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Factor IXa Inhibition Aptamer Technology Overview and First Results with RB006/RB007

Factor IXa Inhibition Aptamer Technology Overview and First Results with RB006/RB007. Mauricio G. Cohen, MD Associate Professor of Medicine Director, Cardiac Cath Lab. Disclosure Statement of Financial Interest.

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Factor IXa Inhibition Aptamer Technology Overview and First Results with RB006/RB007

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  1. Factor IXa InhibitionAptamer Technology Overview and First Results with RB006/RB007 Mauricio G. Cohen, MD Associate Professor of Medicine Director, Cardiac Cath Lab

  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. Affiliation/Financial RelationshipCompany Grant/Research Support REGADO BIOSCIENCES

  3. Search for the Ideal Anticoagulant

  4. Aptamers: Nucleic Acids and Monoclonal Antibodies Monoclonal Antibody Aptamer Rusconi CP et al., Nature 2002;419:90-94

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

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

  7. REG1 Anticoagulant System • Synthetic single strand oligonucleotides • Metabolized by nucleases in the blood with no ‘active’ metabolites • No protein binding RB006 Anticoagulant aptamer RB007 Active control agent • Specific affinityfor Factor IXa • Long half life (>24hr) • 50 Kda (31 nucleotides+ 40 kDa PEG) • Specific affinityfor RB006 • Very short half life(<5min) • 5 Kda (15 nucleotides) 6

  8. 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. Arterioscler Thromb Vasc Biol 2002;22:1381-1389.

  9. Rationale for Targeting Factor IXa • FVIIIa/FIXa activation of FX is the rate limiting step in thrombin generation • FIX knockout mice lack occlusive clot formation following vascular injury due to insufficient generation of thrombin to form platelet aggregates. • 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 • Transgenic mice overexpressing FIXa have a shorter lifespan and develop arterial thrombosis and myocardial fibrosis with vascular distribution patterns similar to those of ischemic cardiomyopathy in humans • Hemophilia B Carriers-Reduced CHD Mortality • Foreign materials (eg. catheters and guidewires) lead directly to FIX activation

  10. REG1 Phase 1 Studies- Overview Total: 172 Dyke C, et al. Circulation 2006;114:2490-2497 Chan MY, et al. Circulation 2008;117:2865-2874 Chan MY, et al. J Thromb Haemost 2008; 6:789–96 9

  11. CLIN101 – Phase 1A Study • Study Design • 85 healthy volunteers • Multi-center, randomized, subject blinded, placebo controlled • Evaluate safety of dose escalation of REG1 system or components and pharmacokinetic/pharmacodynamic relationships • Single-dose, dose escalation through 4 dose levels • RB006, RB007, and REG1 treatment arms at each dose level • Results • 1 SAE but no trend of safety signals • RB006 produced dose dependent aPTT levels • RB007 neutralized observed pharmacodynamic effects of RB006

  12. CLIN101 – REG1 Activity in Healthy Volunteers Inject RB007 Inject RB007 APTT (seconds) Placebo/Placebo Placebo/Placebo 15 mg RB006/30 mg RB007 30 mg RB006/60 mg RB007 ULN 60 mg RB006/120 mg RB007 LLN 90 mg RB006/180 mg RB007 APTT (seconds) Time Post RB006 Injection (hrs) ULN LLN Time Post RB006 Injection (hrs) Dyke C, et al. Circulation 2006;114:2490-2497

  13. Study Design 50 patients w/ stable CAD on aspirin/clopidogrel 56-68 years of age Multi-center, randomized, double-blind, placebo-controlled Evaluate safety of dose escalation of the REG1 system and pharmacokinetic/pharmacodynamic relationships Single-dose, dose escalation through 4 dose levels RB006 and REG1 treatment arms at each dose level Results No SAE’s or safety signals RB006 produced dose-dependent aPTT levels RB007 neutralized observed pharmacodynamic effects of RB006 Stable CAD – Phase 1B Study

  14. Stable CAD – Phase 1B StudyResults Inject RB007 Placebo/Placebo 15 mg RB006/30 mg RB007 30 mg RB006/60 mg RB007 50 mg RB006/100 mg RB007 75 mg RB006/150 mg RB007 APTT (seconds) ULN LLN Time Post RB006 Administration (hrs) Chan MY, et al. Circulation 2008;117:2865-2874

  15. Study Design 38 healthy volunteers Single-center, randomized, double-blind, placebo controlled Primary endpoints: Evaluate safety and tolerability of repeated doses of REG1 system Determine the optimal dose ratio for RB007 and RB006 3 consecutive weight-adjusted, drug-antidote treatment cycles or double placebo Fixed doses of RB006 followed by titrated dose of RB007 (2:1 – 0.125) Results Achieved highly reproducible aPTT levels with repeat doses of RB006 Reversed aPTT levels with RB007 dose-dependently and reproducibly Repeat-dose – Phase IC Study

  16. Repeat-dose – Phase IC StudyAntidote Dose Response Inject RB007 Placebo 2:1 AD:DR 1:1 AD:DR 0.5:1 AD:DR 0.3:1 AD:DR 0.2:1 AD:DR 0.125:1 AD:DR APTT (seconds) ULN LLN Time Post RB006 Administration (hrs) Chan MY, et al. J Thromb Haemost 2008; 6:789–96

  17. Repeat-dose – Phase IC StudyActivity In Healthy Volunteers Low inter/intra-subject variability 100 n=38 (healthy volunteers) Placebo Group 1 80 Group 2 Group 3 60 APTT (sec) 40 20 0 Day 1 Day 3 Day 5 Chan MY, et al. J Thromb Haemost 2008; 6:789–96

  18. Phase 1 Program Summary Phase 1 Program Highlights: • Demonstrated safety of RB006, controlling agent (RB007) and the overall REG1 system • Demonstrated controlling agent efficacy • No known drug interactions with common anti-platelet therapy • Demonstrated RB006 and RB007 PK and elimination • Understanding of relationship between RB006 PK and PD • Identified optimal dose of RB006 for maximal FIXa inhibition • Demonstrated ability to titrate the controlling agent • Ability to proceed to Phase II development of REG1 in PCI and ACS Dyke C, et al. Circulation 2006;114:2490-2497 Chan MY, et al. Circulation 2008;117:2865-2874 Chan MY, et al. J Thromb Haemost 2008; 6:789–96 17

  19. PCI Pilot – Reversal PCI • Feasibility study comparing the REG1 system with UFH in stable CAD patients undergoing elective PCI • Multi-center, open-label, randomized (10/07–10/08) • Black Hills Cardiology (Rapid City, SD) • Henry Ford Hospital (Detroit, MI) • University of North Carolina at Chapel Hill (NC) • The Care Group (Indianapolis, IN) • Hospital Italiano (Buenos Aires, Argentina) • Central Coordination: Duke Clinical Research Institute • Primary Endpoint • Major Bleeding using the ACUITY bleeding criteria until hospital discharge or 48 hours whichever occurs first. • Composite of death, nonfatal myocardial infarct (MI), and urgent target vessel revascularization (TVR) through Day 14

  20. PCI Pilot – Reversal PCI Stable CAD pts undergoing PCIAll on ASA and Clopidogrel preload (>6hs) Stable CAD pts undergoing PCIAll on ASA and Clopidogrel preload (>6hs) RB006 dose:1mg/kg in all subjects Roll-in Phase: 2 patientsReg 1 system + EptifibatideRB007:RB006 (0.2:1) Complete Reversal @ 4 hs Sheath Pull RB007:RB006 (1.8:1) Arm 1: 12 patients5:1 randomizationHeparin vs. Reg1 w/partial reversalRB007:RB006 (0.2:1) Complete Reversal @ 4 hs Sheath Pull RB007:RB006 (1.8:1) Safety Committee Review Arm 1: 12 patients5:1 randomization Heparin vs. Reg1 w/complete reversal Immediate Complete Reversal  Sheath Pull RB007:RB006 (2.0:1)

  21. Timeline of Procedures Informed consent will be executed prior to administration of any sedativesClopidogrel 600 mg loading dose and ASA 250-500 mg at least 4 hours prior to PCIPatients who receive heparin during diagnostic cath will wait at least 4 hours for the PCI procedure Baseline Data 14 daysEnd of Follow-up ACTPTT (lab)Whole Blood PTT (POC) PCI TnT, CKMB, CK q8h x 3 End Immediately Post PCIRoll-In andGroup I:Partial Reversalor Group II:Complete Reversal andSheath Pull StudyDrug 5 min 15 min 4 hoursRoll-In andGroup IComplete Reversal and Sheath PullorHeparinSheath Pull IndefiniteASA Clopidogrel recommend12 months

  22. Baseline Characteristics

  23. Procedural Characteristics

  24. Primary Outcomes Measures * Through Hospital Discharge or 48 hrs, whichever occurs first ** Urgent TVR on D6, Index lesion/stent patent, not related to REG1

  25. Pharmacodynamics – WB PTT POC Stable and Predictable Anticoagulation 200 PartialReversal Median 160 151 Interquartile range of max RB006 effect 147 145.5 146.5 145 139 Total Reversal Median 120 Whole blood PTT (seconds) Mean 83 82 80 40 Baseline 5 min Post Study Drug 15 min Post Study Drug End of PCI

  26. Pharmacodynamics – ACT Stable and Predictable Anticoagulation 350 Arm 1:PartialReversal 300 250 Arm 2: Total Reversal Activated Clotting Time (seconds) 200 Control: UFH 150 15 min post 1st RB007 Dose 15 min post 2nd RB007 Dose Baseline 5 min Post Study Drug 15 min Post Study Drug End of PCI

  27. Conclusions: Reversal PCI • All procedures were successfully completed. • No signs of catheter or guidewire thrombosis. • Monitoring by ACT, POC aPTT and plasma aPTT demonstrated measurable differences in both partial and total RB007 reversal doses. • The REG1 System was well tolerated. • RB007 facilitated early sheath removal. • RB006 (1mg/kg) demonstrated rapid onset with consistent coagulation measures during PCI.

  28. In Summary… • The REG 1 System offers the possibility of balancing the bleeding-ischemia risk in PCI patients • This concept can be expanded to other clinical scenarios in which anticoagulation can be tailored to individual patient needs • The Phase 2b RADAR trial will evaluate the safety and efficacy of the REG1 System in 800 acute coronary syndrome patients undergoing cardiac catheterization.

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