c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy Roberto Bolli, - - PowerPoint PPT Presentation

Roberto Bolli, M.D.

Los Angeles, CA

c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy

Institute of Molecular Cardiology University of Louisville

American Heart Association Scientific Sessions American Heart Association Scientific Sessions

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FINANCIAL DISCLOSURE: None UNLABELED/UNAPPROVED USES DISCLOSURE: None

c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy

Roberto Bolli, M.D.

SCIPIO

(Study of Cardiac Stem Cells Infusion in Patients with Ischemic CardiOmyopathy)

• Phase I, open-label, randomized trial
• Single center
• 20 treated and 13 control patients
• http://clinicaltrials.gov/ct2/show/NCT00474461

Publius Cornelius Scipio Africanus (235–183 BC)

SCIPIO

(Study of Cardiac Stem Cells Infusion in Patients with Ischemic CardiOmyopathy)

Piero Anversa Annarosa Leri Jan Kajstura Domenico D’Amario John Loughran Atul Chugh Brandon Elmore Sohail Ikram Marcus Stoddard Steve Wagner Garth Beache

Institute of Molecular Cardiology Brigham and Women’s Hospital

Primary Objective

• 1. To assess the feasibility and safety of infusing autologous

c-kitpos CSCs in patients with ischemic heart failure. Secondary Objective

• 2. To obtain preliminary evidence for or against the efficacy
• f CSCs in augmenting LV function, improving functional

status, and promoting myocardial regeneration.

The overall goal is to translate the discovery of CSCs into clinically useful therapies.

SCIPIO: Objectives

SCIPIO: Time Line

A result of many years of preclinical work:

Trial opened to enrollment in February 2009 First CSC infusion July 17, 2009 FDA contacted in October 2004

2004 2012

IND application submitted on January 2006

2006

FDA approval on August 8, 2008

2008 2010

First patient enrolled on March 13, 2009 Last Patient Enrolled May 17, 2011

November 14, 2011

 LVEF ≤ 40%  A history of Q-wave MI with a residual scar (as

evidenced by ECG, cardiac MRI, low-dose dobutamine stress echo, and/or rest perfusion images on a sestamibi SPECT study)

 Patient scheduled for CABG within 2 weeks of the initial

screening.

SCIPIO Inclusion Criteria

Enrollment

CABG & Tissue Harvesting

< 2 Weeks

SCIPIO: Protocol

At the time of CABG, the right atrial appendage is resected and prepared for CSC isolation CSC isolation and expansion

Enrollment

CABG & Tissue Harvesting

< 2 Weeks

SCIPIO: Protocol

4 ± 1 Months

• Cardiac MRI
• 2-D & 3-D Echo
• ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class

assessment

Follow-Up

2 Years

CSC Infusion

SCIPIO: Protocol

CSC Rx

• ECG x 3
• BMP, LFTs
• CBC
• Cardiac enzymes x

3

• Physical exam
• 2-D & 3-D Echo
• 24-h Holter monitor
• ECG
• BMP & LFTs
• CBC, & cardiac enzymes
• Physical Exam
• 2-D & 3-D Echo
• 24-h Holter monitor
• ECG
• BMP & LFTs
• CBC, & cardiac enzymes
• Physical Exam

Follow-up

24h Week 1 Week 2 Week 4 Month 4

• ECG
• BMP, LFTs
• CBC
• Cardiac enzymes
• Physical exam
• 2-D & 3-D Echo
• Cardiac MRI
• ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class

assessment

CSC Rx

Follow-up

Month 8 Year 1 Year 2

• 2-D & 3-D Echo
• Cardiac MRI
• ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class assessment
• ECG
• BMP, LFTs
• CBC
• 2-D & 3-D Echo
• Cardiac MRI
• ECG, Physical Exam
• BMP, LFTs, CBC, and BNP
• Minnesota Heart Questionnaire and NYHA class assessment

SCIPIO: Protocol

SCIPIO Phenotype of CSCs

SCIPIO: Phenotype of CSCs

SCIPIO: Phenotype of CSCs

SCIPIO Phenotype of CSCs

SCIPIO: Phenotype of CSCs

SCIPIO: Phenotype of CSCs

SCIPIO: Phenotype

• f CSCs

Telomere Length

SCIPIO: Phenotype of CSCs

SCIPIO: Results

Ejection Fraction at 4 Months After CSCs Absolute EF Units

Baseline 4 months Pre-CSC 4 months Controls (n=7) CSC-treated (n=14)

20 40 60

30.3±1.9 38.5±2.8

P=0.001

30.1±2.4 30.2±2.5

5 10 15 20

SCIPIO: Results

Change in Ejection Fraction After CSC Treatment

4 months

P=0.001

8.2±2.0 12.3±2.1

Absolute EF Units

P<0.001

12 months

n=14 n=8

10 20 30 40 50 60 70 80 90

Ejection Fraction (MRI) After CSC Therapy

4 months 12 months Pre-CSC n=8 n=8 n=5 27.5 35.1 41.2

Absolute EF units

SCIPIO: MRI Results

P=0.004 P=0.013

5 10 15 20 25

Change in Ejection Fraction (MRI) After CSC Therapy

n=5 n=8

P=0.004

7.7±1.8

P=0.013

13.6±3.2

ΔEF (absolute EF units)

4 months 12 months

SCIPIO: MRI Results

Baseline EF: 27.5%

10 20 30 40

• 40
• 20

20 40 60 80

Regional Ejection Fraction in Infarct-Related Segments After CSC Therapy

n=8 n=8 n=5

10.3 24.5 21.5 Pre-CSC 4 months 12 months

Absolute EF units

4 months 12 months

n=5 n=8

P=0.008 14.2±3.9 P=0.085 17.9±7.9

ΔEF (absolute EF units)

SCIPIO: MRI Results

10 20 30 40 10 20 30 40 50

P=0.008 n=8

24.5±6.4 10.3±6.9 Pre-CSC 4 months

P=0.085 n=5

21.5±7.3 3.5±6.7 Pre-CSC 12 months

Absolute EF units

Regional Ejection Fraction (MRI) in Infarct- Related Segments After CSC Therapy

SCIPIO: MRI Results

20 40 60 80

• 40
• 20

20 40

Regional Ejection Fraction in Dyskinetic Segments After CSC Therapy

4 months 12 months Pre-CSC

n=7 n=7 n=4

• 20.6

3.9 7.9

Absolute EF units ΔEF (absolute EF units)

n=4 n=7

P=0.014 24.5±7.1 P=0.030 35.7±9.1 4 months 12 months

SCIPIO: MRI Results

20 40 60 80

• 100
• 80
• 60
• 40
• 20

20 40 60 80

Regional Ejection Fraction in the Least Functional Segment After CSC Therapy

4 months 12 months Pre-CSC

n=8 n=8 n=5

• 32.7
• 7.1

2.7

Absolute EF units ΔEF (absolute EF units)

n=5 n=8

P=0.020 25.6±8.5 P=0.023 40.2±11.3 4 months 12 months

SCIPIO: MRI Results

0.0 0.5 1.0 1.5 2.0 2.5 3.0

SCIPIO: Results

Global Wall Motion Score Index 4 Months After CSC Treatment

Baseline 4 months Pre-CSC 4 months Controls (n=7) CSC-treated (n=14)

P=0.005

1.91 1.73 1.89 1.88

1 2 3 4 5

Global WMSI After CSC Treatment in Patients Who Have Completed 12 Month Follow-up

4 months Pre-CSC 12 months

P=0.010 P=0.008

n=8 1.99±0.08 1.73±0.10 1.68±0.12

SCIPIO: Results

SCIPIO: Infarct Regression

Before CSCs 24 months after CSCs

• 30
• 25
• 20
• 15
• 10
• 5

10 20 30 40 50

SCIPIO: MRI Results

Change in Infarct Size by CMR Using a Semi- automated (FWHM) Method After CSC Treatment

n=6 n=9 P=0.003

• 15.2±2.8
• 44.8%

P<0.001

• 13.3±2.3
• 38.1%

4 months 12 months 4 months 12 months Pre-CSC

Mass (g) Change in mass (g)

n=9 n=9 n=6

34.9 21.6 18.7

• 30
• 25
• 20
• 15
• 10
• 5

SCIPIO: MRI Results

Change in Non-Viable Tissue by CMR After CSC Treatment

10 20 30 40 50 60

4 months 12 months Pre-CSC

Mass (g)

n=9 n=9 n=6

24.1 12.1 10.4

Change in mass (g)

• 12.0±2.5

P=0.001

• 49.7%
• 14.8±3.9

P=0.013

• 58.6%

n=9 n=6 4 months 12 months

10 20 30 40 50 60 70 50 100 150 200 250 300

SCIPIO: MRI Results

4 months 12 months Pre-CSC

Mass (g) Change in mass (g)

4 months 12 months

n=9 n=9 n=6

151.1 162.6 177.8 n=9 n=6

7.6%

11.6±5.2 P=0.055

21.5%

31.5±11.0 P=0.035

Change in Viable Tissue by CMR After CSC Treatment

1 2 3 4

Baseline 4 months Pre-CSC 4 months Controls (n=7) CSC-treated (n=16)

P=0.172 P=0.003

2.0±0.0 1.7±0.2

New York Heart Association Score 4 Months After CSC Treatment

2.2±0.2 1.6±0.2

SCIPIO: Results

1 2 3 4 5 6

NYHA Score After CSC Treatment in Patients Who Have Completed 12 Month Follow-up

4 months Pre-CSC 12 months

P=0.024 P=0.004

n=10 2.4±0.22 1.8±0.20 1.5±0.17

SCIPIO: Results

20 40 60 80 Pre-CSC 4 months Baseline 4 months Controls (n=7) CSC-treated (n=16)

P<0.001

MLHFQ Score 4 Months After CSC Treatment

38.1±10.5 40.4±9.2 46.4±5.2 26.7±4.9

SCIPIO: Results

MLHFQ After CSC Treatment in Patients Who Have Completed 12 Month Follow-up

20 40 60 80 4 months Pre-CSC 12 months

P<0.001 P=0.007

n=10 41.7±7.5 27.7±6.9 23.5±8.0

SCIPIO: Results

i) Feasibility and safety The initial results of SCIPIO indicate that, in patients with ischemic cardiomyopathy:

1.

Isolation, expansion, and infusion of a highly pure population of c-kitpos CSCs are feasible in virtually all cases.

2.

It is possible to obtain viable CSCs with high telomerase activity and telomeres >7 kbp.

3.

Intracoronary infusion of autologous CSCs is not associated with appreciable adverse effects.

SCIPIO: Summary

ii) Efficacy The initial results of SCIPIO indicate that:

4.

Infusion of CSCs results, 4 months later, in a reduction in infarct size, an increase in viable myocardium, and a marked improvement in LV EF, NYHA functional class, and quality of life (MLHFQ).

5.

These effects persist and are even more pronounced at 1 year.

SCIPIO: Summary

The initial results of SCIPIO suggest that administration of autologous c-kitpos CSCs is feasible and safe and produces a sustained increase in viable myocardium, LV systolic function, and functional capacity in patients with ischemic cardiomyopathy. Larger, Phase II studies are warranted.

SCIPIO: Conclusions

Acknowledgments

Xian-Liang Tang Yiru Guo Gregg Rokosh Qianghong Li Atul Chugh John Loughran Sohail Ikram Marcus Stoddard Steve Wagner Garth Beache Mark Slaughter Boston group Piero Anversa Annarosa Leri Jan Kajstura

Institute of Molecular Cardiology

Thank You