1. Pegnivacogin (RB006), a Direct Factor IXa Inhibitor, Results in Consistent and Near Complete Inhibition of Factor IX Activity in Patients with Acute Coronary Syndromes: A Prospective RADAR Pharmacokinetic and Pharmacodynamic Substudy Thomas J. Povsic MD, PhD; William A. Wargin PhD; Mauricio G. Cohen MD; Roxana Mehran, MD; Christoph Bode MD; Joshua Krasnow MD; Merill Krolick DO; Christopher P. Rusconi PhD; Steven L. Zelenkofske DO; Richard A. Becker MD; John H. Alexander MD, MHS

2. Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. In addition, DCRI receives research funding from Regado Biosciences. Affiliation/Financial RelationshipCompany Grant/Research SupportRegado Biosciences

3. Search for the Ideal Anticoagulant Efficacy Ability to prevent thrombosis Safety Low risk of bleeding Titratability Ability to adjust the level of anticoagulation to individual clinical needs Reversibility Ability to safely, rapidly and predictably neutralize the anticoagulant effect when clinically indicated Convenience Daily single-bolus injections without need for continuous infusions or routine monitoring Assessable Monitoring via established coagulation assays

4. Aptamers: A Unique Class of Direct Protein Antagonists n Single-stranded nucleic acids that adopt a defined shape n Unique MOA’s for robust blocking of protein-protein interactions n Selected for specific target binding properties n Minimal toxicity n Low/no immunogenicity n IV or subcutaneous injectables n “Tunable” pharmacokinetics n PEG-conjugated aptamers cleared by nucleolytic breakdown in the blood n Manufactured by a solid phase chemical process 4 SELEX TM

5. Pegnivacogin (RB006): An anticoagulant aptamer n Targets factor IX n Long half life n Metabolized by nucleases in the blood n Titratable as part of REG1 system

6. AptamerControllingAgent REG1: An aptameric system Rusconi CP et al., Nature 2002;419:90-94 PegnivacoginAnivamersen

7. Aptamer ControllingAgent Aptamers Encode Their Own Controlling Agents Rusconi CP et al., Nature 2002;419:90-94

8. Rationale for Targeting Factor IXa n Factor IXa is the proximal driver of clot propagation n Factor IXa is ~7 fold more thrombogenic then factor Xa and ~60 fold more thrombogenic than thrombin on a molar basis n FVIIIa/FIXa activation of FX is the rate limiting step in thrombin generation n FIXa concentration is lower than Xa and thrombin, making high levels of target inhibition more readily achievable n High Factor IX levels are associated with increase in ACS and venous thromboembolism n Foreign materials directly activate Factor IX n Factor IX depletion (Hemophilia B) characterized by aPTT prolongation proportional to degree of disease 8 8

9. CLIN101: Pegnivacogin Provides Predictable and Durable Anticoagulation Time (hrs) Activated Partial Thromboplastin Time (seconds) Activated Partial Thromboplastin Time (seconds) Dyke, C et al, Circulation 2006 90 mg pegnivacogin 60 mg pegnivacogin 30 mg pegnivacogin 15 mg pegnivacogin Placebo 1201009080706050403020 0123012301230123

10. 410 aPTT is Reflective of FIX Depletion

11. CLIN101 and 102: Combined Dosing Analysis 411

12. 1 mg/kg pegnivacogin n = 600 1 mg/kg pegnivacogin n = 600 Heparin ± IIb/IIIa n = 200 Heparin ± IIb/IIIa n = 200 75% reversal n=100 75% reversal n=100 50% reversal n=100 50% reversal n=100 25%reversal n=200 25%reversal n=200 Unblinded Txt Assignment Blinded Assignment of Anivamersen Femoral Cardiac Catheterization / PCI 100% reversal n=200 100% reversal n=200 Std. Care ACS-NSTEMI n=800 Planned Catheterization < 24 h ACS-NSTEMI n=800 Planned Catheterization < 24 h RADAR Design:

13. RADAR PK/PD Substudy: Objectives n Verify adequacy of a 1 mg/kg pegnivacogin dose to achieve: Target plasma concentrations of 18-30  g/ml Target plasma concentrations of 18-30  g/ml Near complete factor IX inhibition in an ACS cohort Near complete factor IX inhibition in an ACS cohort n Assess stability of anticoagulation during the treatment period

14. Unblinded Txt Assignment ACS-NSTEMI n=800 Planned Catheterization < 24 h ACS-NSTEMI n=800 Planned Catheterization < 24 h Substudy Design: Pre-dose Pegnivacogin n = 30 N = 20 heparin naive Pegnivacogin n = 30 N = 20 heparin naive Post- dose Pre-cath Post-cath 1 mg/kg pegnivacogin Plasma collected, frozen, centrally analyzed

15. RADAR PK/PD Substudy: Patient Population N% Age 66.9 ± 9.7 Male1152% White1676% Diabetes943% CRI314% + Troponin 1048% h/o CAD 1467% Δ ST seg 314% Prior MI 733% Prior CPI 838% Prior CABG 419%

16. RADAR PK/PD Substudy: Timing of Sampling Median (min). [25 th, 75 th ] Post-Dosing 30 [21, 45] Pre-Cath 96.5 [55.5, 162.8] Post-Cath 123.5 [56, 179]

17. RADAR PK Substudy: Pegnivacogin concenrations

18. RADAR PD Substudy: aPTT

19. RADAR PD Substudy: Fold Increase in aPTT

20. RADAR PD Substudy: Inferred Degree of FIX Inhibition

21. RADAR PD Substudy * Non-heparin naïve patients excluded

22. Conclusions Pegnivacogin (1 mg/kg) achieves: Pegnivacogin (1 mg/kg) achieves: Therapeutic plasma concentrations Therapeutic plasma concentrations Near complete inhibition of factor IX Near complete inhibition of factor IX Stable levels of anticoagulation throughout period of catheterization/PCI Stable levels of anticoagulation throughout period of catheterization/PCI Findings consistent with early phase results Findings consistent with early phase results Higher doses unlikely to be beneficial Higher doses unlikely to be beneficial Clinical utility of REG1 awaits RADAR and future larger studies Clinical utility of REG1 awaits RADAR and future larger studies Sets the foundation for interpretation of RADAR and future clinical trials Sets the foundation for interpretation of RADAR and future clinical trials

24. Standard Curve

25. Rationale for Targeting FIXa TF-bearing cell Activated platelet Platelet VIIa X Xa VIIa IX IXa IXa XIa IX II X IIa II Propagation Amplification Initiation Xa IIa FIXa inhibitor TF Va TF VIIIa Va Monroe DM. Arterioscler Thromb Vasc Biol 2002;22:1381-1389.

26. SampleNMean (µg/mL) SD (µg/mL) Min (µg/mL) Median (µg/mL) Max (µg/mL) Pre330.00 Post3026.084.5917.4026.3533.90 Pre-Cath2225.614.8515.7025.1037.00 Post-Cath2823.704.4813.6023.3035.90 RADAR PK Substudy: Pegnivacogin Concentrations

27. Sample*NMean (sec) SD (sec) Min (sec) Median (sec) Max (sec) CV% Pre2130.843.7924.5029.5041.5012.30 Post2092.959.4880.7090.90113.9010.20 Pre-Cath1395.1727.5064.3090.90177.1028.90 Post-Cath1995.7516.1282.9094.50158.1016.83 RADAR PD Substudy: aPTT Results * Non-heparin naïve patients excluded

28. Sample*NMean (sec) SD (sec) Min (sec) Median (sec) Max (sec) CV% Pre211.00 Post203.03.382.233.033.8012.5% Pre-Cath132.97.612.262.854.7719.8% Post-Cath193.11.542.13.014.7617.8% RADAR PD Substudy: Fold Increase aPTT * Non-heparin naïve patients excluded