Translational Science in Translational Science in Drug Development Drug Development A Clinician-Scientist A Clinician-Scientist Perspective Perspective Richard C. Becker, MD Richard C. Becker, MD Professor of Medicine Professor of Medicine Duke University School of Medicine Duke University School of Medicine Duke Cardiology GR, 2012
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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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Translational Science in Drug Translational Science in Drug DevelopmentDevelopment
A Clinician-Scientist PerspectiveA Clinician-Scientist Perspective
Richard C. Becker, MDRichard C. Becker, MD
Professor of MedicineProfessor of Medicine
Duke University School of MedicineDuke University School of Medicine
Duke Cardiology GR, 2012
Career DevelopmentCareer Development
• Personal DevelopmentPersonal Development
Evolution informed by :experience within a Evolution informed by :experience within a field of interest, mentorship, progress, field of interest, mentorship, progress, success and integration.success and integration.
• Organizational DevelopmentOrganizational Development
Mentors, Peers and Collaborators**Mentors, Peers and Collaborators**
• Helen Berry, PhDHelen Berry, PhD
• Richard Bozian, MDRichard Bozian, MD
• Fred Lucas, MDFred Lucas, MD
• James Weick, MDJames Weick, MD
• Joseph Alpert, MDJoseph Alpert, MD
• Desire Collen, MD, PhDDesire Collen, MD, PhD
• Ted Bovill, MDTed Bovill, MD
• Bruce Sullenger, PhDBruce Sullenger, PhD
Partial list**
Translational Science in Drug DevelopmentTranslational Science in Drug Development
• Nucleic Acids/oligonucleotides: A Duke Nucleic Acids/oligonucleotides: A Duke University Medical Center ExperienceUniversity Medical Center Experience
Translational ScienceTranslational Science
Improvement of human health through scientific discoveries that are subsequently
translated into practical applications.
Basic Science Bedside Community
T2T1
National Institutes of Health InitiativesNational Institutes of Health Initiatives
1.1.Captivate, advance and nurture a cadre of well-Captivate, advance and nurture a cadre of well-trained multi-and inter-disciplinary investigators and trained multi-and inter-disciplinary investigators and research teams; research teams;
2.2.Create an incubator for innovative research tools Create an incubator for innovative research tools and information technologies; and and information technologies; and
3.3.Synergize multi-disciplinary clinical and translational Synergize multi-disciplinary clinical and translational research and researchers to catalyze the application research and researchers to catalyze the application of new knowledge and techniques to clinical practice of new knowledge and techniques to clinical practice at the front lines of patient care. at the front lines of patient care.
Duke University Experience : Translational Duke University Experience : Translational Science in Drug Development Science in Drug Development
• Nucleic Acid/oligonucleotide-based Nucleic Acid/oligonucleotide-based anticoagulants and active control agentanticoagulants and active control agent
Aptamers (Aptamers (latin : aptus, to fit or attach tolatin : aptus, to fit or attach to) are ) are single-stranded nucleic acids that inhibit a single-stranded nucleic acids that inhibit a selected target proteins function by folding into selected target proteins function by folding into a specific 3-D structure.a specific 3-D structure.
Aptamers: A Unique Class ofAptamers: A Unique Class of Direct Protein Antagonists Direct Protein Antagonists
SELEXTM
Tuerk and Gold. Science 1990.
MonoclonalAntibody
AptamerAptamer
Aptamer
Antidote
Aptamer
Aptamer-antidote PairsAptamer-antidote PairsAptamers Encode their Own AntidotesAptamers Encode their Own Antidotes
DCRI/ Regado Biosciences
Anti-FIXa Aptamer Candidate DevelopmentAnti-FIXa Aptamer Candidate Development
White = 2′FBlue= 2′OHStem 1
Loop 1
Stem 2
Loop 2
A—UG—CG—CG—CG—CU—AA—U
G—UC—GG—C
C
C
C
C
C
U
U
U
U
A
A
A
AG
5′PEG— —idT 3′
Project GoalsEliminate manufacturing challenges in Stem 1Stabilize backboneReduce sizeReduce 2’F contentMaintain potency of drug and reversal agent
Project PlanOptimize 2°structural elementsin a step-wise fashionSubstitute 2’F and 2’OH with 2’OMeAssess impact using activityassays
RB002
Neutralization of PD Effect Neutralization of PD Effect Injection of Antidote (RB007) at 3 HoursInjection of Antidote (RB007) at 3 Hours
1.0
Dyke C et al. Circulation 2006: 114: 2490-2497.Dyke C et al. Circulation 2006: 114: 2490-2497.
Drug (RB006) Followed By Antidote Drug (RB006) Followed By Antidote (RB007): Regado Phase 1B(RB007): Regado Phase 1B
APTT
Sec
APTT
Sec
Chan M et al. Circulation 2008;117:2865-2874.Chan M et al. Circulation 2008;117:2865-2874.