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

American Heart Association Scientific Sessions American Heart Association Scientific Sessions c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy Roberto Bolli, M.D. Institute of Molecular Cardiology University of Louisville Los Angeles, CA

Presenter Disclosure information Roberto Bolli, M.D. c-Kit Stem Cell Therapy of Ischemic Cardiomyopathy FINANCIAL DISCLOSURE: None UNLABELED/UNAPPROVED USES DISCLOSURE: None

Publius Cornelius Scipio Africanus (235 – 183 BC) 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

SCIPIO (Study of Cardiac Stem Cells Infusion in Patients with Ischemic CardiOmyopathy) Institute of Molecular Brigham and Cardiology Women’s Hospital John Loughran Atul Chugh Piero Anversa Brandon Elmore Sohail Ikram Annarosa Leri Marcus Stoddard Steve Wagner Jan Kajstura Domenico D’Amario Garth Beache

SCIPIO: Objectives The overall goal is to translate the discovery of CSCs into clinically useful therapies. Primary Objective 1. To assess the feasibility and safety of infusing autologous c-kit pos CSCs in patients with ischemic heart failure. Secondary Objective 2. To obtain preliminary evidence for or against the efficacy of CSCs in augmenting LV function, improving functional status, and promoting myocardial regeneration.

SCIPIO: Time Line A result of many years of preclinical work: FDA First patient Last Patient FDA contacted approval on enrolled on Enrolled in October August 8, March 13, May 17, 2004 2008 2009 2011 2004 2006 2008 2010 2012 IND application Trial opened to First CSC infusion submitted on enrollment in July 17, 2009 January 2006 February 2009

November 14, 2011

SCIPIO Inclusion Criteria  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: Protocol < 2 Weeks CABG & Tissue Enrollment Harvesting At the time of CABG, the right atrial appendage is resected and prepared for CSC isolation CSC isolation and expansion

SCIPIO: Protocol 2 Years < 2 Weeks 4 ± 1 Months CSC CABG & Tissue Enrollment Follow-Up Harvesting Infusion • Cardiac MRI • 2-D & 3-D Echo • ECG, Physical Exam • BMP, LFTs, CBC, and BNP • Minnesota Heart Questionnaire and NYHA class assessment

SCIPIO: Protocol • 2-D & 3-D Echo • Cardiac MRI • 2-D & 3-D Echo • ECG, Physical Exam • BMP, LFTs, CBC, and BNP • 24-h Holter monitor • Minnesota Heart Questionnaire and NYHA class • ECG • BMP & LFTs assessment • CBC, & cardiac enzymes • Physical Exam Follow-up CSC 24h Week 1 Week 2 Week 4 Month 4 Rx • 2-D & 3-D Echo • ECG x 3 • ECG • BMP, LFTs • BMP, LFTs • 24-h Holter monitor • CBC • CBC • ECG • Cardiac enzymes x • Cardiac enzymes • BMP & LFTs • Physical exam • CBC, & cardiac enzymes 3 • Physical exam • Physical Exam

SCIPIO: Protocol • 2-D & 3-D Echo • Cardiac MRI • ECG, Physical Exam • BMP, LFTs, CBC, and BNP • Minnesota Heart Questionnaire and NYHA class assessment Follow-up CSC Month 8 Year 1 Year 2 Rx • 2-D & 3-D Echo • ECG • Cardiac MRI • BMP, LFTs • CBC • ECG, Physical Exam • BMP, LFTs, CBC, and BNP • Minnesota Heart Questionnaire and NYHA class assessment

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 of CSCs

SCIPIO: Phenotype of CSCs Telomere Length

SCIPIO: Results Ejection Fraction at 4 Months After CSCs 60 P =0.001 Absolute EF Units 38.5 ± 2.8 40 30.1 ± 2.4 30.2 ± 2.5 30.3 ± 1.9 20 0 Baseline 4 months Pre-CSC 4 months Controls (n=7 ) CSC-treated (n=14)

SCIPIO: Results Change in Ejection Fraction After CSC Treatment n=14 n=8 20 Absolute EF Units P <0.001 12.3 ± 2.1 15 P =0.001 8.2 ± 2.0 10 5 0 4 months 12 months

SCIPIO: MRI Results Ejection Fraction (MRI) After CSC Therapy 90 n=8 n=8 n=5 80 Absolute EF units 70 P =0.013 60 P =0.004 41.2 50 35.1 40 27.5 30 20 10 0 Pre-CSC 4 months 12 months

SCIPIO: MRI Results Change in Ejection Fraction (MRI) After CSC Therapy Baseline EF: Δ EF (absolute EF units) n=8 n=5 25 27.5% P =0.013 20 13.6 ± 3.2 15 P =0.004 7.7 ± 1.8 10 5 0 4 months 12 months

SCIPIO: MRI Results Regional Ejection Fraction in Infarct-Related Segments After CSC Therapy Δ EF (absolute EF units) 80 n=8 n=8 n=5 n=8 n=5 40 Absolute EF units 60 P =0.085 30 17.9 ± 7.9 24.5 40 21.5 P =0.008 10.3 14.2 ± 3.9 20 20 0 10 -20 -40 0 Pre-CSC 4 months 12 months 12 months 4 months

SCIPIO: MRI Results Regional Ejection Fraction (MRI) in Infarct- Related Segments After CSC Therapy n=8 n=5 50 P =0.008 P =0.085 Absolute EF units 40 40 24.5 ± 6.4 30 21.5 ± 7.3 30 20 10.3 ± 6.9 20 3.5 ± 6.7 10 10 0 0 Pre-CSC 4 months Pre-CSC 12 months

SCIPIO: MRI Results Regional Ejection Fraction in Dyskinetic Segments After CSC Therapy Δ EF (absolute EF units) 40 80 n=7 n=7 n=4 n=7 n=4 Absolute EF units 7.9 20 P =0.030 60 3.9 35.7 ± 9.1 P =0.014 0 40 24.5 ± 7.1 - 20.6 -20 20 -40 0 Pre-CSC 4 months 12 months 4 months 12 months

SCIPIO: MRI Results Regional Ejection Fraction in the Least Functional Segment After CSC Therapy Δ EF (absolute EF units) 80 n=8 n=8 n=5 n=8 n=5 80 60 Absolute EF units P =0.023 40 40.2 ± 11.3 2.7 60 20 -7.1 P =0.020 0 -32.7 25.6 ± 8.5 40 -20 -40 20 -60 -80 -100 0 Pre-CSC 4 months 12 months 4 months 12 months

SCIPIO: Results Global Wall Motion Score Index 4 Months After CSC Treatment 3.0 P =0.005 2.5 1.91 1.88 1.89 1.73 2.0 1.5 1.0 0.5 0.0 Baseline 4 months Pre-CSC 4 months Controls (n=7) CSC-treated (n=14)

SCIPIO: Results Global WMSI After CSC Treatment in Patients Who Have Completed 12 Month Follow-up 5 n=8 4 P =0.008 P =0.010 3 1.99 ± 0.08 1.73 ± 0.10 1.68 ± 0.12 2 1 0 Pre-CSC 4 months 12 months

SCIPIO: Infarct Regression Before CSCs 24 months after CSCs

SCIPIO: MRI Results Change in Infarct Size by CMR Using a Semi- automated (FWHM) Method After CSC Treatment Change in mass (g) n=9 n=9 n=6 50 -5 34.9 40 Mass (g) -10 30 21.6 -15 18.7 P<0.001 20 -13.3 ± 2.3 P=0.003 -20 -15.2 ± 2.8 -38.1% 10 -44.8% -25 n=9 n=6 0 -30 12 months Pre-CSC 4 months 4 months 12 months

SCIPIO: MRI Results Change in Non-Viable Tissue by CMR After CSC Treatment 60 n=9 n=6 n=9 Change in mass (g) -5 50 -10 40 Mass (g) 24.1 30 -15 -12.0 ± 2.5 12.1 20 10.4 P =0.001 -14.8 ± 3.9 -20 -49.7% 10 P =0.013 -58.6% -25 0 n=9 n=6 -30 Pre-CSC 4 months 12 months 4 months 12 months

SCIPIO: MRI Results Change in Viable Tissue by CMR After CSC Treatment 300 70 n=9 n=9 n=6 n=9 n=6 Change in mass (g) 60 21.5% 250 31.5 ± 11.0 177.8 50 Mass (g) 162.6 200 P =0.035 151.1 40 150 7.6% 30 11.6 ± 5.2 100 P =0.055 20 50 10 0 0 Pre-CSC 4 months 12 months 4 months 12 months

SCIPIO: Results New York Heart Association Score 4 Months After CSC Treatment 4 P =0.172 P =0.003 3 2.2 ± 0.2 2.0 ± 0.0 1.7 ± 0.2 2 1.6 ± 0.2 1 0 Baseline 4 months Pre-CSC 4 months Controls (n=7) CSC-treated (n=16)

SCIPIO: Results NYHA Score After CSC Treatment in Patients Who Have Completed 12 Month Follow-up 6 n=10 5 P =0.004 4 P =0.024 3 2.4 ± 0.22 1.8 ± 0.20 1.5 ± 0.17 2 1 0 Pre-CSC 4 months 12 months

SCIPIO: Results MLHFQ Score 4 Months After CSC Treatment 80 P <0.001 40.4 ± 9.2 60 46.4 ± 5.2 38.1 ± 10.5 40 26.7 ± 4.9 20 0 Baseline 4 months Pre-CSC 4 months Controls (n=7) CSC-treated (n=16)

SCIPIO: Results MLHFQ After CSC Treatment in Patients Who Have Completed 12 Month Follow-up n=10 P =0.007 80 P <0.001 60 41.7 ± 7.5 27.7 ± 6.9 40 23.5 ± 8.0 20 0 Pre-CSC 4 months 12 months

SCIPIO: Summary i) Feasibility and safety The initial results of SCIPIO indicate that, in patients with ischemic cardiomyopathy: Isolation, expansion, and infusion of a highly pure 1. population of c-kit pos CSCs are feasible in virtually all cases. It is possible to obtain viable CSCs with high 2. telomerase activity and telomeres >7 kbp. Intracoronary infusion of autologous CSCs is not 3. associated with appreciable adverse effects.

SCIPIO: Summary ii) Efficacy The initial results of SCIPIO indicate that: Infusion of CSCs results, 4 months later, in a 4. reduction in infarct size, an increase in viable myocardium, and a marked improvement in LV EF, NYHA functional class, and quality of life (MLHFQ). These effects persist and are even more pronounced 5. at 1 year.