1. By Justin Klee and Lucy Schultz
Stem Cell Therapy for Major Adverse Cardiac Events Following Acute Myocardial Infarction
By Justin Klee and Lucy Schultz

2. Overview Basic Physiology of the Heart
About Acute Myocardial Infarction (AMI)
Adverse Post-AMI Events
Stem Cell Therapy As Treatment
How it Works
Current Status
Conclusion

3. The Heart Supplies the Body With Blood
Responsible for pumping blood through the body
About 2,000 gallons
of blood/day
Four chambers
Three Tissue Layers
Pericardium - Protection
Myocardium - Involuntary smooth muscle
Epicardium - Lining

4. Acute Myocardial Infarction (AMI) is a Disruption of this Central Process
A.K.A. Heart attack
Interruption of blood flow to a part of the heart muscle
Symptoms:
Squeezing pain, heaviness, tightness, or pressure in chest; pain in back, left arm, jaw, or neck; shortness of breath; dizziness; weakness; nausea or vomiting; irregular heartbeat; sweating; feeling of doom
For women: heartburn, pain in abdomen, unusual fatigue, clammy skin
Risk Factors:
Smoking, high fat diet, lack of exercise, being overweight or obese, family history of heart attack, diabetes, high blood pressure, being male or a female who has gone through menopause, stress
usually because of coronary artery blockage or arthersclerosis

5. ST-Elevated Myocardial Infarction (STEMI) is a Severe Subset
Coronary artery is completely blocked off by blood clot
Heart muscle supplied by affected artery begin to die
Results in reduced Left Ventricular Ejection Fraction (LVEF) < 50%
Named for elevated ST wave on ECG
Target population for AMR-001 therapy
Braunwald et al. 2002
20% of AMIs; 160,000 patients/year

6. Impact on Patients is Large
10 million AMI events each year worldwide
715,000 AMI events each year in the US
20%, or 160,00 AMI patients have a ST-Elevation MI
95% of people hospitalized with a heart attack survive
Yet,
1 in 5 MI patients older than 45 will be dead within a year
Why?

7. Heart Function is Impaired After MI
Cardiac cell death leads to infarct expansion (scar)
Remaining heart muscle unable to compensate for damaged heart tissue
Patients at significant risk of adverse effects such as:
Congestive heart failure
Recurrent MI
Arrhythmias
Premature death
$30,000-$80,000 in medical costs per patient per year
60% of patients; Physiological changes in the heart due to acute loss of myocardium, Myocyte necrosis results in a cascade of biochemical intracellular signaling processes that initiate and modulate reparative changes, Peri-Infarct Zone forms surrounding infarct tissue , Has inadequate blood supply, Works harder to compensate for neighboring, non functioning myocardium, Signals for increased perfusion, Without response, this tissue begins to undergo apoptosis, Expands infarction region
Image courtesy of Amorcyte
Jagtap et al., 2005

8. Most Currently Available Treatments are Ineffective
Lifestyle changes (exercise, diet, smoking, etc.)
Medications
Aspirin, nitroglycerin, ACE inhibitors, Beta-blockers, Statins
Surgical treatments
Coronary Artery Bypass Graft (CABG)
Percutaneous Coronary Intervention (PCI)
LVEF is improved after PCI by only 3% to 4%
Percutaneous coronary intervention only restore heart muscle function to a minor degree
Longstanding (up to 3 years and more) improvement of ventricular performance after therapy

9. Can adult stem cells be administered after a patient has suffered a heart attack to preserve heart muscle that would otherwise die?
Milk Genomics Consort

10. Amorcyte (Neostem) Believes Yes
Clinical development-stage cell therapy company
Focused on treatments for cardiovascular disease
Lead product candidate is AMR-001
Therapy for the preservation of heart muscle function and prevention of major adverse cardiac events following STEMI
Granted first US patent for a chemotactic hematopoietic stem cell product, its delivery, as well as cell potency and stability

11. AMR-001 Stem Cell Therapy is Accessible and Promising
Autologous bone marrow CD34+ stem cell product
Contain several cell populations able to proliferate, migrate, and differentiate
Bone Marrow Stem Cells (BMSC) easily accessed, renewable, autologous source for regenerative cells
Image courtesy of Amorcyte
Hematopoetic, mesenchymal, endothelial progenitor, and side population cells

12. Patients Who Have Suffered an AMI Are Eligible for Therapy
Previous myocardial infarction with LVEF < 50%
Intracoronary stent implant
Wall motion abnormality in infarct-related artery myocardium
Studies suggest age of infarct less relevant for regenerative potency of BMCs

13. Therapy Administered During Out-Patient Procedure
Adult bone marrow blood aspirated from iliac crest under local anesthesia
CD34+/CXR4+ cells harvested
Single dose
Infused via infarct-related artery 6-11 days following STEMI
Conscious sedation and local anesthesia
Out-patient procedure in catheterization laboratory
Balloon catheter within stent
Automatic sorting mechanism to separate nucleated or mononuclear cells from aspirate
Images courtesy of Amorcyte

14. BMSC Therapy Models Natural Response Mechanism
Mechanism modeled after natural response
Distress signal induced by hypoxia in peri-infarct zone
Induces synthesis of SDF-1 and VEGF, which are natural signal to mobilize CD34+ CXCR4+ cells
BMSC differentiate into cardiomyocyte-like cells
Enhance angiogenesis
Improve regional blood flow
Enhance angiogenesis
Improve regional blood flow
Decrease infarction size
Improve cardiac function
Supply angiogenic ligands and cytokines
Supply angioblasts
Increase survival of endothelial lineage cells
Supply antiapoptotic factors for endothelial cells

15. Clinical Benefits Found for AMI Patients
Threshold dose >10 million cells
Increase in ejection fraction by 3-36% (mean 11.4%)
Decreased infarct size by 1- 60% (mean 34%)
Longstanding (up to 3 years and more) improvement of ventricular performance after therapy
Benefits sustained up to 5 year follow-up
Large variety of effects may be stem cell-related methods or dependent on different methods of evaluation
Strauer, Bodo-Eckehard et al. 2010

16. Clinical Benefits Found for AMI Patients
Schachinger et al., 2011

17. AMR-001 Clinical Trial Shows Beneficial Results
Phase I Clinical Trial Amorcyte
31 patients
Results demonstrated that patients receiving million cells showed significant improvement in perfusion rates after 3 months
Improvement in ejection fraction, end systolic volume, infarct size, and tissue death after 6 months
Quyyumi et al., 2011
Image courtesy of Amorcyte

18. No Complications Yet Found
Effective and safe therapy
Did not find:
Major stem cell-related side effects
Procedure-related side effects
Tumor formation
Progression of coronary artery diseases
Cardiac arrhythmias
Immunosuppressive therapy necessary
Inflammation
inflammation assessed by: Assessed through white blood cell count, serum levels of C-reactive protein, and creatine phopshpokinase

19. AMR-001 is Being Tested in a Larger, Longer Phase II Clinical Trial
Current Phase II Clinical Trial
To evaluate the potential to improve perfusion, preserve cardiac function, and improve clinical outcomes
Placebo controlled, double-blind study
Began enrolling patients in January 2012
Intend to enroll 160 patients
Patients will initially be followed for 6 months
Tracked for 3 years post treatment
(80 control, 80 treatment)

20. AMR-001 Is a Promising Treatment Option
AMR-001 and other autologous Bone Marrow Stem Cell therapies are safe and effective procedures able to greatly improve patient outcome after severe heart attack.
Great option for patients who have just suffered a heart attack

21. What's Next? Therapy for Congestive Heart Failure?
Other Ischemic Injuries?

22. References
Quyyumi, Arshed A. et al. CD34+ cell infusion after ST elevation myocardial infarction is associated with improved perfusion and dose dependent. American Heart Journal: 2011.
Strauer, Bodo-Eckehard et al. 10 Years of Intracoronary and Intramyocardial Bone MArrow Stem Cell Therapy of the Heart. Journal of American College of Cardiology: 2011.
Schachinger, Volker et al. Improved clinical outcome after intracoronary administration of bone- marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the repair AMI trial. European Society of Cardiology: 2006.
Sutton, Martin G. et al. Left Ventricular Remodeling AFter Myocardial Infarction: Pathophysiology and Therapy. Circulation: 2000.
Kamihata, Hiroshi et al. Implantation of bone marrow mononculear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation: 2001.
Kinnaird, T. et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research: 2004.
Neostem.com
Hare, Joshua et al. A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells After Acute Myocardial Infarction. Journal of American Cardiology: 2009.
Mocetti, Tiziano et al. Sustained improvement in left ventricular function after bone marrow-derived cell therapy in pateints with acute ST elevation myocardial infarction. Swiss Medical Weekly: 2012.

23. Thank you!