20090417

Post-MI Alginate to Prevent Post-MI Alginate to Prevent RemodellingRemodelling

Mitchell W. Krucoff Mitchell W. Krucoff MDMD

FACC, FAHA, FSCAIFACC, FAHA, FSCAI

Professor of Medicine / CardiologyProfessor of Medicine / Cardiology

Duke University Medical CenterDuke University Medical Center

Director, Cardiovascular Devices UnitDirector, Cardiovascular Devices Unit

Duke Clinical Research InstituteDuke Clinical Research Institute

20090417

ConflictsConflicts

Research Grants & Consulting:Research Grants & Consulting: IkariaIkaria MedtronicMedtronic Abbot VascularAbbot Vascular

50 years of Mortality reduction in stemi

• 1960-1978: CCU observation: 20-25%

• 1978-1998: Thrombolytics: 10-15%

• 1998-2004: Direct PCI: <10%

• 2005-2011: DTBT < 5%

3

30%

15%

1980 201020001990

STEMI SURVIVORS STILL HAVE BIG MI’S

• Late presentations• Rural presentations • Reperfusion “injury”

– Microvascular obstruction

– Cellular toxicity

4Yellon D et al, N Engl J Med 2007;357:1121-35Yellon D et al, N Engl J Med 2007;357:1121-35

Elderly: growing survivor populationLittle knowledge, much morbidity

5Circulation. 2007;115:2570-2589

“Heart failure and pulmonary edema, complications along this spectrum of adverse occurrences, occur inmore than half of patients 75 years and 65% of patients 85 years of age.”

Post-MI Lv dilatation

3 decades of signal

6

50 100 150 200

15

10

5

1

Rela

tive R

isk

Normal End-Systolic

Volume SD End-Systolic Volume, ml

End-Systolic Volume Post-MI:Mortality risk

White et al. Circulation. 1987;76:44

20090417

Baseline LVIDD and All Cause Mortality

Wong M et al. J Am Coll Cardiol. 2002;40:970−975.

Months

1.0

0.9

0.8

0.7

0.6

0 4 8 12 16 20 24 28 32

Q1

Q2

Q3

Q4

LVIDDP

rop

ort

ion

Alive

P < 0.00001

20090417

Therapies for Established Post-MI LV dilatation:Therapies for Established Post-MI LV dilatation:Treating Established HF & ArrhythmiasTreating Established HF & Arrhythmias

CHF meds:CHF meds: Afterload reducersAfterload reducers Preload reducersPreload reducers Diuretics/nitratesDiuretics/nitrates

CRTCRT

VADsVADs

TransplantationTransplantation

Cell therapyCell therapy

20090417

Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629UCSD

Biomaterials to Reverse or Prevent LV DilatationBiomaterials to Reverse or Prevent LV Dilatation

20090417

Biomaterials For MI Treatment:Biomaterials For MI Treatment:Post-MI LV remodellingPost-MI LV remodelling

LV restraintsLV restraints

Epicardial patchesEpicardial patches

Injectable therapiesInjectable therapies

Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629

20090417

Injectable BiomaterialsInjectable Biomaterials

Mechanisms:Mechanisms: Cell delivery vehiclesCell delivery vehicles Bio-degradable: Bio-degradable:

material degradation material degradation allowing for cell allowing for cell infiltrationinfiltration

Inherent bioactivityInherent bioactivity

Gelation with Gelation with percutaneous deliverypercutaneous delivery:: AlginateAlginate Myocardial matrix Myocardial matrix

Outcome objectives:Outcome objectives: Prevent remodellingPrevent remodelling Improve EfxImprove Efx Reduce MI sizeReduce MI size Increase Increase

neovascularizationneovascularization

Rane AA et al, J. Am. Coll. Cardiol. 2011;58;2615-2629

20090417

Injectable Alginate: Injectable Alginate: Seaweed derived polysaccharideSeaweed derived polysaccharide

Gelation scaffold in MI zoneGelation scaffold in MI zone

Enhance scar thicknessEnhance scar thickness

Bioabsorbable material (>6 months)Bioabsorbable material (>6 months)

Pre-clinical:Pre-clinical: Porcine 1 week post-MIPorcine 1 week post-MI Rodent 1 week post-MIRodent 1 week post-MI

Prevent LV remodelling/dilatation/EDVIPrevent LV remodelling/dilatation/EDVI

FIM Clinical IRA injection in acute STEMIFIM Clinical IRA injection in acute STEMI

Mukherjee R et al Ann Thorac Surg 2008;86:1268 –77Landa N et al Circulation 2008;117:1388 –96

BioLineRx L. Safety and Feasibility of the Injectable BL-1040 Implant. Study NCT00557531, 2009. Available at: http:// www.ClinicalTrials.gov. Accessed March 19, 2012

Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute

Myocardial Infarction

PRESERVATION 1: A Study of IK5001 Bioabsorbable Cardiac Matrix (BCM) After Large

STEMI

Mechanistic assumption: Calcium concentration in sub-acute MI zone will activate alginate cross-linking sufficient to provide structural resistance to post-MI LV remodelling over 6 months prior to bio-absorption

Clinical Hypothesis: Sub-selective infusion of IK5001 BCM will prevent LV remodelling and associated functional debility and heart failure following “big” MIs.

16

PRESERVATION I: Operations• Study Co-PIs: Sunil Rao MD, Uwe Zeimer MD

• Study Chair: Mitchell Krucoff MD

• DSMC Chair: E. Magnus Ohman MD

• Study Sponsor: Ikaria

• Data Center: Duke Clinical Research Institute (DCRI)

• Echo Core Lab: DCRI (Pam Douglas MD)

• Angio Core Lab: Perfuse (Michael Gibson MD)

PRESERVATION I: Design• Multicenter, 2:1 randomized, double blind, placebo controlled‑

• 306 “Big MI” STEMI patients

• 60 sites: EU, Australia, Canada, Middle East, USA

• Dedicated 3-7 day post-MI deployment procedure:

– 4 cc sub-selective IRA-IC IK5001 BCM infusion over 30 seconds

• Mechanistic primary endpoint:

– LV End-diastolic dimension index by 3-D echo

• Secondary endpoint: new onset CHF

IN-HOSPITAL PROTOCOL

Successful Index PCI For STEMI

Day 0

Screening

ConsentSPECT/MRIEcho, ECG6 min walk

KCCQNYHA classNT-Pro-BNP

Labs, UA

DeploymentProcedure(Index visit)

Day 2-5

Coronary angioRandomization

24-hr ECGCKMB

PK sample

Post-Deployment

Coronary angio24-hr ECG

EchoLabs incl. CKMB

Discharge

Clinical outcomesUrinalysisPK sample

Randomize3 second sub-selective IK5001 BCM deployment into IRA

“Big MI” criteriaConsent

POST-DISCHARGE PROTOCOL

1-month± 3 d

EchoECG

KCCQ6-min walk

NYHA ClassNT-Pro-BNP

LabsPK Sample

3 months± 7d

6 months± 14d

EchoECG

KCCQ6-min walk

NYHA ClassNT-Pro-BNP

LabsPK Sample

EchoECG

KCCQ6-min walk

NYHA ClassNT-Pro-BNP

LabsHealthcare Utilization and

Clinical outcomes

12 months± 14d

EchoKCCQ

6-min walkNYHA Class

Healthcare Utilization and Clinical outcomes

Primary Endpoint

Key Inclusion Criteria3-5 day “Big” MI after Successful Acute STEMI PCI

• “Big” MI defined as:

– Peak cardiac enzyme value within 48 hours of symptom onset as follows:

• Creatine kinase MB fraction (CK-MB) > 30x the upper limit of normal OR

• Troponin I > 200x upper limit of normal OR

• Troponin T > 60x the upper limit of normal

– AND at least 1 of the following 3 criteria:• Delayed presentation with PCI > 6 hours from onset of symptoms• Significant new Q waves in ≥ 2 anterior leads or anterior ST segment

elevation of at least 3 mm persistent at 24 hours after PCI• New onset of congestive heart failure (CHF) (Killip class 3-4) or

cardiogenic shock persistent at 24 hours after PCI– AND at least 1 of the following 2 criteria:

• MI ≥ 20% by Single Photon Emission Computed Tomography scan (SPECT) or cardiac MRI with defect in the appropriate distribution

• Ejection fraction ≤ 35% at baseline imaging assessment with wall motion abnormality in the appropriate distribution

20090417

Conclusion: Conclusion: Injectables To Prevent LV DilatationInjectables To Prevent LV Dilatation Many challenges remainMany challenges remain

Stiffness vs. elasticityStiffness vs. elasticity

Optimal degradation rateOptimal degradation rate

Inflammatory responseInflammatory response

Stand-alone vs. Stand-alone vs. cell/compound loadedcell/compound loaded

Timing & modality of Timing & modality of administrationadministration

Endpoint selection:Endpoint selection: ImagingImaging Ventricular twist modelsVentricular twist models Electro-mechanical modelsElectro-mechanical models

Human studiesHuman studies

PRESERVATION I:•First RCT in human subjects•Challenges:

• Timely “Big” MI definition• Optimal imaging F/U• Assessment of HF prevention

20090417

Post-MI Alginate to Prevent Post-MI Alginate to Prevent RemodellingRemodelling

Mitchell W. Krucoff Mitchell W. Krucoff MDMD

FACC, FAHA, FSCAIFACC, FAHA, FSCAI

Professor of Medicine / CardiologyProfessor of Medicine / Cardiology

Duke University Medical CenterDuke University Medical Center

Director, Cardiovascular Devices UnitDirector, Cardiovascular Devices Unit

Duke Clinical Research InstituteDuke Clinical Research Institute