STEM CELL THERAPY FOR

HEART FAILURE:

THEY WORK!

LESLIE W MILLER, MD

Leslie Miller, MD

REGENERATIVE MEDICINE

• Use of Stem Cells or Genes to

activate the body’s Native Repair

To

• Recover or Repair Any damaged

or dysfunctional organs, tissues,

or vessels

Stem Cell

Endothelium

Adipose

Neural/Brain

Cardiac Myocytes Fibroblasts

WHAT DEFINES A STEM CELL?

Blood Cells*

Skeletal Muscle Bone

Smooth Muscle

Endless SELF RENEWAL

DIFFERENTIATE into ALL Cell Types

SOURCES OF STEM CELLS: 2010

STEM

CELLS Embryonic

Bone

Marrow

Stem Cell Catheter Delivery in Acute MI

KKey role of Inflammation in HOMING of cells to area of infarct

Cell Therapy for Acute MI

Bone Marrow Source • 17 RPC trials to date, including NIH trials

• Small-modest sample size trials (60-120)

• Variable time of delivery post MI, # cells, prep

• Nearly all Autologous Bone Marrow:

• Entire Mononuclear Cells > CD 34+ or CD 133+

• Variable results: EF change= + 2% (0-4%)*

• Best in those with lowest EF/greatest injury

• BAMI Trial of 3,000 pt Europe

*Jeevananthum Circ 2012

Impact of AGE on Frequency of

Stem Cells in Bone Marrow

AJ Caplan et al J Path 2009; 217: 318-324

Bone Marrow Stem Cells in

Heart Failure: NIH FOCUS Trial

• Phase II Randomized, Placebo controlled

• 92 patients with stable Ischemic HF (EF=27%)

• Randomized 2:1 to Autologous BM: Placebo

• 100 million cells delivered

• NOGA catheter endocardial cell delivery

• No inflammatory signal to direct homing of SCs

• Follow up at 6, 12, and 24 months

• E Perrin et al JAMA March 2012

E Perin et al JAMA 2012

NOGA Catheter

2D 3D

Endoventricular Stem Cell Delivery

FOCUS Trial

• Results: No change in SPECT, EF, LVEDV,

• No difference in Angina score

• Patients > 62 yrs Change in EF= 0 %

• Patients < 62 yrs EF increased 4.7%

• Autologous Bone Marrow is safe

• AGE may be a significant limitation Signature of

• Signature of Responders: (DA Taylor core lab)

Higher Number and Percentage of CD34+ cells

New Stem Cell Trials for HF

CardiAMP

• Phase III Pivotal trial

• 275 Patients with Ischemic HF

• Bone marrow source; 2:1 randomization

• Intramyocardial Delivery

• Enrollment based on BM markers

• Maximize odds of identifying Responders

• End Points: Survival and Remodeling

Autologous CD 34 + Cells for

Non-Ischemic Heart Failure

• 131 patients screened 2005-2006

• Average Age= 54 yrs; 80% males;

• EF = 25%; LVEDD= 7.0 cm; NT-BNP= 2400

• No CAD by cath

• Nuclear Scan all patients; Many had reversible Isch

• Bone Marrow source CD 34+ cells after GCSF

• Randomize 1:1 Cells vs Placebo

• Intracoronary Delivery

Vrtovec et al Circ Res Jan 2013

CD 34+ Stem Cells for

Non-Ischemic Heart Failure:

• 5 yr follow up Results:

• EF: increase 6% (24-30%, p=0.02)

• 6 Min Walk: increase (344-477, p<0.001)

• BNP: decreased 54% (2322-1011, p<0.01)

• Total Mortality: lower (14 vs 35%, p=0.01)

• Pump Failure Death: lower (5 vs 18%, p=0.03)

• Sudden Death: lower (9 vs 16%, p=0.39)

• Most benefit seen by 1 yr; persisted 5 yrs

• Vrtovec et al Circ Res 2013

N= 59 patients with Ischemic HF

Average Age = 65.5 years

Average EF = 28.1 ± 8.8%

Randomized 2:1, Cells(n=39) : Placebo(n=20)

Autol BM Aspirate Mesenchymal SCs

Endocardial Delivery of Cells

6 month follow up EP’s

Autologous Bone Marrow Mesenchymal SC’s

for Ischemic Heart Failure

Bruun, Methiason et al. EHJ Aug 2014

Stem Cells Placebo P Value

(n = 39) (n = 20)

LV End Syst Vol - 8.2 ± 14.2 + 6.0 ± 13.4 0.001

Ejection Fraction + 5.5 ± 3.8% - 1.4 ± 4.0% < 0.0001

Stroke Volume + 17.4 ± 14 - 3.1 ± 12.1 < 0.0001

End Syst Mass, g +10.1 ± 10 - 2.1 ± 8.9 < 0.0001

Scar Mass gm - 5.4 ± 5.1 - 4.4 ± 5.1 0.017 (MRI)

Age may be less important that cell type

Bone Marrow MNC’s for Ischemic Heart Failure

Bruun et al. EHJ July 2014

Allogenic Mesenchymal SC’s

• Any Allogenic (foreign) cell was thought to

require long term immunosuppression

• Mesenchymal SCs are “Immune Privileged”

• Minimal Alloimmune(antibody) response- trials*

• Cardiotrophic: Endothelium, Cardiomyocytes,

Smooth Muscle, Skel Muscle

• Equally effective as Autologous cells*

• Off-the-shelf therapy for any age or need

*Hare JAMA 2013

Allogenic Mesenchymal SCs for HF

DREAM trial

• PHASE III Pivotal trial of Allogeneic MSCs

• 1700 patients International trial-Class II/III

• Both Ischemic and Non-Ischemic HF etiology

• Intramyocardial Delivery of 150 M MSCs

• Ideal 20 yo donor for all patients

• Primary End Point:Composite Event Driven

• Secondary EPs include Echo Remodeling

SOURCES OF STEM CELLS: 2015

STEM

CELLS

Umbilical

Cord

Adipose

Tissue Bone

Marrow

Genetic

Engineered

Somatic Cells

Menstrual

Cells

Resident

Progenitor

Cells

Placenta

Adipose Derived Stem Cells for Ht Failure

PRECISE Trial*

• Phase IIB Trial at 2 centers in Belgium

• 40 Patients Prior MI; EF < 40%

• 2:1 randomization: Cells : Placebo

• Liposuction, processing in O.R.

• Endocardial Delivery via NOGA system

• End Point is Change in EF

• Follow up at 6, 12 months

•

•

•

E Duckers et al AHJ May, 2014

PRECISE Trial of Adipose Derived Stem Cells for HF

24.4 cc

Difference

(-72,2%)

P=0.03

Perin et al Am Ht J May 2014;

End

Diastolic

Volume

Baseline 6 Mos 18 Mos

Transplant List

20.0 18.0 16.0 14.0

ADRCs for Ischemic HF: PRECISE Trial

Impact on Peak VO2:

19.0

15.5 15.3

16.6

17.1 17.2

ADRC’s Standard of Care

P<0.05 P<0.05

Pe

ak V

O2

Perin et al

AHJ May 2014 ATHENA Trial now enrolling in US same protocol

8 yrs older

Cardiac Progenitor Cells for HF:

CADUCEUS Trial • Phase IIA trial: 31 Pts < 30 days post MI, EF < 45%

• Endomyocardial Biopsy- Autologous source

• Cardiospheres: Cultured into millions cells-weeks

• Randomized 3:1 to CSP Cells vs Placebo

• Endocardial Delivery via NOGA catheter

• Results: Reduced scar mass by MRI by 24%

• Increased myocardial mass*(myogenesis)

Reduced LVESV and LVEDV

Improved EF by 39%

ALLSTAR Trial: 274 pts-Allogeneic Phase IIB

Maraban et al Lancet ‘12

Genetic Engineering Cell

Transformation

Cardiomyocyte

Fibroblast

iPSCs

Reprogramming

Oct3,4;SOX;MFT, cMyk

TranscriptionFactors

Differentiation Using

small molecules/GF’s

Direct

Reprogramming

Additional TF’s

Step1

Step 2

Unresolved Issues: Heterogeneity; Immune reactivity; Arrhythmia

Genetic Engineering of Lineage Specific

Cardiopoietic SCs: C-CURE study

• Skin fibroblasts exposed to a “cocktail” of growth

factors (4 genes) and tropic substances that

• Drives the cells into functioning cardiomyocytes

• Pilot of 45 patients; MI < 6 months; EF 40-50%

• Endocardial catheter delivery

• RESULTS: Decrease LVEDV, LVESV,

• Decrease LV Scar, increase Mass

• Increase EF % 26%

• Phase III Euro enrolling; US Phase II Andre Terzic et al JACC

Multipotent Adult Progenitor Cells (MAPCs)v

Penn et al JACC 2011

Stem Cell or Gene Therapy for Heart Failure

Delivery

Delivery Routes for Stem Cell/Gene

Trial of Multiple Administrations

EF

Units

6 Months 12 Months

CELLS

Placebo

FULL

EVAL

CELLS

CELLS

FULL

EVAL

Assmus, Zeiher

Euro HJ May, 2014

LONG TERM SURVIVAL/REHOSPITALIZATION BENEFIT OF BMMNC FOR AMI

FUNCTIONAL ASSAY TO PREDICT STEM CELL RESPONSE

Assmus,Zeiher

Euro J HF 2014

STEM CELL/GENE VENDORS-CV PHASE I

CardioCell

Medistem

Pleuristem

Celladon

HFPEF

PAH

* Cell

PHASE IIA

PHASE IIB

Mesoblast

Capricor

Cardio-3

Cytori

Bioheart

Neostem

Cell Prothera

Athersys

Aastrom

NIH LVAD-Allo MSC

NIH Allo Vs Auto MSC

NIH C-Kit + Allo MSC

Juventas

PHASE III

Teva

Cell Prothera

Zensun

Celladon

Harvest

Athersys

Baxter

Arteriocyte

Aldagen

Multigeyi

Cook

Renova

Juventas

PAD,

NSTEMI

Ottawa

Stem Cell Therapy for HF:

THEY WORK

• Learning to utilize the body’s native repair

• Stem Cells are clearly SAFE

• Multiple studies showing significant benefit

• New Era in Stem Cell therapy

• New Cells, Sources, Delivery, Doses, Frequency

• Many Phase IIB and III Clinical trials enrolling

• Will rewrite to potential benefit of

• Stem Cell Therapy for all of CV Disease

STEM CELL/GENE TRIALS

PHASE I

Hypoxia MSC

Umbilical Cord

Placental MSC

Endometrium

* Viral *Cell

PHASE IIA

PHASE IIB

Cardiosphere CPC

C-kit Card Progen

Genet Transf MSC

LVAD-ALLO MSC

LVAD-ADRCs

Allo Vs Auto MSC

C-Kit + Allo MSC

Adipose Derived SC

Bone Marrow Modif

Bone Marrow CD34+

SERCA 2-a*

SDF-1*

Neuregulin

PHASE III

Allo MSC

Auto CD34/

BM Select

Neuregulin*

MAPCs

Adenyl

Cyclase*

CD34+/eN

OS *

SDF-PAD

SDF-

NSTEMI

TISSUE ENGINEERING in RM

ENHANCED RETENTION

BEADS

PATCHES

SCAFFOLDS

STENTS

ORGANOGENESIS

PROTEIN ENGINEERING