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Translational Science in Drug Development A Clinician-Scientist Perspective

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. Career Development. Personal Development

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Translational Science in Drug Development A Clinician-Scientist Perspective

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

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

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

  4. Translational Science in Drug Development • Translational Science - Definitions • NIH Initiatives • 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) • Captivate, advance and nurture a cadre of well-trained multi-and inter-disciplinary investigators and research teams; • Create an incubator for innovative research tools and information technologies; and • 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 • Oligonucleotide-based platelet antagonists • Universal nucleic acid antidotes

  8. What is an Aptamer ? • 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 SELEXTM Tuerk and Gold. Science 1990.

  10. Aptamer-antidote PairsAptamers Encode their Own Antidotes Aptamer MonoclonalAntibody Antidote Aptamer Aptamer Aptamer DCRI/ Regado Biosciences

  11. Anti-FIXa Aptamer Candidate Development 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 A U G A U C Loop 2 G—U C—G G—C Stem 2 C C A U C A Loop 1 U C A—U G—C G—C G—C G—C U—A A—U White = 2′F Blue= 2′OH Stem 1 —idT 3′ 5′PEG—

  12. Neutralization of PD Effect Injection of Antidote (RB007) at 3 Hours 1.0 Dyke C et al. Circulation 2006: 114: 2490-2497.

  13. Drug (RB006) Followed By Antidote (RB007): Regado Phase 1B APTT Sec Chan M et al. Circulation 2008;117:2865-2874.

  14. Regado IC: Repeat RB006/RB007 Dosing Chan M et al. J Thromb Haemost 2008:6:789-796.

  15. Regado 1C: Effect of Antidote De-escalation Chan M et al. J Thromb Haemost 2008;6:789-796.

  16. Combined IA and IB Pharmacodynamic Model Chan M et al. J Thromb Haemost 2008;6:789-796

  17. 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)

  18. Pharmacodynamics – Phase 2a 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 Cohen M et al.. Circulation 2010;122:614-622.

  19. Dose selection for Phase 2B-RADAR Povsic T et al. J Thromb Thrombolysis 2011;32:21-31..

  20. RADAR Final Enrollment NSTE-ACS N = 640 Planned Catheterization < 24 h Open Label Pegnivacogin 1 mg/kg n = 479 Randomize Femoral Access Heparin n = 161 Blinded Anivamersen Reversal Immediate Sheath Removal 25% Reversal n = 41 50% Reversal n = 117 75% Reversal n = 120 100% Reversal n = 210 Standard Care n = 161 Povsic T Et al.. Eur Heart J Aug 2,2012.

  21. RADAR PK PD Substudy Povsic T et al. Eur Heart J 2011;32:2412-2419.

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

  23. RADAR: Ischemic Events Povsic T et al. Eur Heart J Aug 2, 2012.

  24. VWF Aptamers R9.3 and R9.14 Inhibit Platelet Function Oney S et al. Oligonucleotides 2007;17:265-274.

  25. Binding Site Characterization of VWF Aptamers Oney S et al. Oligonucleotides 2007:17:265-274.

  26. AO6 Inhibits VWF R9.14 Binding To VWF Oney S et al. Oligonucleotides 2007:17:265-274.

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

  28. 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 Fuchs. PNAS 2010;107:15880-15885.

  30. 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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