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“ Next steps in stem cell therapy for heart repair :

Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany. “ Next steps in stem cell therapy for heart repair : The clinical view – a ( very ) personal view !“. 7th International Symposium on Stem Cell Therapy & CV Innovations, Madrid, 05 / 2010.

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“ Next steps in stem cell therapy for heart repair :

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  1. Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany “Next steps in stemcelltherapyforheartrepair: The clinicalview – a (very) personal view !“ 7th International Symposium on Stem Cell Therapy & CV Innovations, Madrid, 05 / 2010 Disclosure information: Guidant (research support) t2cure (co-founder, advisor)

  2. Cells for functional cardiac repair Embyronic-like stem cells (iPS) 4 genes: Oct4, Klf4, Sox2, myc somatic cells (skin fibroblasts) Cardiac stem cells Modified from Dimmeler et al, JCI 2005

  3. Cell therapy in cardiovascular diseases AcuteMyocardialInfarction Refractory Angina Peripheralarterialocclussivedisease Chronic post-infarctionheartfailure

  4. LV contractile recovery within 1 week after successful reperfusion determines clinical outcome in STEMI There is no linear correlation between mortality and ejection fraction after AMI ! Volpi et al., Circulation 1993; 88: 416-429

  5. VALIANT Valsartan in Acute Myocardial Infarction Trial 23% in 1 year 30 % in 2 years • 14703 patients • STEMI • 0.5 - 10 days • EF < 40% • Killlip I-III • Diuretics 60%, • Beta-Blocker 71% Probability of cardiac death, re-MI rehospitalisation for heart failure NEJM 2003, 349: 1893-1906

  6. Enhanced contractile recovery by BMC is confined to patients with failed initial recovery p for interaction = 0.020 10 p = 0.002 p = 0.81 8 6 Absolute change in global LVEF (%) 4 2 3.70.7 4.00.6 2.51.1 7.51.1 0 Placebo Placebo BMC BMC n = 52 41 40 54 Baseline LVEF by QLVA EF below median ( 48.9 %) EF above median (> 48.9 %) Schächinger et al., N Engl J Med 2006

  7. REGENT FINNCELL trial < median > median < median p = 0.04 30 BMC 25 Placebo 60 20 p=0.007 36 50 15 31 40 Change in EF (%) 10 30 5 0 20 -5 10 0 6 months 0 0 6 months 6 months Courtesy of H. Huikuri, European Heart Journal, 2008 Enhanced contractile recovery by BMC in patients with failed initial recovery – results of recent controlled trials REGENT trial Controls N=20 BMC N=46 80 80 p=0.01 p=0.73 70 70 37 40 39 39 60 60 50 50 40 40 30 30 20 20 10 10 Courtesy of M Tendera, European Heart Journal, 2009

  8. BMC therapy is associated with improved clinical outcome at 2 years - Death, MI, Rehospitalization forheartfailure - 100 BMC 90 Placebo 80 Event-freesurvival (%) (death, myocardialinfarction, rehospitalization f. heartfailure) p = 0.009 70 (log rank) 60 0 days 0 100 200 300 400 500 600 700 Placebo 103 93 90 86 86 BMC 101 99 98 97 95 # exposed to risk CirculationHeartFail 2009

  9. a large-scale clinical endpoint trial is warranted to document the effects on mortality and morbidity Next step in celltherapyof AMI In patients with acute post-infarction heart failure despite successful reperfusion therapy

  10. Cell therapy in cardiovascular diseases AcuteMyocardialInfarction Refractory Angina Peripheralarterialocclussivedisease Chronic post-infarctionheartfailure

  11. Cell Therapy for Refractory Angina JAMA, May 2009

  12. Cell Therapy for Refractory Angina JAMA, May 2009

  13. Phase II ACT34–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 5mcg/kg/d x 5d) Apheresis on Day 5 Randomization 1 x 10^5 CD34+ cells/kg (n = 55) Placebo (n = 56) 5 x 10^5 CD34+ cells/kg (n = 56) Endomyocardial Mapping and Injection with NOGA Isolex selected CD34+ 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 Courtesy of Doug Losordo

  14. ACT-34 CMI: Increase in Exercise Time Total ETT Time Change from baseline at 6 months p=0.013 Seconds Courtesy of Doug Losordo

  15. a phase III clinical trial aiming at approval of NOGA-guided injection of BMC or CD34+ cells for treatment of stable refractory angina, e.g. like ranolazine Next step in celltherapyofrefractoryangina

  16. Cell therapy in cardiovascular diseases AcuteMyocardialInfarction Refractory Angina Peripheralarterialocclussivedisease Chronic post-infarctionheartfailure

  17. Vascularization  Apoptosis  Paracrine factors Chronic Post-Infarction Heart Failure Cardiac Regeneration - Very modest effects on improvement of LV function - Lack of larger randomized controlled trials - Lack of data on clinical outcome with hard endpoints Aims of cell therapy Acute Infarction Chronic Heart Failure Adverse LV Remodeling Reverse LV Remodeling  ? LV- Dilatation 1. Prevent post-infarction heart failure 2. Reverse established heart failure

  18. BMC therapy in CHF – effects on mortality? Limited data on efficacy is available that suggest rather small beneficial effects on cardiac function, but there exists no data on mortality. • Comparison of observed and model-predicted * mortality in 297 consecutive patients treated with intracoronary BMC infusion. Seattle Heart Failure Model (SHFM):multivariable risk model that predicts all-cause and cause-specific mortality in patients with chronic heart failure, including contemporary pharmacological and device therapies: (validated in 9942 patients from large clinical trials: ELITE2, Val-HeFT, UW, RENAISSANCE, IN-CHF)

  19. Consistently lower observed mortality than model-predicted mortality throughout 3 years Fup Val-HeFT 25 20 Mortality (%) 15 observed 10 model-predicted 5 0 1 2 3 Years of Follow Up n = 295 244 202

  20. observed Model-predicted Single BMC Administration 25 mean SHFM Score 0.48 ± 0.9 mean SHFM Score 0.45 ± 0.9 Single BMC administration 20 Repeated BMC administration 15 Mortality (%) 1.00 10 5 0.95 0 1 2 3 Years of Follow Up 0.90 n = 189 158 132 Estimated cumulative survival [%] Repeated BMC Administration 30 0.85 P=0.048 20 0 Mortality (%) 10 0 1 2 3 Years of Follow Up 0 1 2 3 Years of Follow Up n = 106 86 70 Only repeated intracoronary BMC treatment is associated with lower mortality than SHFM-model predicted mortality

  21. Tertile I (CFU ≤ 17.5) (n=95) 30 25 20 15 Mortality (%) 10 5 1.00 0 1 2 3 Tertile II (17.5 ≤ CFU ≤29.5) (n=96) 0.90 25 20 15 Mortality (%) 10 0.80 I Tertile 5 Cumulative survival [%] 0 1 2 3 II Tertile Tertile III (CFU > 29.5) (n=94) 20 0.70 16 0 12 Mortality (%) III Tertile 8 P (log rank)=0.02 4 3 0 1 2 4 0 1 2 3 Years follow-up Years of Follow Up Application of functionally competent BMCs is essential for lower mortality than predicted

  22. Pretreatment of cells Recruitment in target tissue Bone marrow Skeletal muscle Adipose tissue Other sources Blood Cell therapy * small molecules genes Pretreatment of the target region * * * * * * * * * * * * * * * * * * * * * Enhancement strategies for cell therapy as next steps in chronic heart failure eNOS enhancer p38 inhibitors PPARg agonist shock wave pretreatment nanofiber-based delivery Seeger et al, Nat Clin Pract Cardiovasc Med, 2007

  23. Stefanie Dimmeler Birgit Assmus Volker Schächinger www.REPAIR-AMI.org

  24. Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main Clinician Scientists: J. Honold, R. Lehmann U. Fischer-Rasokat S. Fichtlscherer F. Seeger, C.Kissel S. DeRosa N. Bellera Gotarda Experimental Studies C. Urbich, A. Kühbacher M. Potente A. Aicher E. Chavakis, G. Carmona L. Rössig, D. Scharner M. Koyanagi, M. Iwasaki Th. Ziebart, C. Yoon & technical help (Andrea, Nicole,Ariane, Marion, Tino) Dept. of Hematology H. Martin / W. Hofmann D. Hoelzer Kerckhoff Clinic C. Hamm / T. Dill Dept. of Radiology N. Abolmaali / J. Schmitt T. Vogl Red Cross Frankfurt T. Tonn / Seifried T. Brühl, M. Vasa,K. Sasaki, C. Badorff, C. Heeschen

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