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PROTECTION AMI PROTECTION AMI ion of ion of -Protein Kinase C for Reduction of -Protein Kinase C for Reduction of Size in Acute Myocardial Infarction Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. A. Michael Lincoff, M.D. Director, C5Research Director, C5Research (Cleveland Clinic Coordinating (Cleveland Clinic Coordinating Center for Clinical Research) Center for Clinical Research) Vice Chairman for Clinical Vice Chairman for Clinical Research, Research, Lerner Research Institute Lerner Research Institute Vice Chairman of Cardiovascular Vice Chairman of Cardiovascular Medicine Medicine Professor of Medicine Professor of Medicine Heart and Heart and Vascular Vascular Institute Institute Late Breaking Clinical Trials – ACC 2011 Late Breaking Clinical Trials – ACC 2011

PROTECTION AMI Inhibition of -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

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Page 1: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

PROTECTION AMIPROTECTION AMIInhibition of Inhibition of -Protein Kinase C for Reduction of Infarct-Protein Kinase C for Reduction of Infarct

Size in Acute Myocardial InfarctionSize in Acute Myocardial Infarction

A. Michael Lincoff, M.D.A. Michael Lincoff, M.D.

Director, C5ResearchDirector, C5Research(Cleveland Clinic Coordinating Center for (Cleveland Clinic Coordinating Center for

Clinical Research)Clinical Research)

Vice Chairman for Clinical Research,Vice Chairman for Clinical Research,Lerner Research InstituteLerner Research Institute

Vice Chairman of Cardiovascular MedicineVice Chairman of Cardiovascular Medicine

Professor of MedicineProfessor of Medicine

Heart and Vascular Heart and Vascular InstituteInstitute

Late Breaking Clinical Trials – ACC 2011Late Breaking Clinical Trials – ACC 2011

Page 2: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

AntheraAnthera AstraZenecaAstraZeneca AtherosysAtherosys Bristol-Myers Squibb (BMS)Bristol-Myers Squibb (BMS) CentocorCentocor CordisCordis GuidantGuidant HeartscapeHeartscape J&JJ&J KAI PharmaKAI Pharma LillyLilly MannkindMannkind Medicines CompanyMedicines Company

MedtronicMedtronic NovartisNovartis Novo NordiskNovo Nordisk PfizerPfizer ResverlogixResverlogix Roche / GenentechRoche / Genentech SankyoSankyo Sanofi-AventisSanofi-Aventis Schering-PloughSchering-Plough SciosScios TakedaTakeda VasoGenixVasoGenix

Speaker Disclosure – A. Michael Lincoff, MDSpeaker Disclosure – A. Michael Lincoff, MDRelationships with Industry Research Sponsors Relationships with Industry Research Sponsors

ConsultantConsultant

Schering-PloughSchering-Plough BiolineBioline BMSBMS MerckMerck BaxterBaxter Aztra ZenecaAztra Zeneca RocheRoche

Page 3: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

PKC in Ischemia-Reperfusion InjuryPKC in Ischemia-Reperfusion Injury

activated in a variety of human, rodent and pig cells activated in a variety of human, rodent and pig cells exposed to ischemic conditions exposed to ischemic conditions in vitro in vitro andand in vivo in vivo

during reperfusion, activated during reperfusion, activated PKC translocates to the PKC translocates to the mitochondria and mediates necrosis and apoptosismitochondria and mediates necrosis and apoptosis

PKC KO mice have reduced free radical production PKC KO mice have reduced free radical production from endothelial cells and decreased damage following from endothelial cells and decreased damage following cardiac ischemia, and reduced infarct size after stroke.cardiac ischemia, and reduced infarct size after stroke.

PKC Activation in Response to IR InjuryPKC Activation in Response to IR Injury

Page 4: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

DelcasertibDelcasertib

Peptide Inhibitor of PKC Localization - Selective InhibitorPeptide Inhibitor of PKC Localization - Selective Inhibitor

• disrupts binding of activated disrupts binding of activated PKC with its RACK (Receptor for PKC with its RACK (Receptor for Activated C-Kinase)Activated C-Kinase)

• reaches steady state within 5 - 30 minutes after the start of infusion, reaches steady state within 5 - 30 minutes after the start of infusion, terminal Tterminal T1/21/2 of 2 to 5 minutes of 2 to 5 minutes

• well-tolerated across range of doseswell-tolerated across range of doses

Animal Models:Animal Models:

• reduced infarct size, myocyte and endothelial reduced infarct size, myocyte and endothelial cellular damagecellular damage

• enhanced recovery of myocardial metabolic enhanced recovery of myocardial metabolic activity and regional LV functionactivity and regional LV function

• improved infarct zone microvascular flowimproved infarct zone microvascular flow

Ikeno F et al. Cardiovasc Res 2007;73:699-709Ikeno F et al. Cardiovasc Res 2007;73:699-709

Page 5: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

DELTA MI TrialDELTA MI Trial

Intracoronary Delcasertib in 1o PCI for Anterior STEMIDose Escalation Phase 1/2 Trial – 154 Evaluable Patients

Intracoronary Delcasertib in 1o PCI for Anterior STEMIDose Escalation Phase 1/2 Trial – 154 Evaluable Patients

Roe MT et al. Circulation 2008 117: 857-859 Roe MT et al. Circulation 2008 117: 857-859

0.05 mg 0.5 mg 1.25 mg 5.0 mg Concurrent Placebo0.05 mg 0.5 mg 1.25 mg 5.0 mg Concurrent Placebo

55496459

5185 56516956

8540 8914

10822

0

2000

4000

6000

8000

10000

12000

0.05 mg 0.5 mg 1.25 mg 5.0 mg

ST

AU

C (

uV

/min

)

55496459

5185 56516956

8540 8914

10822

0

2000

4000

6000

8000

10000

12000

0.05 mg 0.5 mg 1.25 mg 5.0 mg

ST

AU

C (

uV

/min

)

4001

52265740

6662

4858

69347352

8230

0

3000

6000

9000

0.05 mg 0.5 mg 1.25 mg 5.0 mg

CK

-MB

AU

C (

ng

/ml/m

in)

4001

52265740

6662

4858

69347352

8230

0

3000

6000

9000

0.05 mg 0.5 mg 1.25 mg 5.0 mg

CK

-MB

AU

C (

ng

/ml/m

in)

CK-MB AUCCK-MB AUC ST Recovery AUCST Recovery AUC

Page 6: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Inhibition of δ-PROTEin kinase C for the reducTION of infarct size in Acute Myocardial Infarction (PROTECTION AMI)

Inhibition of δ-PROTEin kinase C for the reducTION of infarct size in Acute Myocardial Infarction (PROTECTION AMI)

Study Hypothesis:Study Hypothesis:

intravenous administration of delcasertib will reduce infarct intravenous administration of delcasertib will reduce infarct size in subjects with anterior ST elevation myocardial infarction size in subjects with anterior ST elevation myocardial infarction (STEMI) undergoing primary PCI. (STEMI) undergoing primary PCI.

Delcasertib in STEMIDelcasertib in STEMI

international, multi-center Phase 2b trialinternational, multi-center Phase 2b trial

randomized, placebo-controlled, double-blind, randomized, placebo-controlled, double-blind, parallel groupparallel group

acute STEMI subjects undergoing primary PCIacute STEMI subjects undergoing primary PCI

Page 7: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Trial DesignTrial DesignInclusion and Exclusion CriteriaInclusion and Exclusion Criteria

Acute STEMI with planned primary Acute STEMI with planned primary PCIPCI

Cardiac ischemia for at least 30 Cardiac ischemia for at least 30 minutes, arriving at PCI facility minutes, arriving at PCI facility within 6 hrs of symptom onsetwithin 6 hrs of symptom onset

Persistent ST elevation of:Persistent ST elevation of:

• ≥ ≥ 2 mm in at least two contiguous 2 mm in at least two contiguous precordial leads (V1-V4) (anterior precordial leads (V1-V4) (anterior STEMI cohort) STEMI cohort)

• ≥ ≥ 2 mm in two inferior leads (II, III, 2 mm in two inferior leads (II, III, aVF) with ST depression in two aVF) with ST depression in two other contiguous leads - total ≥ 8 other contiguous leads - total ≥ 8 mm (inferior STEMI cohort) mm (inferior STEMI cohort)

x Prior CABGPrior CABG

x LBBB or paced rhythmLBBB or paced rhythm

x Persistent SBP <90 mm Hg Persistent SBP <90 mm Hg unresponsive to IV fluidsunresponsive to IV fluids

x Vasopressors or inotropesVasopressors or inotropes

x ESRD on dialysisESRD on dialysis

x Severe hepatic dysfunctionSevere hepatic dysfunction

x Fibrinolysis within prior 72 hFibrinolysis within prior 72 h

x Pregnancy or breastfeedingPregnancy or breastfeeding

x Suspicion of non-thrombotic Suspicion of non-thrombotic cause of ST elevationcause of ST elevation

Page 8: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Trial DesignTrial DesignEndpointsEndpoints

PrimaryPrimary

• CK-MB area under the curve (AUC)CK-MB area under the curve (AUC)

SecondarySecondary

• ECG – continuous 24 hr AUC and ST recoveryECG – continuous 24 hr AUC and ST recovery

• CK-MB Peak; Troponin I and CK AUC and Peak CK-MB Peak; Troponin I and CK AUC and Peak

• Clinical Events – death, heart failure (HF), or serious ventricular Clinical Events – death, heart failure (HF), or serious ventricular arrhythmia through 1 yeararrhythmia through 1 year

• Serum NT-pro-B-type natriuretic peptide level at 3 monthsSerum NT-pro-B-type natriuretic peptide level at 3 months

• LV Ejection Fraction (LVEF) by MUGA at 3 months – anterior LV Ejection Fraction (LVEF) by MUGA at 3 months – anterior STEMI cohort onlySTEMI cohort only

Page 9: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Trial DesignTrial Design

Inferior CohortInferior Cohort~150 Pts (75 per group)~150 Pts (75 per group)

Inferior CohortInferior Cohort~150 Pts (75 per group)~150 Pts (75 per group)

PlaceboPlaceboPlaceboPlacebo DelcasertibDelcasertib50 mg/hr50 mg/hr

DelcasertibDelcasertib50 mg/hr50 mg/hr

DelcasertibDelcasertib150 mg/hr150 mg/hr

DelcasertibDelcasertib150 mg/hr150 mg/hr

DelcasertibDelcasertib450 mg/hr450 mg/hr

DelcasertibDelcasertib450 mg/hr450 mg/hr PlaceboPlaceboPlaceboPlacebo DelcasertibDelcasertib

450 mg/hr450 mg/hrDelcasertibDelcasertib450 mg/hr450 mg/hr

STEMI to Undergo Planned Primary PCISTEMI to Undergo Planned Primary PCI

Anterior CohortAnterior Cohort~908 Patients (227 per group)~908 Patients (227 per group)

Anterior CohortAnterior Cohort~908 Patients (227 per group)~908 Patients (227 per group)

Randomize 1:1:1:1Randomize 1:1:1:1 Randomize 1:1Randomize 1:1

Study drug (~2.5 hr infusion) and continuous 12-lead ECG immediately after randomizationStudy drug (~2.5 hr infusion) and continuous 12-lead ECG immediately after randomization

Cardiac catheterization and PCI per standard of careCardiac catheterization and PCI per standard of care

Serial cardiac enzymes x 72 hSerial cardiac enzymes x 72 h12-lead ECG monitoring x 24 h12-lead ECG monitoring x 24 hSerial cardiac enzymes x 72 hSerial cardiac enzymes x 72 h12-lead ECG monitoring x 24 h12-lead ECG monitoring x 24 h

Clinical Endpoints, NT-Pro BNP Clinical Endpoints, NT-Pro BNP and MUGA* at 3 monthsand MUGA* at 3 months

Clinical Endpoints, NT-Pro BNP Clinical Endpoints, NT-Pro BNP and MUGA* at 3 monthsand MUGA* at 3 months

Page 10: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

StatisticsStatistics

Sample Size CalculationsSample Size Calculations

Primary analysis and sample size based upon anterior MI cohortPrimary analysis and sample size based upon anterior MI cohort• Inferior MI cohort exploratory – sample not statistically basedInferior MI cohort exploratory – sample not statistically based

Randomization stratified by region and Killip Class I vs II/IIIRandomization stratified by region and Killip Class I vs II/III

AssumptionsAssumptions

CK-MB AUC in placebo group – mean 7156, SD 4666 ng-hr/mLCK-MB AUC in placebo group – mean 7156, SD 4666 ng-hr/mL

20% reduction in mean with delcasertib20% reduction in mean with delcasertib

= 0.05 (2-sided); = 0.05 (2-sided); = 0.80 = 0.80

Target 227 patients per Rx group – total 908 in anterior cohortTarget 227 patients per Rx group – total 908 in anterior cohort

Page 11: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Academic LeadershipAcademic Leadership

Steering Committee / National CoordinatorsSteering Committee / National Coordinators

A. Michael Lincoff (PI)A. Michael Lincoff (PI)

Mitchell Krucoff (Co-PI)Mitchell Krucoff (Co-PI)

Matthew Roe, USAMatthew Roe, USA

John Galla, USAJohn Galla, USA

Phil Aylward, AustraliaPhil Aylward, Australia

Andrezej Rynkiewcz, PolandAndrezej Rynkiewcz, Poland

Victor Guetta, IsraelVictor Guetta, Israel

Micheal Zelizko, Czech RepublicMicheal Zelizko, Czech Republic

Neal Kleiman, USANeal Kleiman, USA

Tamàs Forster, HungaryTamàs Forster, Hungary

Antonio Fernández-Ortiz, SpainAntonio Fernández-Ortiz, Spain

Harry Suryapranata, NetherlandsHarry Suryapranata, Netherlands

A. Michael Lincoff (PI)A. Michael Lincoff (PI)

Mitchell Krucoff (Co-PI)Mitchell Krucoff (Co-PI)

Matthew Roe, USAMatthew Roe, USA

John Galla, USAJohn Galla, USA

Phil Aylward, AustraliaPhil Aylward, Australia

Andrezej Rynkiewcz, PolandAndrezej Rynkiewcz, Poland

Victor Guetta, IsraelVictor Guetta, Israel

Micheal Zelizko, Czech RepublicMicheal Zelizko, Czech Republic

Neal Kleiman, USANeal Kleiman, USA

Tamàs Forster, HungaryTamàs Forster, Hungary

Antonio Fernández-Ortiz, SpainAntonio Fernández-Ortiz, Spain

Harry Suryapranata, NetherlandsHarry Suryapranata, Netherlands

David Erlinge, SwedenDavid Erlinge, Sweden

Svend Eggert Jensen, DenmarkSvend Eggert Jensen, Denmark

Harvey White, New ZealandHarvey White, New Zealand

Danny Schoors, BelgiumDanny Schoors, Belgium

Peter Radke, GermanyPeter Radke, Germany

Shamir Mehta, CanadaShamir Mehta, Canada

Shaun Goodman, CanadaShaun Goodman, Canada

Dan Atar, NorwayDan Atar, Norway

Michael Laine, FinlandMichael Laine, Finland

Jorge Manuel dos Santos Jorge Manuel dos Santos Ferreira, PortugalFerreira, Portugal

Guido Belli, ItalyGuido Belli, Italy

David Erlinge, SwedenDavid Erlinge, Sweden

Svend Eggert Jensen, DenmarkSvend Eggert Jensen, Denmark

Harvey White, New ZealandHarvey White, New Zealand

Danny Schoors, BelgiumDanny Schoors, Belgium

Peter Radke, GermanyPeter Radke, Germany

Shamir Mehta, CanadaShamir Mehta, Canada

Shaun Goodman, CanadaShaun Goodman, Canada

Dan Atar, NorwayDan Atar, Norway

Michael Laine, FinlandMichael Laine, Finland

Jorge Manuel dos Santos Jorge Manuel dos Santos Ferreira, PortugalFerreira, Portugal

Guido Belli, ItalyGuido Belli, Italy

OperationsOperationsCommitteeCommittee

Page 12: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Trial OrganizationTrial Organization

Cleveland Clinic Coordinating Cleveland Clinic Coordinating Center for Clinical ResearchCenter for Clinical Research

Ellen McErlean, RN – Project MngerEllen McErlean, RN – Project Mnger

Cleveland Clinic Coordinating Cleveland Clinic Coordinating Center for Clinical ResearchCenter for Clinical Research

Ellen McErlean, RN – Project MngerEllen McErlean, RN – Project Mnger

Trial SponsorsTrial Sponsors

Gregory Bell, MD - KAIGregory Bell, MD - KAI

Fred Fiedorek, MD - BMSFred Fiedorek, MD - BMS

Trial SponsorsTrial Sponsors

Gregory Bell, MD - KAIGregory Bell, MD - KAI

Fred Fiedorek, MD - BMSFred Fiedorek, MD - BMS

CROCRO

Medpace, IncMedpace, Inc

Cincinnati, OHCincinnati, OH

Data Safety Monitoring CommitteeData Safety Monitoring Committee

Michel Bertrand, MD - ChairMichel Bertrand, MD - Chair

Christopher Cannon, MDChristopher Cannon, MD

David Holmes, MDDavid Holmes, MD

Kerry Lee, PhDKerry Lee, PhD

Michel Bertrand, MD - ChairMichel Bertrand, MD - Chair

Christopher Cannon, MDChristopher Cannon, MD

David Holmes, MDDavid Holmes, MD

Kerry Lee, PhDKerry Lee, PhD

Page 13: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

EnrollmentEnrollmentCountryCountry National CoordinatorNational Coordinator PatientsPatientsPolandPoland Prof. Andrezej Rynkiewcz Prof. Andrezej Rynkiewcz 226226IsraelIsrael Prof. Victor Guetta Prof. Victor Guetta 222222Czech RepublicCzech Republic Dr. Micheal ZelizkoDr. Micheal Zelizko 133133AustraliaAustralia Prof. Phil AylwardProf. Phil Aylward 8585United StatesUnited States Dr. Neal KleimanDr. Neal Kleiman 7777NetherlandsNetherlands Dr. Harry Suryapranata Dr. Harry Suryapranata 5353HungaryHungary Prof. Tamàs Forster Prof. Tamàs Forster 5252SpainSpain Dr. Antonio Fernández-Ortiz Dr. Antonio Fernández-Ortiz 5050SwedenSweden Prof. David ErlingeProf. David Erlinge 4949DenmarkDenmark Dr. Svend Eggert JensenDr. Svend Eggert Jensen 4545New ZealandNew Zealand Dr. Harvey White Dr. Harvey White 4545BelgiumBelgium Dr. Danny SchoorsDr. Danny Schoors 3939GermanyGermany Dr. Peter Radke Dr. Peter Radke 2828CanadaCanada Drs. Shamir Mehta/Shaun Goodman Drs. Shamir Mehta/Shaun Goodman 2323NorwayNorway Dr. Dan AtarDr. Dan Atar 2222FinlandFinland Dr. Michael LaineDr. Michael Laine 1919PortugalPortugal Dr. Jorge Manuel dos Santos Ferreira Dr. Jorge Manuel dos Santos Ferreira 1212ItalyItaly Dr. Guido Belli Dr. Guido Belli 11

1176 1176 PatientsPatients

RandomizeRandomizedd

1176 1176 PatientsPatients

RandomizeRandomizedd

EnrollmentEnrollment

Dec 4, 2008 Dec 4, 2008 June 21, 2010June 21, 2010

18 Countries18 Countries

114 Hospitals114 Hospitals

Page 14: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

EnrollmentEnrollment

Top 10 Enrolling SitesTop 10 Enrolling Sites

CountryCountry Principal InvestigatorPrincipal Investigator # Randomized# Randomized

PolandPoland Dr. Jaroslaw TrebaczDr. Jaroslaw Trebacz 6363

PolandPoland Dr. Andrzej RynkiewiczDr. Andrzej Rynkiewicz 5454

Czech RepublicCzech Republic Dr. David HorakDr. David Horak 4848

IsraelIsrael Dr. Arthur PollakDr. Arthur Pollak 3737

PolandPoland Dr. Jaroslaw WojcikDr. Jaroslaw Wojcik 3636

IsraelIsrael Dr. Jonathan BalkinDr. Jonathan Balkin 3434

DenmarkDenmark Dr. Svend Eggert JensenDr. Svend Eggert Jensen 2828

IsraelIsrael Prof. Morris MosseriProf. Morris Mosseri 2626

IsraelIsrael Prof. Yoseph RozenmanProf. Yoseph Rozenman 2525

IsraelIsrael Prof. Hanoch HodProf. Hanoch Hod 2525

AustraliaAustralia Prof. Joseph SelvanayagamProf. Joseph Selvanayagam 2525

Page 15: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Patient FlowPatient FlowAnterior STEMI CohortAnterior STEMI Cohort

Efficacy PopulationEfficacy Population

11 patients11 patientsnot treatednot treated

2 patients2 patientsPCI onlyPCI only

86 patients86 patientsno PCIno PCI

1010 patients 1010 patients randomizedrandomized

911 patients911 patientstreated withtreated with

study drug and PCIstudy drug and PCI

997 patients 997 patients treated withtreated withstudy drugstudy drug

Treated PopulationTreated Population

Efficacy PopulationEfficacy Population

5 patients5 patientsnot treatednot treated

2 patients2 patientsPCI onlyPCI only

4 patients4 patientsno PCIno PCI

166 patients 166 patients randomizedrandomized

155 patients155 patientstreated withtreated with

study drug and PCIstudy drug and PCI

159 patients 159 patients treated withtreated withstudy drugstudy drug

Treated PopulationTreated Population

Inferior STEMI CohortInferior STEMI Cohort

Page 16: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Demographics and TreatmentDemographics and TreatmentPlaceboPlacebo

N = 249N = 249

DelcasertibDelcasertib

50 mg/hr50 mg/hr

N = 254N = 254

DelcasertibDelcasertib

150 mg/hr150 mg/hr

N = 248N = 248

DelcasertibDelcasertib

450 mg/hr450 mg/hr

N = 246N = 246

Age (yrs - median, IQR)Age (yrs - median, IQR)6161

[52, 70][52, 70]6060

[53, 69][53, 69]6161

[53, 70][53, 70]5959

[52, 70][52, 70]

Male (%)Male (%) 79.579.5 78.378.3 81.081.0 79.379.3

BMI (kg/mBMI (kg/m22 - median, IQR) - median, IQR)2727

[24, 30][24, 30]2727

[24, 30][24, 30]2727

[25, 30][25, 30]2727

[25, 30][25, 30]

Diabetes (%)Diabetes (%) 17.817.8 19.419.4 16.616.6 16.716.7

Prior MI (%)Prior MI (%) 11.711.7 11.111.1 10.910.9 11.011.0

Killip 2 or 3 (%)Killip 2 or 3 (%) 8.88.8 8.78.7 8.58.5 8.98.9

Anterior MI Cohort, Treated PopulationAnterior MI Cohort, Treated Population

Page 17: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Treatment TimesTreatment Times

Time in minutesTime in minutes

Median and [IQR]Median and [IQR]

PlaceboPlacebo

N = 249N = 249

DelcasertibDelcasertib

50 mg/hr50 mg/hr

N = 254N = 254

DelcasertibDelcasertib

150 mg/hr150 mg/hr

N = 248N = 248

DelcasertibDelcasertib

450 mg/hr450 mg/hr

N = 246N = 246

Symptoms to hospital Symptoms to hospital presentationpresentation

120120[77, 188][77, 188]

120120[63, 175][63, 175]

115115[73, 185][73, 185]

120120[77, 181][77, 181]

Symptoms to study drug Symptoms to study drug initiationinitiation

173173[122, 255][122, 255]

175175[130, 244][130, 244]

171171[122, 245][122, 245]

171171[122, 230][122, 230]

Symptoms to PCISymptoms to PCI193193

[148, 272][148, 272]191191

[143, 255][143, 255]190190

[140, 275][140, 275]186186

[143, 251][143, 251]

Study drug initiation to Study drug initiation to PCIPCI

17 17 [10, 25][10, 25]

1616[9, 27][9, 27]

1717[10, 29][10, 29]

1414[9, 24][9, 24]

Anterior MI Cohort, Treated PopulationAnterior MI Cohort, Treated Population

Page 18: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

11oo Endpoint – Anterior MI Endpoint – Anterior MICK-MB Enzymes – Efficacy Population CK-MB Enzymes – Efficacy Population

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

20002000

40004000

60006000

80008000CK-MB AUC (ng-hr/ml)CK-MB AUC (ng-hr/ml)

6471647159175917

5650565062046204

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

100100

200200

300300

400400

500500CK-MB Peak (ng/ml)CK-MB Peak (ng/ml)

369369352352

337337360360

Mean and SEMp = 0.337

Mean and SEMp = 0.715

N=228 N=229 N=227 N=227 N=228 N=229 N=227 N=227

Page 19: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

ECG – Anterior MIECG – Anterior MIContinuous 24 hr ECG – Efficacy PopulationContinuous 24 hr ECG – Efficacy Population

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

20002000

40004000

60006000

80008000

1000010000ECG ST Recovery AUC (microV-min)ECG ST Recovery AUC (microV-min)

8377837777077707 77797779

81888188

Mean and SEMp = 0.420

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

2020

4040

6060

8080

100100

120120Time to Stable ST Recovery (min)Time to Stable ST Recovery (min)

9191

81817575

7070

Mean and SEMp = 0.523

Page 20: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Clinical Events – 3 MonthsClinical Events – 3 Months

EndpointEndpoint

(% of patients)(% of patients)

PlaceboPlacebo

N = 249N = 249

DelcasertibDelcasertib

50 mg/hr50 mg/hr

N = 254N = 254

DelcasertibDelcasertib

150 mg/hr150 mg/hr

N = 248N = 248

DelcasertibDelcasertib

450 mg/hr450 mg/hr

N = 246N = 246

Death, shock, CHF, or Death, shock, CHF, or arrhythmiaarrhythmia

8.88.8 8.78.7 8.98.9 7.37.3

Death, shock, CHFDeath, shock, CHF 8.48.4 8.38.3 8.58.5 6.56.5

DeathDeath 3.23.2 3.93.9 4.04.0 2.42.4

Cardiogenic shockCardiogenic shock 3.63.6 2.42.4 3.23.2 0.80.8

CHFCHF 4.44.4 3.93.9 2.82.8 4.54.5

Ventricular arrhythmiaVentricular arrhythmia 1.21.2 0.80.8 0.40.4 1.61.6

Anterior MI Cohort, Treated PopulationAnterior MI Cohort, Treated Population

Page 21: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

MUGA and NT-Pro BNP MUGA and NT-Pro BNP

Anterior MI Cohort, Efficacy PopulationAnterior MI Cohort, Efficacy Population

3 Month Outcome3 Month Outcome

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

2020

4040

6060

8080

100100LV Ejection Fraction (%)LV Ejection Fraction (%)

50.750.7 51.051.0 49.449.4 49.649.6

% of Pts with EF <30%

8.6% 5.1% 7.3% 9.0%

N=197 N=189 N=186 N=186

Mean and SD

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

2020

4040

6060

8080

100100

120120

140140N terminal Pro-BNP (pg/mL)N terminal Pro-BNP (pg/mL)

95.495.4 96.696.6 99.599.5 97.297.2

Mean and SEM

N=193 N=190 N=187 N=180

Page 22: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Outcome by Pre-PCI TIMI FlowOutcome by Pre-PCI TIMI Flow

Anterior MI CohortAnterior MI Cohort

% of Patients% of Patients PlaceboPlacebo Delc 50Delc 50 Delc 150Delc 150 Delc 450Delc 450

Pre-PCI TIMI 0 or 1Pre-PCI TIMI 0 or 1 51.951.9 60.060.0 58.958.9 65.765.7

Pre-PCI TIMI 2 or 3Pre-PCI TIMI 2 or 3 38.138.1 40.040.0 41.141.1 34.334.3

TIMI 0/1TIMI 0/1

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

20002000

40004000

60006000

80008000

1000010000CK-MB AUC (ng-hr/ml)CK-MB AUC (ng-hr/ml)

80138013

7232723268726872 68796879

TIMI 2/3TIMI 2/3

PlaceboPlacebo Delcas50

Delcas50

Delcas150

Delcas150

Delcas450

Delcas450

00

20002000

40004000

60006000

80008000

1000010000CK-MB AUC (ng-hr/ml)CK-MB AUC (ng-hr/ml)

36063606 33753375 35913591

47434743

p = 0.145p = 0.186

Page 23: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Inferior MI CohortInferior MI Cohort

CK-MB AUC CK-MB AUC

PlaceboPlacebo Delcas450

Delcas450

00

2020

4040

6060

8080

100100NT-Pro BNP (pg/mL)NT-Pro BNP (pg/mL)

42.742.7

70.170.1

p = 0.248

PlaceboPlacebo Delcas450

Delcas450

00

20002000

40004000

60006000

80008000ECG STR AUC (microV-min)ECG STR AUC (microV-min)

68236823 68586858

p = 0.962

PlaceboPlacebo Delcas450

Delcas450

00

10001000

20002000

30003000

40004000

50005000

60006000CK-MB AUC (ng-hr/mL)CK-MB AUC (ng-hr/mL)

50715071 49444944

p = 0.845

ST Recovery AUCST Recovery AUC NT-Pro BNPNT-Pro BNP

Page 24: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Delcasertib in STEMIDelcasertib in STEMI

PROTECTION AMI - ConclusionsPROTECTION AMI - Conclusions

Delcasertib, administered IV prior to and during primary PCI for Delcasertib, administered IV prior to and during primary PCI for acute anterior STEMI, did not reduce myocardial infarct size or acute anterior STEMI, did not reduce myocardial infarct size or improve clinical outcome.improve clinical outcome.

No differences in biomarkers of:No differences in biomarkers of: enzymatic infarct sizeenzymatic infarct size ECG markers of reperfusionECG markers of reperfusion LV function by 3 monthsLV function by 3 months NT-Pro BNPNT-Pro BNP

Other potential applications to IR injury yet to be investigatedOther potential applications to IR injury yet to be investigated

Page 25: PROTECTION AMI Inhibition of  -Protein Kinase C for Reduction of Infarct Size in Acute Myocardial Infarction A. Michael Lincoff, M.D. Director, C5Research

Heart and Vascular InstituteHeart and Vascular Institute