Скачать презентацию Translational Research for Myocardial Regeneration Timothy D Henry Скачать презентацию Translational Research for Myocardial Regeneration Timothy D Henry

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Translational Research for Myocardial Regeneration Timothy D. Henry, MD Director of Research Minneapolis Heart Translational Research for Myocardial Regeneration Timothy D. Henry, MD Director of Research Minneapolis Heart Institute Foundation

Timothy D. Henry, MD Grant Support: Aastrom Biosciences, Inc. , Baxter International, Inc. , Timothy D. Henry, MD Grant Support: Aastrom Biosciences, Inc. , Baxter International, Inc. , Mesoblast and Capricor. Off-Label: All cell therapy is currently research and therefore off-label

Cardiovascular Disease Targets ¨ Refractory angina ¨ Acute myocardial infarction ¨ Congestive heart failure Cardiovascular Disease Targets ¨ Refractory angina ¨ Acute myocardial infarction ¨ Congestive heart failure ¨ Ongoing ischemia ¨ Previous MI ¨ Nonischemic ¨ Peripheral arterial disease ¨ CLI ¨ Claudication

Refractory Angina/Ischemia Refractory Angina/Ischemia

Phase II ACT 34–CMI Study Design Screening and Baseline Visits Subject population (n=167) • Phase II ACT 34–CMI Study Design Screening and Baseline Visits Subject population (n=167) • 21 -80 yrs • CCS class III or IV Angina • Attempted “best” medical therapy • Non-candidate for Surgical/Perc. revasc. • Ischemia on SPECT • 3 -10 min. mod. Bruce protocol with angina or anginal equivalent at baseline Cell Mobilization (GCSF 5 mcg/kg/d x 5 d) Apheresis on Day 5 Randomization 1 x 10^5 CD 34+ cells/kg (n = 55) Placebo (n = 56) 5 x 10^5 CD 34+ cells/kg (n = 56) Endomyocardial Mapping and Injection with NOGA Isolex selected CD 34+ cells / Placebo Rx Follow-up Safety and Efficacy Assessments: 1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months MRI at 6 months, SPECT at 6 & 12 months

ACT-34 CMI: Reduction in Anginal Episodes per Week Change from baseline at 6 months ACT-34 CMI: Reduction in Anginal Episodes per Week Change from baseline at 6 months P=0. 04 Analysis of Variance (ANOVA)

ACT-34 CMI: Exercise Time Total ETT Time Change from baseline at 6 months Seconds ACT-34 CMI: Exercise Time Total ETT Time Change from baseline at 6 months Seconds p=0. 013

Major Adverse Cardiac Events (24 Months) Control 1 x 105 CD 34+cells/kg 5 x Major Adverse Cardiac Events (24 Months) Control 1 x 105 CD 34+cells/kg 5 x 105 CD 34+cells/kg pvalue* Death 7(12. 5%) 1(1. 8%) 2(3. 6%) 0. 081 MI 10 (17. 9%) 9(16. 4%) 6(10. 7%) 0. 587 Death, MI 15(26. 8%) 10(18. 2%) 6(10. 7%) 0. 096 Death, MI, ACS 17(30. 4%) Hospitalization 10(18. 2%) 8(14. 3%) 0. 101 Death, MI, ACS 19(33. 9%) or Worse CHF Hospitalization 12(21. 8%) 9(16. 1%) 0. 078 Pts with MACE events from start of mobilization thru 12 mo in injected pts; *= Fisher’s Exact Test

Angina Counts at 24 Months Diff=5. 3, p=0. 030 Angina Counts at 24 Months Diff=5. 3, p=0. 030

Refractory Angina Phase III RENEW Study Design Screening and Baseline Visits Randomization Subject population Refractory Angina Phase III RENEW Study Design Screening and Baseline Visits Randomization Subject population • 21 -80 yrs • CCS class III or IV • Angina • Attempted “best” medical therapy • Non-candidate for Surgical/Perc. revasc. • Ischemia on SPECT or 3 -10 min. mod. Bruce protocol with angina or anginal equivalent at baseline 1 x 105 CD 34+ cells/kg (n = 200) Active Control (n = 100) Unblinded Standard of Care (n = 100) Cell Mobilization (G-CSF 5 mg/kg/d x 4 d) Apheresis on Day 5 Intramyocardial Mapping and Injection with NOGA ISOLEX selected CD 34+ cells / Placebo Efficacy Assessments during 12 month follow-up: ETT, angina frequency, and Qo. L (SF-36) Safety Assessments during 24 month follow-up: AEs, SAEs, MACE

Still not available at the florist yet…. GETTING CLOSER! Still not available at the florist yet…. GETTING CLOSER!

Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) NHLBI Skarlatos PRC PDC Steering Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) NHLBI Skarlatos PRC PDC Steering Committee Cell Processing QC Lab Texas Heart Institute Willerson Cell Processing Satellites: De. Bakey VA DSMB Chair Simari Skills Development Core Data Coordinating Center UTSPH Moyé P&P Biorepository, c. MRI, Echo, MVO 2, SPECT Core Labs Skills Development Core U FL Pepine Cleveland Clinic Ellis Minneapolis Heart Institute Henry Vanderbilt University Zhao Cell Processing Satellites: Pepin Heart Institute Satellites: University Hospitals. United Heart & Vascular Clinic Metro Cardiology Consultants U MN Mayo Clinic

Published Online First March 24, 2012 Available at www. jama. com Published Online First March 24, 2012 Available at www. jama. com

FOCUS-2 Rationale-Endpoints ¨ Severe ischemic LV dysfunction (<45%) n= 86 pts ¨ Increased dose FOCUS-2 Rationale-Endpoints ¨ Severe ischemic LV dysfunction (<45%) n= 86 pts ¨ Increased dose (100 M cells) ¨ Multicenter-CCTRN ¨ Placebo controlled ¨ Combined Endpoints = SPECT, Echo (LVV), MVO 2 (all core assessed) ¨ Late Breaking Trials ACC 2012 Perin EC, et al. JAMA 2012 Apr 25; 307(16): 1717 -26

Primary Endpoint: LVESV Change in Indexed LVES Volume by Placebo BMC Echo 160 140 Primary Endpoint: LVESV Change in Indexed LVES Volume by Placebo BMC Echo 160 140 120 LVESV (ml) No difference in the change in indexed LVESV by Echo between BMC and Placebo groups from baseline to 6 months 100 80 60 65. 0 40 57. 9 65. 0 57. 0 20 0 Baseline N=54 6 Mo N=54 Baseline N=28 6 Mo N=28 15

Primary Endpoint: MVO 2 BMC Change in MVO 2 Placebo 35 30 Peak VO Primary Endpoint: MVO 2 BMC Change in MVO 2 Placebo 35 30 Peak VO 2 (ml/kg/min) No difference in the change in MVO 2 between BMC and Placebo groups from baseline to 6 months 25 20 15 14. 6 15. 0 15. 3 14. 7 10 5 0 Baseline N=54 6 Mo N=54 Baseline N=28 6 Mo N=28

LVEF Significant difference in the change in LVEF between BMC and Placebo groups from LVEF Significant difference in the change in LVEF between BMC and Placebo groups from baseline to 6 months (1. 4 vs -1. 3, p=0. 030) BMC Baseline N=54 6 Mo N=54 Baseline N=28 6 Mo N=28

Cell Analysis q Immunophenotyping: § q CFU-GM Surface markers (CD 34+, 133+, ) Hematopoietic: Cell Analysis q Immunophenotyping: § q CFU-GM Surface markers (CD 34+, 133+, ) Hematopoietic: § CFU-GM Tube Formation q Endothelial: Tube Formation § Ac LDL incorporation § q Mesenchymal: CFU-F § Population doubling time § q Chemotaxic properties: § q migration (SDF-1, VEGF) Hindlimb ischemia: §immunodeficient murine model CFU-F

Patient ID Mesenchymal Colony Forming Units (CFU-F) 180 CFU Number per 106 BM Mononuclear Patient ID Mesenchymal Colony Forming Units (CFU-F) 180 CFU Number per 106 BM Mononuclear Cells

MSC Growth Kinetics Cell Number (103) Control Time (hours) MSC Growth Kinetics Cell Number (103) Control Time (hours)

Bone Marrow Sample Analysis in Focus HF Age and CFU Age and MVO 2 Bone Marrow Sample Analysis in Focus HF Age and CFU Age and MVO 2 Treatment Control Am Heart J 2011; 161: 1078 -1087

Pre-Specified Analysis Relationship of Age with Endpoints Delta LVEF and Age BMC Placebo R Pre-Specified Analysis Relationship of Age with Endpoints Delta LVEF and Age BMC Placebo R 2= 10% P = 0. 017 R 2= 2% P= NS

Correlation between ΔLVEF and %CD 34 Adjusted for Age and Therapy ΔLVEF Unadjusted %CD Correlation between ΔLVEF and %CD 34 Adjusted for Age and Therapy ΔLVEF Unadjusted %CD 34 R 2= 8% P = 0. 012 R 2= 16% P=0. 043 23

Correlation between ΔLVEF and %CD 133 Adjusted for Age and Therapy ΔLVEF Unadjusted R Correlation between ΔLVEF and %CD 133 Adjusted for Age and Therapy ΔLVEF Unadjusted R 2= 8% P = 0. 010 R 2= 16% P=0. 041 24

AMI The Problem The Solution AMI The Problem The Solution

Ejection Fraction Change EF change % (SE) ASTAMI Burtanek et al BOOST Jannsens et Ejection Fraction Change EF change % (SE) ASTAMI Burtanek et al BOOST Jannsens et al MAGIC 3 Meluzin et al REPAIR-AMI Strauer et al. TCT-STAMI Zhan-Quan et al - 1. 4 (0. 72) - 3. 1 (3. 10) - 2. 8 (1. 12) - 1. 1 (0. 79) - 5. 2 (1. 01) - 2. 0 (0. 49) - 2. 5 (0. 54) - 1. 0 (1. 56) - 6. 7 (1. 63) - 5. 5 (0. 85) Total (95% CI) Test for heterogeneity Chi 2 = 33. 62, df=9, (p=0. 0001), I 2 = 73. 2% Test for overall effect: Z = 5. 35 (p 0. 00001) + 3. 0% [1. 9% to 4. 1%] -10 -5 Favors cell therapy 0 5 10 Favors control Lipinski, JACC 2007; 50: 1761

Controls BMMNC P< 0. 001 LVESV -7. 4 ml [-12. 2 to -2. 7] Controls BMMNC P< 0. 001 LVESV -7. 4 ml [-12. 2 to -2. 7] MI size -5. 6% [-8. 7% to -2. 5%] P= 0. 002 Lipinski, JACC 2007; 50: 1761

REPAIR-AMI Team Hamburg Mathey Bad Oeynhausen Horstkotte / Farr Lippe-Detmold Tebbe / Cueno Bochum REPAIR-AMI Team Hamburg Mathey Bad Oeynhausen Horstkotte / Farr Lippe-Detmold Tebbe / Cueno Bochum Mügge / Germing Echo Core Lab Giessen Hölschermann Bad Nauheim Hamm / Elsässer Dill MRT Core Lab Mainz Münzel / Horstick Homburg / Saar Böhm / Nickenig Ludwigshafen Senges / Mark Mannheim Haase / Süsselbeck Zürich Lüscher / Corti Berlin Rutsch Suhl Haberbosch Bad Berka Lauer Leipzig Hambrecht / Schuler / Erbs Doppler Core Lab Frankfurt / Rotes Kreuz Haase Frankfurt / J. W. Goethe Uni Zeiher / Schächinger Dimmeler / Martin Coordination / Angio Core Lab BSD Hessen Tonn / Krzossok / Seifried Cell Processing Center

REPAIR AMI 5 years clinical follow up - Kaplan Meier Analysis - - Death, REPAIR AMI 5 years clinical follow up - Kaplan Meier Analysis - - Death, MI, Rehospitalization for heart failure - BMC 0. 8 Placebo 0. 6 0. 4 0. 2 1. 0 Event-free survival (%) (death, myocardial infarction, revascularization) Event-free survival (%) (death, myocardial infarction, rehospitalization f. heart failure) 1. 0 - Death, MI, Revascularization - 0. 8 BMC 0. 6 0. 4 Placebo 0. 2 p = 0. 140 (log rank) p = 0. 035 (log rank) 0 0 0 500 1000 1500 2000 Days follow-up

TIME Study Design ¨ Study Aim: assess the effect of autologous BMCs and timing TIME Study Design ¨ Study Aim: assess the effect of autologous BMCs and timing ¨ ¨ ¨ of delivery at Day 3 vs. Day 7 post MI on measures of LV function Target Population: 120 patients w/first anterior MI, reperfused by PCI + stent, with residual LV dysfunction (EF≤ 45%) Treatment: 150 x 106 autologous BMCs or placebo delivered by intracoronary infusion (Stop Flow) Primary Endpoints: change in global and regional LV function from baseline to 6 months by cardiac MRI Secondary Endpoints: change in infarct size and LV volumes Subgroups: age, LVEF 30

Infarct Size and Treatment Times 3 Days BMC (N=43) Placebo (N=24) 7 Days BMC Infarct Size and Treatment Times 3 Days BMC (N=43) Placebo (N=24) 7 Days BMC (N=36) Placebo (N=17) 32

Primary Endpoint: Global No difference in the change in LVEF between BMC (n=75) and Primary Endpoint: Global No difference in the change in LVEF between BMC (n=75) and Placebo (n=37) groups from baseline to 6 months 33

Effect of Delivery Timing on the Change from Baseline to Six Months for LVEF Effect of Delivery Timing on the Change from Baseline to Six Months for LVEF Results for both infarct zone and border zone wall motion were also not significant by therapy group for 3 days, 7 days, or overall. 34

Secondary Endpoints: Infarct Size and LV Volumes 35 Secondary Endpoints: Infarct Size and LV Volumes 35

Clinical/Safety Outcomes at 6 -month Endpoint Window 36 Clinical/Safety Outcomes at 6 -month Endpoint Window 36

Conclusions ¨ Intracoronary delivery of autologous BMCs 3 or 7 days following primary PCI Conclusions ¨ Intracoronary delivery of autologous BMCs 3 or 7 days following primary PCI + stenting after moderate to large acute MIs is safe. ¨ No improvement in global and regional LV function is observed at 6 months by c. MRI in response to intracoronary BMC delivery. ¨ Young patients at Day 7 randomized to BMCs had significant improvement with LVEF compared with placebo. 37

Strategies to Enhance Cell Therapy 1. Increase the number of cells (autologous) ¨ Whole Strategies to Enhance Cell Therapy 1. Increase the number of cells (autologous) ¨ Whole bone marrow (Harvest) 2. Selected cells (autologous) ¨ Adipose derived cells (Cytori) ¨ CD 34+ cells (Baxter) ¨ ALD-bright (Aldagen) 3. Expand and/or enhanced cells (autologous) ¨ Aastrom Biosciences ¨ C-Cure ¨ Allogeneic ¨ MPC (Mesoblast-Teva) ¨ MSC (Osiris) ¨ MAPC (Athersys) ¨ Cardiac derived ¨ Caduceus (Capricor) ¨ SCIPIO

CADUCEUS Design ¨ Post-MI (<30 days at screening) & LV dysfunction (EF 25 -45%) CADUCEUS Design ¨ Post-MI (<30 days at screening) & LV dysfunction (EF 25 -45%) ¨ Randomized (2: 1), controlled, dose-escalation safety and preliminary efficacy study (MRI for scar mass, viable mass, volumes, & function) ¨ Two centers (Cedars-Sinai Heart Institute; Johns Hopkins) ¨ Endomyocardial biopsies; CDCs manufactured at Cedars-Sinai Heart Institute ¨ Intracoronary infusions of autologous CDCs

How we harvest and grow cardiosphere-derived cells (CDCs) Explants (1) Biopsy Cardiosphere -forming cells How we harvest and grow cardiosphere-derived cells (CDCs) Explants (1) Biopsy Cardiosphere -forming cells (4) Cardiospheres (5) Cardiospherederived cells (CDCs, 6) 2, 3 1 2 200 mm 4 5 100 % of cell total 3 100 mm 6 80 60 40 20 200 mm 0 c-Kit+ CD 133+ CD 105+ Clinical yield: ~70 M CDCs in 5 weeks 50 mm CD 90+ R. Smith et al. , Circulation 115: 896 – 908, 2007

Regenerative efficacy in CADUCEUS: Representative MR images baseline 0005 -CDC 01 -014 CDC-treated 0005 Regenerative efficacy in CADUCEUS: Representative MR images baseline 0005 -CDC 01 -014 CDC-treated 0005 -CDC 01 -002 Control 6 m

CDC therapy reduces scar and increases healthy heart muscle in CADUCEUS Δ scar mass CDC therapy reduces scar and increases healthy heart muscle in CADUCEUS Δ scar mass Δ viable mass 6 mos 12 mos p=0. 001 p: 0. 01 p=0. 001 p: 0. 02 n=8 All bars represent +/- 1 SEM n=15 n=7 n=8

Cardiovascular Disease Targets ¨ Refractory angina ¨ Acute myocardial infarction ¨ Congestive heart failure Cardiovascular Disease Targets ¨ Refractory angina ¨ Acute myocardial infarction ¨ Congestive heart failure ¨ Ongoing ischemia ¨ Previous MI ¨ Nonischemic ¨ Peripheral arterial disease ¨ CLI ¨ Claudication

We still need better Options!! Will it be Cell Therapy? ? We still need better Options!! Will it be Cell Therapy? ?