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

• Translational Science - DefinitionsTranslational Science - Definitions

• NIH InitiativesNIH Initiatives

• 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

Clinical Translational Science AwardsClinical Translational Science Awards

(October 2006)(October 2006)

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

• Oligonucleotide-based platelet antagonistsOligonucleotide-based platelet antagonists

• Universal nucleic acid antidotesUniversal nucleic acid antidotes

What is an Aptamer ?What is an Aptamer ?

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.

Regado IC: Repeat RB006/RB007 DosingRegado IC: Repeat RB006/RB007 Dosing

Chan M et al. J Thromb Haemost 2008:6:789-796.Chan M et al. J Thromb Haemost 2008:6:789-796.

Regado 1C: Effect of Antidote De-escalationRegado 1C: Effect of Antidote De-escalation

Chan M et al. J Thromb Haemost 2008;6:789-796.

Chan M et al. J Thromb Haemost 2008;6:789-796.

Combined IA and IB Pharmacodynamic ModelCombined IA and IB Pharmacodynamic Model

Chan M et al. J Thromb Haemost 2008;6:789-796

PCI Pilot – Reversal PCIPCI Pilot – Reversal PCIStable CAD pts undergoing PCI

All on ASA and Clopidogrel preload (>6hs)Stable CAD pts undergoing PCI

All on ASA and Clopidogrel preload (>6hs)

Roll-in Phase: 2 patientsReg 1 system + Eptifibatide

RB007:RB006 (0.2:1)

Roll-in Phase: 2 patientsReg 1 system + Eptifibatide

RB007:RB006 (0.2:1)

Arm 1: 12 patients5:1 randomization

Heparin vs. Reg1 w/partial reversalRB007:RB006 (0.2:1)

Arm 1: 12 patients5:1 randomization

Heparin vs. Reg1 w/complete reversal

Complete Reversal @ 4 hsSheath Pull

Immediate Complete Reversal Sheath Pull

Complete Reversal @ 4 hsSheath Pull

Safety Committee Review

RB006 dose:1mg/kg in all subjects

RB007:RB006 (1.8:1)RB007:RB006 (1.8:1)

RB007:RB006 (1.8:1)RB007:RB006 (1.8:1)

RB007:RB006 (2.0:1)RB007:RB006 (2.0:1)

Arm 1:Partial

Reversal

Arm 2: Total

Reversal

Acti

vate

d C

lott

ing

Tim

e (

secon

ds)

150

250

200

300

350

Control: UFH

Baseline 5 min PostStudy Drug

15 min PostStudy Drug

End of PCI 15 min post 1st RB007

Dose

15 min post2nd RB007 Dose

Pharmacodynamics – Phase 2aPharmacodynamics – Phase 2a Stable and Predictable Anticoagulation

Cohen M et al.. Circulation 2010;122:614-622.

Dose selection for Phase 2B-RADARDose selection for Phase 2B-RADAR

Povsic T et al. J Thromb Thrombolysis 2011;32:21-31..

Pegnivacogin

1 mg/kg

n = 479

Pegnivacogin

1 mg/kg

n = 479

Heparin

n = 161

Heparin

n = 161

75% Reversal

n = 120

75% Reversal

n = 120

50% Reversal

n = 117

50% Reversal

n = 117

25% Reversal

n = 41

25% Reversal

n = 41

Open Label

Randomize

Femoral Access

100% Reversal

n = 210

100% 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.

RADAR PK PD SubstudyRADAR PK PD Substudy

Povsic T et al. Eur Heart J 2011;32:2412-2419.

RADAR: BleedingRADAR: BleedingB

leed

ing

,%

Povsic T et al. Eur Heart J Aug 2,2012.

REG125%n=40

REG150%

n=116

REG175%

n=119

REG1100%n=198

REG1Overalln=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)

MI 3 (7.5) 1 (0.9) 5 (4.2) 4 (2.0) 13 (2.7) 7 (4.3)

Urg TVR 1 (2.5) 0 - 1 (0.8) 1 (0.5) 3 (0.6) 1 (0.6)

RADAR: Ischemic EventsRADAR: Ischemic Events

Povsic T et al. Eur Heart J Aug 2, 2012.

Aptamer Aptamer [1µM][1µM]

Closing Time Closing Time (sec)(sec)

Sel2 librarySel2 library104104

9696

VWF R9.3VWF R9.3>300>300

>300>300

VWF R9.4VWF R9.4106106

9797

VWF R9.14VWF R9.14>300>300

>300>300

0

100

200

300

VWF Aptamers R9.3 and R9.14 Inhibit Platelet VWF Aptamers R9.3 and R9.14 Inhibit Platelet Function Function

Oney S et al. Oligonucleotides 2007;17:265-274.

Binding Site Characterization of VWF Binding Site Characterization of VWF AptamersAptamers

Oney S et al. Oligonucleotides 2007:17:265-274.

AO6 Inhibits VWF R9.14 Binding To VWFAO6 Inhibits VWF R9.14 Binding To VWF

Oney S et al. Oligonucleotides 2007:17:265-274.

VWF Aptamer and Murine Carotid InjuryVWF Aptamer and Murine Carotid Injury

0 20 40 600.0

0.5

1.0

1.5

2.0

Time (min)

Tra

nsit

tim

e (

ml/m

in)

Nimjee S et al. Mol Therapy 2011

Universal Antidotes for VWF AptamerUniversal Antidotes for VWF Aptamer

0

100

200

300

0

100

200

300

CDP and VWF Aptamer PDA-DPA and VWF Aptamer

Oney S et al. Nature Medicine Oct 4, 2009.

Extracellular DNA Traps and ThrombosisExtracellular DNA Traps and Thrombosis

Fuchs. PNAS 2010;107:15880-15885.

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

Translational ScienceTranslational Science

Improvement of human health through scientific discoveries that are subsequently

translated into practical applications.

Basic Science Bedside CommunityT2T1

Translational Medicine Quality FrameworkTranslational Medicine Quality Framework