Cell Therapy Update what have we learned from clinical trials?

Transcription

1 Andreas M. Zeiher, MD Dept. of Internal Medicine III University of Frankfurt Germany Cell Therapy Update what have we learned from clinical trials? Cardiology Update 2011, Davos, 2 / 2011 Disclosure information: t2cure (co-founder, advisor)

2 The Heart is a Regenerating Organ Undisputable Evidence from DNA Integration of C-14 generated during nuclear bomb testing during cold war - Bergmann O et al., Science 2009; 324:98-102

3 Activation of endogenous regeneration by bone marrow-derived cells Lofredo/Steinhauser et al, Cell Stem Cells in press GFP+ = existing cardiomyocytes LacZ+ = newly formed cardiomyocytes

4 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlusive disease Chronic post-infarction heart failure

5 Cell Therapy in Acute Myocardial Infarction: therapeutic targets Acute Myocardial Infarction Adverse LV Remodeling Chronic Heart Failure infarct expansion chronic LV- dilatation Vascularization Apoptosis Paracrine factors Cardiac Regeneration Metaanalysis of randomized and cohort studies of progenitor cell therapy in ischemic heart disease N = 976; overall treatment effect percentage points increase in LV-EF ( p < ) Abdel-Latif, Arch Intern Med 2007; 167:989

6 Cell Therapy for Ischemic Heart Failure The patient population at risk post-ami Effects of cell therapy in patients at risk Derivation of the clinical benefit

7 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:

8 Cell Therapy for Ischemic Heart Failure The patient population at risk post-ami Effects of cell therapy in patients at risk

9 Enhanced contractile recovery by BMC is confined to patients with failed initial recovery Absolute change in global LVEF ( %) Baseline LVEF by QLVA EF below median ( 48.9 %) p for interaction = p = p = Placebo BMC Placebo BMC n = EF above median (> 48.9 %) Schächinger et al., N Engl J Med 2006

10 Enhanced contractile recovery by BMC in patients with failed initial recovery results of recent controlled trials REGENT trial REGENT FINNCELL trial Controls N=20 p= BMC < median N=46 p=0.01 p= months 0 6 months European Heart J 1 /2009 Change in EF (%) < median > median p = 0.04 BMC Placebo Courtesy of H. Huikuri, European Heart Journal, 2008

11 Adverse remodeling is confined to patients with failed initial recovery of EF and abrogated by BMC therapy EF < median EF > median Change of endsystolic volumes over time (MRI) 140 p = 0.01 Endsystolic volume (ml) p = 0.7 p = 0.06 p = 0.9 p = 0.7 p = 0.5 BMC Placebo 0 Baseline 4 months 12 months Baseline 4 months 12 months Baseline EF: % Baseline EF: % Dill et al., AHJ 2009

12 Cell Therapy for Ischemic Heart Failure The patient population at risk post-ami Effects of cell therapy in patients at risk Derivation of the clinical benefit

13 Do beneficial effects of BMC therapy on adverse remodeling translate into clinical benefit?? Therapies preventing adverse remodelling reduce adverse cardiovascular events ACEI, ARB, ß-Blocker, Aldosteron-Ant.

14 BMC therapy is associated with improved clinical outcome at 2 years - Death, MI, Rehospitalization for heart failure Event-free survival (%) (death, myocardial infarction, rehospitalization f. heart failure) p = (log rank) BMC Placebo days # exposed to risk Placebo BMC CirculationHeartFail 2009

15 2 years clinical follow up - Hazard Ratios - Death Myocardial infarction Revascularization Rehospitalization for heart failure p = p = 0.18 p = p = 0.26 Combined Death or MI Death, MI or Rehospitalization for heart failure Death, MI or Revascularization CircHeartFail 2009 p = p = p = ,01 0,05 0,1 0,2 0, BMC better Placebo better

16 5 years clinical follow up - Kaplan Meier Analysis - Death 1.0 BMC Event-free survival (%) (death) Placebo p = (log rank) Days follow-up

17 5 years clinical follow up Per patient analysis Placebo n = 99 number of patients BMC n = 97 p value Ventricular arrhythmia or syncope (n) PM / ICD Implantation (n) Stroke (n) Cancer (n) (lung, colon, sigma, prostate) Combined Death, MI Death, Rehosp. for heart failure (n) Death, MI, Rehosp. for heart failure (n) Death, MI, Revascularization (n)

18 BMC Therapy in Acute Myocardial Infarction Mechanisms of action?

19 Putative mechanisms for cardiac regeneration Cell homing and tissue integration EC Differentiation SMC Differentiation Paracrine Effects Cardiac Differentiation Fusion Angiogenesis Attraction/ Activation of CSC Arteriogenesis Cardiomyocyte Proliferation Vasculogenesis Cardiomyogenesis Cardiomyocyte Apoptosis Modulation of Inflammation Scar Remodelling FUNCTIONAL CARDIAC REGENERATION

20 Mechanistic Insights from Coronary Flow Assessment Assessment of maximum coronary vascular conductance Adenosine (140 µg/kg i.v.) NTG (epicardial vessel dilation) Doppler wire (Flowire ) APV Infarct artery and Reference vessel Coronary flow reserve Relative flow reserve CFR = APV adenosine / APV basal rcfr = CFR target vessel / CFR reference vessel Core Lab: Sandra Erbs / Rainer Hambrecht (Herzzentrum Leipzig) 3 Centers (54 patients) Herzzentrum Leipzig (32), J. W. Goethe University Frankfurt (20), Herz- u. Diabeteszentrum Bad Oeynhausen (2)

21 Intracoronary BMC Administration Normalizes Coronary Flow Reserve Infarct vessel CFR Relative CFR (infarct vessel normalized to reference vessel) p = ,8 p = abs. infarct vessel CFR 2,0 1,5 1,0 0,5 0, abs. Relative CFR 0,6 0,4 0,2 0, Placebo BMC Placebo BMC n = 26 n = 28 Erbs et al., Circulation 2007 n = 26 n = 27

22 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlusive disease Chronic post-infarction heart failure

23 Cell Therapy for Refractory Angina JAMA, May 2009

24 Cell Therapy for Refractory Angina JAMA, May 2009

25 Phase II ACT34 CMI Study Design Screening and Baseline Visits Subject population (n=167) Cell Mobilization (GCSF 5mcg/kg/d x 5d) Apheresis on Day 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 1 x 10^5 CD34+ cells/kg (n = 55) Randomization 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

26 Seconds ACT-34 CMI: Increase in Exercise Time Total ETT Time Change from baseline at 6 months p=0.013 Placebo Low High Series Courtesy of Doug Losordo

27 ACT-34 CMI: SPECT Total Severity Score - Stress Change from baseline at 6 months p= Placebo Low High Series Courtesy of Doug Losordo

28 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlusive disease Chronic post-infarction heart failure

29 Randomized-start, placebo controlled, multicenter trial with a cross-over phase PROVASA Study Flow Chart 40 Patients R Baseline BMC 1:1 Placebo 3 Months (open-label) BMC 6 Months (Optional BMC) Extended Protocol Long-term F/U Mean 30.2 months (6-57 months)

30 5 PROVASA Ulcer Healing- quantitative Analysis 4 P=0.009 Mean Ulcer Area (cm²) P=0.5 P=0.09 SE Placebo (n=12) BM-MNC (n=10) 0 P=0.014 P=0.059 P=0.2 Baseline M3 M6 Randomized-Start All BM-MNC Walter et al., CircIntervention Figure 3A 2011

31 PROVASA Ulcer Area- Absolute Reduction Placebo (n=12) 1x BM-MNC (n=10 ) + (n = 11) 2x BM-MNC (n=19) Mean Reduction of Ulcer Area (cm²) 0-0,5-1 -1,5-2 -2,5-3 Placebo 1x BM-MNC 2x BM-MNC P=0.16 vs Placebo P=0.018 vs Placebo Walter et al., CircIntervention 2011

32 PROVASA Pain Analysis-Absolute Reduction Placebo (n=15) 1x BM-MNC (n=15 ) + (n = 10) 2x BM-MNC (n=10) 0-0,5 Placebo 1x BMC 2x BMC -1 Pain scale -1,5-2 -2,5-3 P=0.1 vs Placebo -3,5-4 -4,5 P=0.002 vs Placebo Walter et al., CircIntervention 2011

33 Multivariate Analysis Clinical Improvement (Healing or Pain Reduction) Factor P Exp (B) Hazard 95% CI Age Ulcer size EF Pain at baseline Creatinine < 1.4 mg/dl Buerger s disease (TAO) Repeated BM-MNC administration as well as the number and functionality of administered BM-MNC were significant independent predictors for clinical improvement Cell number Repeated BM-MNC ( 2 applications) Cell function Walter et al., CircIntervention 2011

34 Cell therapy in cardiovascular diseases Acute Myocardial Infarction Refractory Angina Peripheral arterial occlusive disease Chronic post-infarction heart failure

35 Aims of cell therapy Acute Infarction Adverse LV Remodeling Chronic Heart Failure Reverse LV Remodeling? Vascularization Apoptosis Paracrine factors Cardiac Regeneration 1. Prevent post-infarction heart failure LV- Dilatation 2. Reverse established heart failure

36 Bone marrow cells in ischemic heart failure: specific issues in chronic heart failure Reverse LV Remodeling? - healed infarction -established scar -lack of inflammation -remodeled LV -chronically ill patient

37 Moderate improvement in EF is associated with decreased NT-proBNP serum levels after BMC therapy in patients with chronic post-infarction heart failure LV-EF NT-proBNP p = Change in LV ejection fraction absolute (mean ± SEM, %) p = 0.03 p = 0.38 NT-proBNP serum levels Mean ± SEM [pg/ml] p = BMC N=28 CPC N=26 Control N=18 0 Baseline Follow-up (3 months) BMC therapy; N=61 Assmus et al., N Engl J Med 2006 Assmus et al., Circ Res 2007

38 Single vs. Repetitive Cell Administration in CHF Number of Administrations N of patients Time between administrations (median/sem) Single Repeated -> (0.75) months Repeated -> (2.8) months Repeated -> (2) months n = 188 -> single administration day 0 n at risk = 297 month 4 n = 109 -> repeated administration 3 years

39 Multiple administrations of BMC may be associated with better long-term outcome compared to single treatment Single Administration Repeated Administration Mortality (%) ± ± Years of Follow Up Years of Follow Up n = lost = observed estimated

40 Effect of BMC therapy on mortality in patients with heart failure Landmark analysis Cumulative survival [%] Years follow-up Single BMC treatment Repeated BMC treatment p = 0.048

41 Number of cell administrations, togheter with age and baseline SHFM score is an independent predictor of death at 3 years Multivariate Analysis Beta p value Age NT-proBNP SHFM Score < Single/Repeated Th SHFM Score: Seattle Heart Failure Model Score

42 Cell Therapy for Cardiovascular Diseases: Where are we now? Acute Myocardial Infarction - Evidence for beneficial effects in patients at risk - Strong signals towards a possible clinical benefit - Large-scale clinical outcome trials are warranted Refractory Angina / PAOD - Promising results in small randomized controlled trials - Persistence of the effects uncertain - Difficult patient cohort to demonstrate clinical effects Chronic Post-Infarction Heart Failure - Very modest effects on improvement of LV function - Lack of larger randomized controlled trials - Lack of data on clinical outcome with hard endpoints

43 Cell therapy of cardiovascular diseases: present and future 2001/ Future Bone marrow Total bone marrow mononuclear cells CD133 + cells Bone marrow Hematopoetic stem cells CD34 + Mesenchymal stem cells Bone marrow CD34 + CXCR4 + Adipose tissuederived cells Cardiac stem cells c-kit+ Cardiospheres Enhancement Shock waves for enhancing cell engraftment Factors to enhance cardiac differentiation New types of adult stem cells New enhancement strategies ips cells? Embryonic stem cells? Cardiac stem cells: SCIPIO trial (c-kit+) CADUCEUS trial (cardiospheres) (first in man 2009) (Chavakis et al, Circulation, 2010)

44 Stefanie Dimmeler Birgit Assmus Volker Schächinger

45 Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main Clinician Scientists: J. Honold, R. Lehmann U. Fischer-Rasokat S. Fichtlscherer F. Seeger, D. Leistner S. DeRosa, S. Palm N. Bellera Gotarda Experimental Studies C. Urbich, A. Bonauer M. Potente A. Aicher E. Chavakis, G. Carmona M. Koyanagi, M. Iwasaki 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