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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.

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Disclosure Statement of Financial Interest

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  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 Support Regado Biosciences

  3. Search for the Ideal Anticoagulant

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

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

  6. REG1: An aptameric system Pegnivacogin Anivamersen Aptamer Controlling Agent Rusconi CP et al., Nature 2002;419:90-94

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

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

  9. 90 mg pegnivacogin 60 mg pegnivacogin 30 mg pegnivacogin 15 mg pegnivacogin Placebo CLIN101: Pegnivacogin Provides Predictable and Durable Anticoagulation 120 100 90 80 70 60 50 40 30 20 Activated Partial Thromboplastin Time (seconds) 0 1 2 3 Dyke, C et al, Circulation 2006 Time (hrs)

  10. aPTT is Reflective of FIX Depletion • 10

  11. CLIN101 and 102:Combined Dosing Analysis • 11

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

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

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

  15. RADAR PK/PD Substudy:Patient Population

  16. RADAR PK/PD Substudy:Timing of Sampling Median (min). [25th, 75th] 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: • Therapeutic plasma concentrations • Near complete inhibition of factor IX • Stable levels of anticoagulation throughout period of catheterization/PCI • Findings consistent with early phase results • Higher doses unlikely to be beneficial • Clinical utility of REG1 awaits RADAR and future larger studies • Sets the foundation for interpretation of RADAR and future clinical trials

  23. Standard Curve

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

  25. RADAR PK Substudy: Pegnivacogin Concentrations

  26. RADAR PD Substudy: aPTT Results * Non-heparin naïve patients excluded

  27. RADAR PD Substudy: Fold Increase aPTT * Non-heparin naïve patients excluded

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