enox q 12h or UFH Aspirin 75-325 mg daily x 6 mths Inclusion: Age 18-75, rest sx > 5min w/i 48h c/w ACS + markers or ST deviation or TIMI Risk Score > 3 Planned early invasive strategy Exclusions:STEMI, creatinine > 4,  bleed risk, planned CABG <7d (rNAPc2/ placebo) Clopidogrel 300/75 (encouraged) Up to 3 doses administered as determined by clinical circumstances and length of hospitalization

8. Baseline Characteristics rNAPc2Placebo No. of patients21540 Age (median)58 yrs56 yrs Age > 65 yrs2818 Women3420 nSTE-MI5350 ST dev > 0.5mm4745 Diabetes3433 Mean TIMI Risk Score (0-7)3.53.7 Data shown are % of patientsAll p = NS

9. Concomitant Treatments rNAPc2Placebo (n=215)(n=40) # Study drug doses:1 8583 2 1418 3 1 0 *Enoxaparin / UFH 71 / 3375 / 33 Clopidogrel 8185 GP IIb/IIIa inhibitor 5353 Treatment Strategy:PCI 4558 CABG 11 3 Medical 4440 Data shown are % of patients * Excludes 52 patients in the heparin de-escalation phaseAll p = NS

10. # patients:40212120212020402626215 † 3/4 major bleeds were CABG-related 2-3 days post dose 1° Study Endpoint: Adjudicated TIMI Major or Minor Bleeding 2.5 4.8 00 5.0 7.5 3.7* Dose of rNAPc2 (mcg/kg) # bleeds -> 111113†3† 4†4† 4 p-value for trend = 0.23 p = NS for each pairwise comparisons with placebo *p = 0.50 for comparison with placebo (1° endpoint) 01 3.8 Dose- Ranging Phase HDE All rNAPc2

11. Other Safety Endpoints rNAPc2Placebo (n = 215)(n = 40)P-value Minimal Bleeding9.8 10.0NS Provoked by procedure 8.4 5.0NS Spontaneous 1.4 5.0NS RBC Transfusion5.6 2.5NS Fresh Frozen Plasma1.4 2.5NS Platelet Transfusion0.5 2.5NS Recombinant FVIIa (antidote) 0 0-- Serious Adverse Events 30 33NS rNAPc2 Antibody @ 42d 13* 00.01 Data shown are % of patients * No allergic symptoms, anaphylaxis, or clinical manifestations were reported

12. Plasma Concentration of rNAPc2 (Dose Ranging Phase) rNAPc2 (ng/mL) rNAPc2 dose Trend p <0.0001 at 2-6h and 48h

13. Median International Normalized Ratio (INR) – Dose Ranging INRrNAPc2 dose Trend p <0.0001 Trend p = 0.02

14. Correlation of Log Conc and INR Adjusted r 2 = 0.26 correlation coefficient = 0.51 p < 0.0001 log(rNAPc2 concentration µg/kg) INR 3456 1 2 3 4 5 2-6 hours post dose

15. F1+2 Concentration: A Measure of New Thrombin Generation (All Pts) %  in Median F1+2 from Randomization rNAPc2 dose Randomization 2-6h48h 7d post *p = 0.04 vs. placebo ** p = 0.005 vs. placebo ***p = 0.002 vs. placebo † p = 0.08 vs. placebo p = NS for all others * ** † ***

16. Incidence of Ischemia by Dose 7/34 % pts 6/184/195/197/193/182/187/79 Dose of rNAPc2 in mcg/kg Trend p = 0.013 Median duration of recording was 6.7 days Continuous ECGs were interpreted by a blinded central core laboratory

17. Incidence of Ischemia % pts p = 0.64 p = 0.12 p = 0.002 3-way p = 0.007 7/3425/939/97

18. Heparin De-Escalation Results Unblinded HDEDouble-blind rNAPc2 dose (mcg/kg)101010 placebo Heparin DoseNone½Std StdStd (n=26)(n=26)(n=40)(n=40) Major/Minor Bleed, % 3.8 07.52.5   Median F1.2 from rand. At 2-6 hours -8%-17*-23* -1 At 48 hours-5%-28%* -9*+31 % Holter ischemia 4 † 13 1021 % Thrombotic Bailout19 ‡ 0 -- -- *p < 0.05 vs placebo† p = 0.12 vs placebo‡ p = 0.051 vs ½ Std heparin. Note: TBO was prospectively assessed only during heparin de-escalation, 1 case was retrospectively identified in patients receiving 10 mcg/kg rNAPc2 + standard heparin

19. Clinical Endpoints at 42 Days rNAPc2placebo (n=215)(n = 40) All-cause Mortality 0 0 New Myocardial Infarct* 2 3 Clinical Rec Ischemia* 8 8 D / MI* / RI* 10 10 Holter ischemia* 0-7 days 18 21 Revasc post discharge 10 13 Stroke 0.5 0 Any of the above30 38 Data shown are % of patients * Central blinded adjudicated All p = NS

20. l rNAPc2 did not increase bleeding despite dose-related increase in INR l Higher dose rNAPc2 (> 7.5 mcg/kg) suppressed new thrombin generation and these doses  ischemia by 50% l Some heparin may be necessary to avoid procedure-related thrombosis l These proof of concept data warrant larger-scale evaluation to determine if rNAPc2 improves clinical outcomes Summary and Conclusions