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Translational Science in Drug Development A Clinician-Scientist Perspective Richard C. Becker, MD Professor of Medicine Duke University School of Medicine.

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Presentation on theme: "Translational Science in Drug Development A Clinician-Scientist Perspective Richard C. Becker, MD Professor of Medicine Duke University School of Medicine."— Presentation transcript:

1 Translational Science in Drug Development A Clinician-Scientist Perspective Richard C. Becker, MD Professor of Medicine Duke University School of Medicine Duke Cardiology GR, 2012

2 Career Development Career Development Personal Development Personal Development Evolution informed by :experience within a field of interest, mentorship, progress, success and integration. Evolution informed by :experience within a field of interest, mentorship, progress, success and integration. Organizational Development Organizational Development

3 Mentors, Peers and Collaborators** Mentors, Peers and Collaborators** Helen Berry, PhD Helen Berry, PhD Richard Bozian, MD Richard Bozian, MD Fred Lucas, MD Fred Lucas, MD James Weick, MD James Weick, MD Joseph Alpert, MD Joseph Alpert, MD Desire Collen, MD, PhD Desire Collen, MD, PhD Ted Bovill, MD Ted Bovill, MD Bruce Sullenger, PhD Bruce Sullenger, PhD Partial list**

4 Translational Science in Drug Development Translational Science in Drug Development Translational Science - Definitions Translational Science - Definitions NIH Initiatives NIH Initiatives Nucleic Acids/oligonucleotides: A Duke University Medical Center Experience Nucleic Acids/oligonucleotides: A Duke University Medical Center Experience

5 Translational Science Improvement of human health through scientific discoveries that are subsequently translated into practical applications. Basic Science Bedside Community T2 T1

6 National Institutes of Health Initiatives Clinical Translational Science Awards (October 2006) 1. Captivate, advance and nurture a cadre of well- trained multi-and inter-disciplinary investigators and research teams; 2. Create an incubator for innovative research tools and information technologies; and 3. Synergize multi-disciplinary clinical and translational research and researchers to catalyze the application of new knowledge and techniques to clinical practice at the front lines of patient care.

7 Duke University Experience : Translational Science in Drug Development Nucleic Acid/oligonucleotide-based anticoagulants and active control agent Nucleic Acid/oligonucleotide-based anticoagulants and active control agent Oligonucleotide-based platelet antagonists Oligonucleotide-based platelet antagonists Universal nucleic acid antidotes Universal nucleic acid antidotes

8 What is an Aptamer ? What is an Aptamer ? n Aptamers (latin : aptus, to fit or attach to) are single-stranded nucleic acids that inhibit a selected target proteins function by folding into a specific 3-D structure.

9 Aptamers: A Unique Class of Direct Protein Antagonists Aptamers: A Unique Class of Direct Protein Antagonists SELEX TM Tuerk and Gold. Science 1990.

10 Monoclonal Antibody Aptamer Antidote Aptamer Aptamer-antidote Pairs Aptamers Encode their Own Antidotes DCRI/ Regado Biosciences

11 Anti-FIXa Aptamer Candidate Development White = 2′F Blue= 2′OH Stem 1 Loop 1 Stem 2 Loop 2 A—U G—C U—A A—U G—U C—G G—C C C C C C U U U U A A A A G 5′PEG— —idT 3′ Project Goals Eliminate manufacturing challenges in Stem 1 Stabilize backbone Reduce size Reduce 2’F content Maintain potency of drug and reversal agent Project Plan Optimize 2°structural elements in a step-wise fashion Substitute 2’F and 2’OH with 2’OMe Assess impact using activity assays RB002

12 Neutralization of PD Effect Injection of Antidote (RB007) at 3 Hours 1.0 Dyke C et al. Circulation 2006: 114:

13 Drug (RB006) Followed By Antidote (RB007): Regado Phase 1B Drug (RB006) Followed By Antidote (RB007): Regado Phase 1B APTT Sec APTT Sec Chan M et al. Circulation 2008;117:

14 Regado IC: Repeat RB006/RB007 Dosing Regado IC: Repeat RB006/RB007 Dosing Chan M et al. J Thromb Haemost 2008:6:

15 Regado 1C: Effect of Antidote De-escalation Regado 1C: Effect of Antidote De-escalation Chan M et al. J Thromb Haemost 2008;6:

16 Combined IA and IB Pharmacodynamic Model Combined IA and IB Pharmacodynamic Model Chan M et al. J Thromb Haemost 2008;6:

17 PCI Pilot – Reversal PCI PCI Pilot – Reversal PCI Stable CAD pts undergoing PCI All on ASA and Clopidogrel preload (>6hs) Roll-in Phase: 2 patients Reg 1 system + Eptifibatide RB007:RB006 (0.2:1) Arm 1: 12 patients 5:1 randomization Heparin vs. Reg1 w/partial reversal RB007:RB006 (0.2:1) Arm 1: 12 patients 5:1 randomization Heparin vs. Reg1 w/complete reversal Complete 4 hs Sheath Pull Immediate Complete Reversal  Sheath Pull Complete 4 hs Sheath Pull Safety Committee Review RB006 dose: 1mg/kg in all subjects RB007:RB006 (1.8:1) RB007:RB006 (2.0:1)

18 Arm 1: Partial Reversal Arm 2: Total Reversal Activated Clotting Time (seconds) Control: UFH Baseline5 min Post Study Drug 15 min Post Study Drug End of PCI 15 min post 1 st RB007 Dose 15 min post 2 nd RB007 Dose Pharmacodynamics – Phase 2a Pharmacodynamics – Phase 2a Stable and Predictable Anticoagulation Cohen M et al.. Circulation 2010;122:

19 Dose selection for Phase 2B-RADAR Dose selection for Phase 2B-RADAR Povsic T et al. J Thromb Thrombolysis 2011;32:

20 Pegnivacogin 1 mg/kg n = 479 Pegnivacogin 1 mg/kg n = 479 Heparin n = 161 Heparin n = % Reversal n = % Reversal n = % Reversal n = % Reversal n = % Reversal n = 41 25% Reversal n = 41 Open Label Randomize Femoral Access 100% Reversal n = % Reversal n = 210 Standard Care n = 161 Standard Care n = 161 NSTE-ACS N = 640 Planned Catheterization < 24 h NSTE-ACS N = 640 Planned Catheterization < 24 h RADAR Final Enrollment Blinded Anivamersen Reversal Immediate Sheath Removal Povsic T Et al.. Eur Heart J Aug 2,2012.

21 RADAR PK PD Substudy RADAR PK PD Substudy Povsic T et al. Eur Heart J 2011;32:

22 RADAR: Bleeding Bleeding,% Povsic T et al. Eur Heart J Aug 2,2012.

23 REG1 25% n=40 REG1 50% n=116 REG1 75% n=119 REG1 100% n=198 REG1 Overall n=473 Heparin n=161 n(%)n n n n n Composite 3(7.5)1(0.9)6(5.0)5(2.5)15(3.2)9(5.6) Death 0-0-1(0.8)0-1(0.2)1(0.6) MI3(7.5)1(0.9)5(4.2)4(2.0)13(2.7)7(4.3) Urg TVR1(2.5)0-1(0.8)1(0.5)3(0.6)1 RADAR: Ischemic Events Povsic T et al. Eur Heart J Aug 2, 2012.

24 Aptamer [1µM] Closing Time (sec) Sel2 library VWF R9.3 >300>300 VWF R VWF R9.14 >300>300 VWF Aptamers R9.3 and R9.14 Inhibit Platelet Function VWF Aptamers R9.3 and R9.14 Inhibit Platelet Function Oney S et al. Oligonucleotides 2007;17:

25 Binding Site Characterization of VWF Aptamers Binding Site Characterization of VWF Aptamers Oney S et al. Oligonucleotides 2007:17:

26 AO6 Inhibits VWF R9.14 Binding To VWF AO6 Inhibits VWF R9.14 Binding To VWF Oney S et al. Oligonucleotides 2007:17:

27 VWF Aptamer and Murine Carotid Injury VWF Aptamer and Murine Carotid Injury Nimjee S et al. Mol Therapy 2011

28 Universal Antidotes for VWF Aptamer Universal Antidotes for VWF Aptamer CDP and VWF Aptamer PDA-DPA and VWF Aptamer Oney S et al. Nature Medicine Oct 4, 2009.

29 Extracellular DNA Traps and Thrombosis Extracellular DNA Traps and Thrombosis Fuchs. PNAS 2010;107:

30 NIH/ NHLBI U54 Grant 2012 NIH/ NHLBI U54 Grant 2012

31 Translational Science Improvement of human health through scientific discoveries that are subsequently translated into practical applications. Basic Science Bedside Community T2 T1

32 Translational Medicine Quality Framework


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