The Jay Cohn Lecture 2012: Therapeutic regeneration of the injured heart

Transcription

1 The Jay Cohn Lecture 2012: Therapeutic regeneration of the injured heart Eduardo Marbán, M.D., Ph.D. Director, Cedars-Sinai Heart Institute Los Angeles, CA Disclosure: founder & stockholder, Capricor Inc. (no products)

2 Outline General considerations in cell therapy for heart disease Clinical experience Cardiosphere-derived cells Scientific rationale Preclinical development CADUCEUS Trial Summary and future directions

3 Heart disease Number #1 killer in Western society Acute ischemic syndromes (e.g., myocardial infarction; 1.1M/yr in US) Chronic heart failure (~7M patients in US) How do we want to use stem cells? To achieve true regeneration in the injured heart

4 re gen er a tion n. Regrowth of lost or destroyed parts or organs. The American Heritage Dictionary of the English Language, Fourth Edition 2000

5 Main indication: myocardial infarction Coronary vessel blockage replacement of (thick) normal heart muscle by (thin) scar Net loss of ~14% of total LV mass within first 4 months* Criteria for genuine regeneration reduction of scar growth of new healthy cardiac tissue improvement of function *A. Hirsch et al., EHJ 2011

6 Types of stem cells Embryonic stem cells* or ips cells # Can evolve into all tissues Tumors Immune reactions Ethically problematic* Imprinting, genetic modification # Adult stem cells Skeletal myoblasts Bone marrow stem cells Autologous (BMCs, EPCs) or allogeneic (MSCs)

7 Lessons learned from human bone marrow-derived cell trials >1200 subacute MI patients treated worldwide since Aug Modest inconsistent functional benefit Excellent safety profile with coronary catheter delivery, including arrhythmias and SCD MRI: small reductions in scar (~3 g), but no increase in viable myocardium Safe, maybe clinically beneficial, but no evidence for regeneration

8 Types of stem cells Embryonic stem cells* or ips cells # Can evolve into all tissues Tumors Immune reactions Ethically problematic* Imprinting, genetic modification # Adult stem cells Skeletal myoblasts Bone marrow stem cells Autologous (BMCs, EPCs) or allogeneic (MSCs) Cardiac-derived cells

9 Major landmarks 2000-present Cardiac stem cells (CSCs) First recognized in 2000 (Deisher) Antigenically-selected in rats and mice (Beltrami et al., Oh et al., 2003) Human cardiospheres (CSps) Outgrowth of human surgical biopsies in primary culture (Messina et al., 2004) Self-organize in suspension, increase post-ischemic function Cardiosphere-derived cells (CDCs) Millions of cardiac stem cells from percutaneous endomyocardial biopsies (Smith et al., 2007) Paradigm for autologous therapeutics

10 Percutaneous heart biopsies to generate cardiospheres and cardiosphere-derived cells

11 How we harvest and grow cardiospheres % of cell total R. Smith et al., Circulation 115: , 2007 Biopsy Explants (1) Cardiosphere -forming cells (4) Cardiospheres (5) 2, mm 200 mm 100 mm c-kit+ CD133 + CD105 + CD mm

12 Cardiosphere microenvironments: surface differentiation, internal stemness CD105 DAPI c-kit DAPI center C-Kit: receptor for SCF CD105 c-kit surface CD105 c-kit CD105: TGFß receptor, MSC/endothelium

13 Cardiosphere phenotype: internal cell proliferation Ki67 DAPI CD105 DAPI center Ki67 CD105 surface Ki67 CD105

14 Considerations in making the first clinical product Cardiospheres interesting biologically, regenerative and effective But, favored clinical delivery route is by intracoronary catheters Safety record with bone marrow cells Widely available, minimally-invasive technology Cardiospheres too large for intracoronary infusion Replating of cardiospheres to produce cardiosphere-derived cells

15 % of cell total How we harvest and grow CDCs R. Smith et al., Circulation 115: , 2007 Biopsy Explants (1) Cardiosphere -forming cells (4) Cardiospheres (5) Cardiospherederived cells (CDCs, 6) 2, mm 200 mm 100 mm c-kit+ CD133 + CD105 + CD mm 6 Yield: >25M CDCs in ~3 weeks 50 mm

16 CDCs and cardiospheres improve cardiac function post-mi Citations as in Malliaras and Marbán, British Medical Bulletin 2011

17 Mechanism of benefit involves primarily indirect effects * * Chimenti et al., Circ. Res., 2010; Cheng et al., Circ. Res., 2010; Cheng et al., Cell Transplantation 2012; Malliaras et al., Circulation, 2012

18 I. Chimenti et al., Circ. Res., 2010

19 How do CDCs compare to other types of stem cells? Functional improvement after transplantation Anti-remodeling effects Human CDCs versus human BMCs, MSCs in SCID mice with acute myocardial infarction T-S Li et al., JACC 2012

20 CDCs superior in boosting cardiac function (LVEF) Baseline (Post MI) weeks after treatment * p=0.038 vs BM-MSC <0.01 vs other groups * p<0.01 vs Control Mean ±SEM CDC BM-MSC AD-MSC High-BMC Control Low-BMC

21 CDCs superior in preventing adverse remodeling CDC BM-MSC (mm) 1.5 * Infarct wall thickness * p<0.05 vs other groups 1.0 AD-MSC high BM-MNC low BM-MNC Control (%) Infarct perimeter (% of total LV) * p<0.05 vs other groups * 0.0 CDC AD-MSC Control BM-MSC High-BMC Low-BMC

22 CDC technology: Summary of Progress in Translation to the Clinic Cell isolation and expansion optimized

23 CDC technology: Summary of Progress in Translation to the Clinic Cell isolation and expansion optimized Engraftment, differentiation and functional benefit demonstrated in mice +, rats # and pigs * + R.R. Smith, Circulation, 2007 # D. Davis et al., JMCC, 2010 * P. Johnston et al., Circulation, 2009

24 CDC technology: Summary of Progress in Translation to the Clinic Cell isolation and expansion optimized Engraftment, differentiation and functional benefit demonstrated in mice, rats and pigs Dosage optimized in pigs* * P. Johnston et al., Circulation, 2009

25 CDC technology: Summary of Progress in Translation to the Clinic Cell isolation and expansion optimized Engraftment and differentiation demonstrated in mice, rats and pigs Dosage optimized in pigs Pivotal preclinical study completed

26 Porcine i.c. CDC experimental protocol Miniature Swine 2 ½ hour balloon occlusion of mid-lad Transmural anterior infarct with ~30% EF Randomized, blinded, placebo-controlled pivotal study (n=14 pigs) MI, Biopsy Autologous IC Cell (or placebo) Infusion Sac (histology) 4 weeks 8 weeks Imaging: MRI MRI Invasive Studies: Hemodynamics Hemodynamics Johnston et al., Circulation 2009 EPS

27 Percent LV Infarcted i.c. CDCs Reduce Infarct Size in Pigs 25 p = 0.25 p = Control CDC Effect consists both of a decrease in scar and an increase of viable myocardium

28 dp/dt Max dp/dt min (-mmhg/sec) Improved Hemodynamics in i.c. CDC- Treated Animals 12 weeks after MI dp/dt Max dp/dt Min 2500 p= Control CDC Control CDC P<0.05

29 CADUCEUS Design Makkar et al., Lancet 2012 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

30 Biopsy 30 minutes digestion in 0.2 mg/ml collagenase CADUCEUS Trial Design Animation Cell harvest by 0.05% trypsin Cardiospheres (CSps) Poly-D-lysine coated Cardiospherederived cells (CDCs) Fibronectin coated Infusion into the same patient

31 CADUCEUS Flow Diagram Enrollment Allocation Follow-up Assessed for eligibility (n=436) CDCs (n=23) n=21 CDCs (n=17) 12.5M (n=4) 17.3M (n=1) Randomized (n=31) Withdrew consent (n=2) Occluded IRA (n=1) Manufacturing failures (n=3) 25M (n=12) Excluded (n=401) Controls (n=8) Controls (n=8)

32 CADUCEUS Safety No biopsy complications (n=21) Normal angiographic flow post-infusion (n=17) No increase in arrhythmias, no increase in SAEs: Serious adverse events (SAEs) 6m CDCs Controls P value 4/17 1/8 1.0 SAEs 12m 6/17 1/8 0.4 Hospitalizations 4/17 1/8 1.0 Sustained VT/VFib 0/17 0/8 1.0 Death/MACE/tumor 0/17 0/8 1.0

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

34 CDC therapy reduces scar and increases healthy heart muscle in CADUCEUS Δ scar mass Δ viable mass 6 mos 12 mos 6 mos 12 mos p=0.001 p:0.01 p=0.001 p:0.02 n=8 n=15 n=7 n=8 n=8 n=15 n=7 n=8 All bars represent +/- 1 SEM

35 Scar mass treatment effect (g) Reductions in scar mass mirror increases in viable mass, consistent with true regeneration r=-0.59 p<0.001 Viable mass treatment effect (g) (g, 6 months and 12 months minus baseline, pooled CDC group)

36 Meanwhile, regional function improves in CDC-treated patients relative to controls Peak Ecc strain (%) in treated 6 months Systolic wall thickening (%) in treated 6 months P=0.001 P=0.02 controls CDCs controls CDCs n=42 (7) n=83 (14) n=48 (8) n=83 (14) All bars represent +/- 1 SEM

37 Pathology of i.c. CDCtreated rat hearts verifies MRI findings and rules out hypertrophy

38 No changes in ejection fraction, but trends to attenuated adverse remodeling EF treatment 6 months P=0.82 EDV treatment 6 months ESV treatment 6 months P=0.37 P=0.14 controls CDCs controls CDCs controls CDCs All bars represent +/- 1 SEM

39 Are the changes in EF consistent with the observed reduction in scar size? CADUCEUS data superimposed on E Wu, R Bonow et al, Heart 2008

40 IS vs EF in CADUCEUS-like Patients Infarct size Ejection Fraction Burns, et al. JACC 2002

41 Conjecture: CDC therapy may lower risk by decreasing infarct size E Wu, et al. Heart 2008

42 CADUCEUS summary Intracoronary injection of CDCs in post-mi patients with LV dysfunction safe & effective Tissue regeneration, improved regional function and trends to reversal of adverse remodeling New concepts to guide future clinical trials Phase 2 for i.c. CDCs planned (ALLSTAR) Allogeneic product safe and effective^ Direct injection viable alternative to intracoronary injection* CSps may be more potent than CDCs*,# Sicker patients (advanced heart failure) ^K Malliaras et al., Circulation 2012; *S-T Lee et al., JACC 2011; # T Li et al., Stem Cells 2010

43 Larger implications for medicine Therapeutic regeneration may be possible Irreversible injury may, in some cases, be reversible Hope for curative approach rather than stabilization and palliation

44 Acknowledgments Cedars-Sinai Heart Institute Raj Makkar Kostas Malliaras John Terrovitis Rachel R. Smith Ke Cheng Linda Marbán Daniel Berman Louise Thomson Lawrence Czer Eugenio Cingolani Tracey Gerez Michelle Domingo Mohamed Aminzadeh EMMES Corporation Adam Mendizabal Johns Hopkins University Gary Gerstenblith Peter Johnston Al Lardo Karl Schuleri Stuart Russell Elayne Breton Jeff Brinker U. of Rome (La Sapienza) Elisa Messina Alessandro Giacomello Funding NIH (NHLBI SCCT) Board of Governors, Cedars-Sinai Medical Center