1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

MEETING #37

Thursday, March 18, 2004

8:30 a.m.

Hilton Hotel

Silver Spring, Maryland

PARTICIPANTS

Mahendra S. Rao, M.D., Ph.D., Chair

Gail Dapolito, Executive Secretary

MEMBERS

Jonathan S. Allan, D.V.M.

Bruce R. Blazar, M.D.

David M. Harlan, M.D.

Katherine A. High, M.D.

Joanne Kurtzberg, M.D.

Alison F. Lawton

James J. Mul, Ph.D.

Thomas H. Murray, Ph.D.

Anastasios A. Tsiatis, Ph.D

CONSULTANTS

Jeffrey S. Borer, M.D.

Susanna Cunningham, Ph.D.

Jeremy N. Ruskin, M.D.

Michael E. Schneider, M.D.

Michael Simons, M.D.

INDUSTRY REPRESENTATIVE

John F. Neylan, M.D.

GUEST HEALTH CANADA REPRESENTATIVE

Norman Viner, M.D.

GUEST SPEAKERS

Stephen Epstein, M.D.

Silviu Itescu, M.D.

Robert J. Lederman, M.D.

Philippe Menasch, M.D.

Emerson C. Perin, M.D., F.A.C.C.

Doris A. Taylor, Ph.D.

NIH PARTICIPANTS

Richard O. Cannon, M.D.

Stephen M. Rose, Ph.D.

FDA PARTICIPANTS

Jesse L. Goodman, M.D., M.P.H.

Philip Noguchi, M.D.

Dwaine Rieves, M.D

Stephen Grant, M.D.

Richard McFarland, Ph.D., M.D.

Donald Nick Jensen, D.V.M., M.S.E.E.

C O N T E N T S

PAGE

Call to Order

Mahendra Rao, M.D., Ph.D., Chair 5

Conflict of Interest Statement

Gail Dapolito, Executive Secretary 5

Introduction of Committee 9

FDA Opening Remarks

Presentation of Certificate of Appreciation

to Retiring Member

Jesse Goodman, M.D., M.P.H. 14

Philip Noguchi, M.D. 16

Open Committee Discussion

Cellular Therapies for Cardiac Disease

FDA Introduction and Perspectives

Dwaine Rieves, M.D. 18

Guest Presentations

Overview Cardiomyopathy and Ischemic Heart

Disease

Emerson Perin, M.D., Ph.D. 35

Q&A 65

Clinical Experience of Autologous Myoblast

Transplantation

Philippe Menasch, M.D. 85

Q&A 115

Bone Marrow Cell Therapy for Angiogenesis:

Present and Future

Steven Epstein, M.D. 128

Q&A 148

Cellular Therapies for Cardiac Disease

Richard McFarland, Ph.D., M.D. 159

Guest Presentations

Myoblasts: The First Generation Cells for

Cardiac Repair: What Have We Learned?

Doris Taylor, Ph.D. 169

Q&A 202

Preclinical Models - Hematopoietic and

Mesenchymal Cell Therapies for Cardiac Diseases

Silviu Itescu, M.D. 219

Q&A 245

C O N T E N T S (Continued)

From Mouse to Man: Is it a Logical Step for

Cardiac Repair?

Doris Taylor, Ph.D. 257

Q&A 275

Cardiac Catheters for Delivery of Cell Suspension

Donald Nick Jensen, D.V.M., M.S.E.E. 292

Transcatheter Myocardial Cell Delivery: Questions

and Considerations from the Trenches

Robert Lederman, M.D. 307

Q&A 333

Open Public Hearing 343

1 P R O C E E D I N G S

2 Call to Order

3 DR. RAO: Good morning. Welcome to the

4 37th meeting of the Biological Response Modifiers

5 Advisory Committee.

6 Today's topic, as you all know, is related

7 to use of cells in cardiovascular disorders, and we

8 have a pretty full schedule for the next couple of

9 days, but before we can start the meeting, we have

10 to have a few sort of committee stuff that needs to

11 be gotten through, so I will turn the mike over to

12 Gail, so that she can make the mandatory

13 announcements.

14 Conflict of Interest Statement

15 MS. DAPOLITO: Good morning.

16 The following announcement addresses

17 conflict of interest issues associated with this

18 meeting of the Biological Response Modifiers

19 Advisory Committee on March 18 and 19, 2004.

20 Pursuant to the authority granted under

21 the Committee Charter, the Associate Commissioner

22 for External Relations, FDA, appointed Drs. Jeffrey

23 Borer and Susanna Cunningham as temporary voting

24 members.

25 In addition, the Director of FDA's Center

1 for Biologics Evaluation and Research, appointed

2 Drs. Jeremy Ruskin, Michael Schneider, and Michael

3 Simons as temporary voting members.

4 Based on the agenda, it was determined

5 that there are no specific products considered for

6 approval at this meeting. The committee

7 participants were screened for their financial

8 interests. To determine if any conflicts of

9 interest existed, the agency reviewed the agenda

10 and all relevant financial interests reported by

11 the meeting participants.

12 The Food and Drug Administration prepared

13 general matters waivers for participants who

14 required a waiver under 18 U.S.C. 208. Because

15 general topics impact on many entities, it is not

16 prudent to recite all potential conflicts of

17 interest as they apply to each member.

18 FDA acknowledges that there may be

19 potential conflicts of interest, but because of the

20 general nature of the discussions before the

21 committee, these potential conflicts are mitigated.

22 We note for the record that Dr. John

23 Neylan is participating in this meeting as a

24 non-voting industry representative acting on behalf

25 of regulated industry. Dr. Neylan's appointment is

1 not subject to 18 U.S.C. 208. He is employed by

2 Wyeth Research and thus has a financial interest in

3 his employer.

4 With regards to FDA's invited guest

5 speakers and guests, the agency determined that

6 their services are essential. The following

7 disclosures will assist the public in objectively

8 evaluating presentations and/or comments made by

9 the participants.

10 Dr. Stephen Epstein is the Executive

11 Director, Cardiovascular Research Institute,

12 Washington Hospital Center. He receives research

13 support, is a consultant to and has financial

14 interests with, firms that could be affected by the

15 committee discussions.

16 Dr. Philippe Menasch is employed at the

17 George Pompidou Hospital in Paris, France. He has

18 an association with a firm that could be affected

19 by the committee discussions.

20 Dr. Emerson Perin is employed by the Texas

21 Heart Institute. He receives consultant fees from,

22 and is a scientific advisor to, firms that could be

23 affected by the committee discussions.

24 Dr. Doris Taylor is employed by the

25 University of Minnesota, Center for Cardiovascular

1 Repair. She receives consultant fees from a firm

2 that could be affected by the committee

3 discussions.

4 Dr. Norman Viner is employed by the

5 Biologics and Radiopharmaceuticals Evaluation

6 Centre, Biologics and Genetic Therapies

7 Directorate, Health Canada, in Ottawa, Canada.

8 FDA participants are aware of the need to

9 exclude themselves from the discussions involving

10 specific products or firms for which they have not

11 been screened for conflicts of interest. Their

12 exclusion will be noted for the public record.

13 With respect to all other meeting

14 participants, we ask in the interest of fairness

15 that you state your name, affiliation, and address

16 any current or financial involvement with any firm

17 whose product you wish to comment upon.

18 Waivers are available by written request

19 under the Freedom of Information Act.

20 Thank you, Dr. Rao.

21 DR. RAO: Now you know why I always have

22 Gail read that statement.

23 Before we start any committee work, I

24 would like to welcome two new members to the

25 committee, Dr. Murray and Dr. James Mul. We

1 generally introduce everyone on the committee

2 first, and we generally go in alphabetical order,

3 but this time I will try and start with the new

4 members, so that they can tell us a little bit

5 about themselves before we have the others

6 introduce themselves.

7 Introduction of Committee

8 DR. MULE: I am Dr. Jim Mul. I am

9 currently the Associate Center Director for the H.

10 Lee Moffitt Cancer Center in Tampa. I oversee all

11 translational research at the Center including all

12 cell-based therapies for the treatment of cancer as

13 it applies to the clinical treatment of patients

14 with advance tumors.

15 Prior to being in Tampa since September of

16 last year, I was at the University of Michigan

17 Cancer Center for 10 years, and prior to that, the

18 NCI for another 10 years, and I am delighted to be

19 here.

20 DR. MURRAY: Good morning. I am Tom

21 Murray. I am President of the Hastings Center,

22 which is celebrating its 35th years as the world's

23 first research institute devoted to ethics in

24 medicine and the life sciences.

25 I spent 15 years as professor at medical

1 schools including 12 at Case Western Reserve

2 University School of Medicine. My interests are

3 fairly broad. I write a lot about ethics and

4 ethics in the life science and science policy.

5 Thank you. I am delighted also to be

6 here.

7 DR. RAO: If we can go down the table, Dr.

8 Tsiatis.

9 DR. TSIATIS: Hi. I am Butch Tsiatis. I

10 am from the Department of Statistics at North

11 Carolina State University.

12 DR. BORER: My name is Jeff Borer. I am a

13 cardiologist. I work at Weill Medical College of

14 Cornell University in New York City. I run a

15 division and an institute at Cornell and, relevant

16 to this meeting, I am the Chairman of the

17 Cardiorenal Drugs Advisory Committee of the FDA.

18 DR. CUNNINGHAM: Good morning. My name is

19 Susanna Cunningham. I am a professor in the School

20 of Nursing at the University of Washington in

21 Seattle, and I am the consumer representative for

22 the Cardiovascular Renal Advisory Committee.

23 DR. SCHNEIDER: I am Michael Schneider. I

24 co-direct the Center for Cardiovascular Development

25 at Baylor College of Medicine, and our interests

1 are in the molecular genetics of cardiac muscle

2 formation, cardiac growth, cardiac cell apoptosis

3 and its relation to heart failure, and, relevant to

4 this meeting, cardiac progenitor cells of different

5 kinds.

6 DR. SIMONS: Hi. I am Michael Simons. I

7 am Chief of Cardiology at Dartmouth Medical School.

8 I work in the area of vascular biology, gene and

9 cell therapy.

10 DR. RUSKIN: Good morning. I am Jeremy

11 Ruskin. I am a cardiologist and

12 electrophysiologist, and I direct the Cardiac

13 Arrhythmia Service at Massachusetts General

14 Hospital.

15 DR. NEYLAN: Good morning. I am John

16 Neylan. I am a nephrologist and an organ

17 transplanter by training. Currently, I am Vice

18 President of Clinical Research and Development at

19 Wyeth, and I serve as a industry representative to

20 the committee.

21 DR. KURTZBERG: Hi. I am Joanne

22 Kurtzberg. I am a pediatric oncologist. I direct

23 the Pediatric Bone Marrow and Stem Cell Transplant

24 Program at Duke University and the Carolinas Cord

25 Blood Bank at Duke.

1 DR. ALLAN: Hi. I am Jon Allan. I am a

2 virologist at the Southwest Foundation for

3 Biomedical Research. My area is nonhuman primate

4 models for AIDS pathogenesis.

5 DR. CANNON: Good morning. I am Richard

6 Cannon. I am at the National Heart, Lung, and

7 Blood Institute. I am Clinical Director of NHLBI,

8 and I am representing NHLBI at this meeting.

9 DR. ROSE: Good morning. I am Stephen

10 Rose. I am Deputy Director for the Recombinant DNA

11 Program in the Office of Biotechnology Activities

12 in the NIH.

13 DR. JENSEN: Good morning. My name is

14 Nick Jensen. I am a reviewer in the Center for

15 Devices and Radiological Health. I am a

16 veterinarian and an engineer.

17 DR. McFARLAND: Good morning. I am

18 Richard McFarland. I am a reviewer in the

19 Pharm/Tox Branch in the Center for Biologics in the

20 Office of Cellular, Tissue and Gene Therapies.

21 DR. RIEVES: Good morning. My name is

22 Dwaine Rieves. I am a medical officer in FDA's

23 Center for Biologics Evaluation and Research.

24 DR. GOODMAN: Good morning. I am Jesse

25 Goodman. I am the Center Director of the Center

1 for Biologics. I would just like to join in

2 welcoming especially the new members. My

3 background is as an infectious disease physician in

4 academic medicine for many years.

5 DR. NOGUCHI: I am Phil Noguchi, Acting

6 Director of the Office of Cellular, Tissue and Gene

7 Therapies in CBER.

8 DR. RAO: Thank you, everyone.

9 We are very fortunate in having some

10 really leaders in the field come and present some

11 of the data which will be the basis of where we can

12 address some of the questions that have been raised

13 by the FDA.

14 I am going to ask them to just briefly

15 introduce themselves, as well.

16 DR. EPSTEIN: I am Steve Epstein, a

17 cardiologist. I am head of the Cardiovascular

18 Research Institute at the Washington Hospital

19 Center. We are involved in vascular biology, gene,

20 and cell therapy.

21 DR. MENASCHE: I am Philippe Menasch. I

22 am cardiac surgeon at the Hospital European George

23 Pompidou in Paris, France.

24 DR. PERIN: Good morning. I am Emerson

25 Perin. I am an interventional cardiologist and

1 Director of Interventional Cardiology at Texas

2 Heart Institute in Houston.

3 DR. TAYLOR: Hi. I am Doris Taylor. I am

4 a scientist. I just moved from Duke University to

5 the University of Minnesota to head the Center for

6 Cardiovascular Repair.

7 DR. ITESCU: Hi. I am Silviu Itescu. I

8 am Director of Transplantation Immunology at

9 Columbia Presbyterian, New York.

10 DR. RAO: I would also like to welcome Dr.

11 Viner who is from Health Canada. Health Canada has

12 been following a lot of what the FDA has been doing

13 and it is nice to have them there.

14 I would like to invite Dr. Goodman to make

15 a statement.

16 FDA Opening Remarks

17 Presentation of Certificate of Appreciation

18 to Retiring Member

19 DR. GOODMAN: My main purpose is to thank

20 Joanne Kurtzberg for I guess about four years of

21 service to the BRMAC. We really appreciate that

22 tremendously. She has also interacted with CBER

23 before that.

24 One of the reasons I really wanted to come

25 by this morning. Joanne is rotating off this

1 committee. I know from interactions both within

2 this committee and outside, and from all the

3 leadership and staff within CBER, just what a

4 tremendous advisor and asset Joanne has been for

5 FDA and for your various fields here.

6 Of course, she has mostly contributed very

7 extensively in her areas of hematopoietic stem

8 cells, et cetera, but she has also been a very

9 important thinker and discussant and contributor on

10 the whole range of other cellular therapies and

11 even gene therapy.

12 Please join me in thanking Joanne for her

13 service over these years. Also, we like to say,

14 particularly CBER, that we are a family and that

15 nobody ever leaves it, and that we, just like a

16 family, we will keep asking for favors in the

17 future and probably causing grief in return.

18 Thanks so much, Joanne. We have a plaque

19 for her, of course.

20 [Applause.]

21 DR. GOODMAN: I guess I will just turn it

22 over to Phil to just give a brief introduction for

23 the meeting, but just to say that, as I mentioned a

24 little while back about the islet cell therapies,

25 we, at FDA, are extremely excited about cellular

1 therapies and their potential, and I think nowhere

2 is some of that potential clearer, but also perhaps

3 more difficult to evaluate and help move forward

4 than in the area of cardiovascular disease whether

5 it is for ischemic disease or heart muscle disease

6 or trauma, et cetera, some of the uses where there

7 have been some very promising reports.

8 So, we think this is a very timely

9 meeting. It is very important to get input about

10 how to go forward with efficient development of

11 those products, how to address some of the clinical

12 and safety issues, and how to hopefully make this

13 field positioned to realize its successes in the

14 most efficient manner and also help FDA get that

15 right to the extent that we all can based on

16 incomplete information.

17 Again, we really look forward to this. I

18 apologize, my usual schedule means I will be in and

19 out, but I really appreciate it.

20 Phil.

21 DR. NOGUCHI: Thank you, Jesse, and, of

22 course, Dr. Kurtzberg, our sincere thanks for the

23 many years of service. Jesse is absolutely right,

24 don't be surprised if the next meeting, you get a

25 funny call early in the morning.

1 This is one of our, in a way, continuing

2 series of dealing with things that seem really

3 wonderful and amazing when they come up, where

4 there is a lot of hope and there is perhaps a

5 little bit of hype, but what we have always found

6 over the years, and here I would like to just

7 acknowledge Dr. Rose in the Office of Biotechnology

8 Activities and the Recombinant DNA Committee, what

9 we have learned from them is that one of the best

10 ways that we have of really dealing with things

11 controversial and where there is both hope and

12 there is some trepidation about whether or not this

13 is actually going to work or not, is to bring

14 everyone together, put them in the same room.

15 Our continuing--and this really goes back

16 at least 25 years through the RAC and many years

17 for the BRMAC--is that when you get reasonable

18 people together who may have differing opinions

19 about things, but are presented the facts and the

20 realities, as well as the unknowns, we all

21 basically pretty much come out with the same

22 conclusion, and then we can make significant

23 progress in making these therapies not just

24 experimental, but a reality.

25 With that, what I would really like to

1 do, because we have such a full schedule, is now

2 turn it over to Dr. Rieves for the introduction.

3 DR. RAO: As Dr. Rieves comes up to the

4 mike, I just want to remind people of a few simple

5 rules. Remember that when you want to ask a

6 question, make sure that you are recognized. Use

7 the button. You will see that the light comes on.

8 When you are done, just hit the button again to

9 switch it off, because otherwise, there is sort of

10 a feedback loop and noise. Make sure you identify

11 yourself when you ask questions.

12 Cellular Therapies for Cardiac Disease

13 FDA Introduction and Perspectives

14 DR. RIEVES: Good morning. My name is

15 Dwaine Rieves. I am a medical officer within FDA's

16 Center for Biologics Evaluation and Research. This

17 morning I am going to present a brief overview of

18 FDA's perspective on cellular products used in the

19 treatment of cardiac diseases.

20 As will be covered in a subsequent

21 presentation, certain cellular products, when

22 either perfused into the heart or directly injected

23 into heart muscle, are thought to be capable of

24 regenerating heart tissue and/or augmenting heart

25 function.

1 Consequently, these products may have

2 special utility in the treatment of heart failure

3 and certain other cardiac diseases. Today and

4 tomorrow, we will discuss issues in the early

5 clinical development of these products.

6 [Slide.]

7 This talk is divided into three major

8 sections. First, I will cite the purpose in

9 convening this advisory committee. Secondly, I

10 will provide a regulatory background on FDA's

11 understanding and activities within the realm of

12 clinical development of these products. Finally, I

13 will introduce the major questions we have proposed

14 for discussion.

15 [Slide.]

16 Unlike many advisory committees where the

17 topics center around assessment of data associated

18 with a specific product or data related to a

19 specific regulatory concern, our purpose in

20 convening this committee is not to obtain

21 definitive regulatory advice, instead, FDA has

22 convened this committee to listen to, and learn

23 from, the voiced thoughts and perspectives with the

24 understanding that this information will enhance

25 our ability to promote the safe clinical

1 development of these products.

2 As you are aware, the clinical development

3 of cellular products is in its infancy and many

4 questions surround the very early stages of product

5 development. Consequently, our purpose today and

6 tomorrow is to stimulate a solid scientific

7 discussion of the major facets associated with the

8 very early clinical development of these products.

9 As noted here, we will focus upon three

10 major areas: manufacturing aspects of the cellular

11 product, preclinical testing of the products, and

12 finally, items related to the early clinical

13 studies.

14 [Slide.]

15 What are the cellular products we will be

16 discussing? These products may be broadly grouped

17 into two categories.

18 Firstly, those manufactured without

19 ex-vivo culture methodology, that is, the cells are

20 harvested from humans, processed, and then

21 delivered to a recipient without maintaining the

22 cells in culture for a period of time.

23 In general, these cells consist of bone

24 marrow mononuclear cells and certain peripheral

25 blood mononuclear cells, hematopoietic progenitor

1 cells that are variously referred to as stem cells,

2 cells thought to be capable of assuming phenotypic

3 characteristics of non-hematopoietic cells.

4 The second category consists of cells

5 that, following harvesting, are maintained in ex

6 vivo culture for a period of time before final

7 processing and administration.

8 In general, these cells consist of those

9 derived from skeletal muscle tissue, cells

10 frequently referred to as myoblasts, and certain

11 bone marrow stromal cells, cells also referred to

12 as mesenchymal cells. Whether these cultured cells

13 should be regarded as forms of stem cells is more

14 questionable than that for the hematopoietic

15 progenitor cells.

16 Lastly, as the slide notes, most of the

17 cellular products we will be discussing today and

18 tomorrow are of autologous origin.

19 [Slide.]

20 The many questions surrounding the

21 scientific basis for cellular product development

22 illustrate the very nascent nature of the field.

23 As we are probably all aware, there is almost no

24 precedent for the clinical development of products

25 intended to regenerate and/or augment disease

1 tissue.

2 The scientific data surrounding this field

3 are relatively new, such that the data are limited

4 in depth and the extent of replication. Hence we

5 come to the table of clinical development with many

6 hypothetical considerations and some, but

7 relatively limited background supportive data.

8 [Slide.]

9 Given these limitations, our discussions

10 today and tomorrow assume a scientific focus in

11 which certain insights and perspectives are

12 presented, and you, the committee members, will be

13 asked to share your thoughts. Three points are

14 cited here.

15 First, we acknowledge that these thoughts

16 are all tentative and susceptible to revision based

17 on accumulating data.

18 Secondly, we are not requesting any

19 definitive assessment of data, and we note that the

20 data presented here today are within the public

21 arena, and have not undergone FDA vetting.

22 Finally, I reiterate an earlier comment,

23 that no specific cellular product discussed here is

24 under review with respect to regulatory

25 decisionmaking.

1 [Slide.]

2 This slide illustrates the

3 interconnectedness of clinical research and

4 regulatory paradigms. The connecting link between

5 the two fields is the science. Clinical research

6 generates the scientific background for clinical

7 development of cellular products and the scientific

8 background forms the major basis for our regulatory

9 paradigms.

10 [Slide.]

11 FDA is charged with many responsibilities,

12 but as cited here, two are especially relevant to

13 this discussion. Specifically, FDA's mission is to

14 promote and protect the public health by optimizing

15 pre-market product development and ensuring

16 sufficient post-marketing product monitoring.

17 The key word in these two statements is

18 "product." A notation that whereas we frequently

19 hear the terms transplant, graft, and procedure, we

20 need to think in terms of a cellular product, a

21 product that is manufactured, labeled, and

22 potentially marketed.

23 [Slide.]

24 A little over 10 years ago, FDA clarified

25 the regulatory basis for oversight of clinical

1 development programs for cellular products. In

2 general, this regulatory framework is the same as

3 that for the drugs and biologic products we

4 commonly recognize as marketed products.

5 Hence, the commonly cited biologic

6 product, drug, and device regulations applied to

7 the clinical development of these cellular

8 products, and the clinical studies must be

9 conducted under the purview of submission of a

10 investigational new drug application.

11 The last bullet on this slide reminds us

12 that clinical development programs may be divided

13 into early and late stages, with the late stages

14 focused upon the ascertainment of data definitive

15 to safety and efficacy, and the early stage, what

16 we are talking about today and tomorrow, focused

17 upon the ascertainment of exploratory safety and

18 bioactivity data.

19 That is, we hope to examine the nature and

20 extent of background data necessary to introduce

21 the cellular products into small, sample size,

22 Phase I clinical studies.

23 [Slide.]

24 As previously noted, the keystone

25 consideration in early clinical development is

1 safety. Specifically, we need to ensure that the

2 tripod of product development is solid. That tripod

3 consists of manufacturing control and testing

4 information, sufficient preclinical testing

5 information, especially information that may inform

6 the design of a clinical study, and finally, the

7 clinical study itself.

8 The next few slides will cite each of

9 these three components.

10 [Slide.]

11 Cellular products must be manufactured in

12 some manner, that is, the cells must be harvested

13 and processed prior to administration to a

14 recipient. Manufacturing aspects may be divided

15 among four major areas, three being shown on this

16 slide.

17 The top bullet notes that documents should

18 describe the cell source and reagents used in the

19 manufacturing process, such as growth factors,

20 sera, salt solutions and additives. We need to be

21 confident that all the reagents used in the

22 manufacturing are of clinical or pharmaceutical

23 grade, or that if they are not pharmaceutical

24 grade, they are sufficient for human use.

25 One may envision many potential concerns

1 with these materials, such as the use of sera that

2 may contain infections agents, or the use of only

3 partially purified reagents that contain harmful

4 excipients.

5 Secondly, documents should describe the

6 procedures used in manufacturing, specifically

7 describing how cells are aseptically harvested,

8 isolated, and potentially selected.

9 For example, a distinct population of

10 cells may be selected based upon the presence of

11 certain cell surface markers, such as the CD34

12 antigen with the selection process involving

13 incubation with an antibody to CD34.

14 As we know, many investigational

15 antibodies have been developed to target cell

16 surface antigens, and we need to be confident that

17 these selection techniques are performed in a

18 reproducible and safe manner.

19 Additionally, documents should describe

20 the storage and tracking of the cellular products,

21 this being of special concern because certain

22 cellular products may be patient-specific products.

23 For example, measures must be in place to

24 ensure that for autologous products, the cellular

25 product is returned to the correct donor. Of

1 course, the cellular product needs to be labeled as

2 one for investigational use only.

3 The bullet at the bottom of this slide

4 emphasizes the importance of testing the cellular

5 product, an especially important concern since

6 cellular products cannot be sterilized in the same

7 manner as one might sterilize a drug product or a

8 device. Notable aspects of testing include tests

9 for sterility, endotoxin, viability, enumeration,

10 or cell counting.

11 [Slide.]

12 The fourth component of manufacturing

13 information is product characterization as

14 highlighted here. When one speaks of product

15 characterization, we are generally talking about

16 cellular phenotype and/or functional

17 characterization and the characteristics of the

18 product's final formulation.

19 For example, a product containing solely

20 CD34 positive cells in saline with no preservatives

21 or media. Product characterization is especially

22 important from a clinical perspective, because

23 failure to consistently manufacture a product makes

24 the clinical data virtually uninterpretable.

25 As noted here, the major aspects of

1 product characterization consist of a description

2 of identity, purity, and potency of the final

3 cellular product.

4 [Slide.]

5 Pre-clinical testing is the second major

6 component of product development, and the major

7 aspects of this testing are cited here. The top

8 bullet notes that consistent with the science, the

9 extent and depth of preclinical testing necessary

10 to support a clinical study is an evolving paradigm

11 and is a major topic for discussion at this

12 meeting. However, we generally take the stance

13 that this preclinical testing paradigm should be

14 consistent with that used for other biological

15 products.

16 The last bullet notes another important

17 aspect of preclinical testing, the testing of the

18 product administration procedure.

19 This is especially important because many

20 cellular products involve injection directly into

21 heart muscle either through the epicardial surface

22 or the endocardial surface. These techniques

23 represent inherent safety concerns that may be best

24 evaluated in animals prior to their use in humans.

25 As noted, all available catheters, whether

1 marketed or not, are regarded as investigational

2 with respect to administration of cellular

3 products.

4 [Slide.]

5 This slide highlights three aspects of

6 preclinical testing that will be the focus of the

7 preclinical questions tomorrow.

8 Firstly, the choice of the relevant

9 species is central to designing preclinical studies

10 with the major choices being between large animals,

11 such as pigs, versus small animals, such as mice,

12 as well as the choice between immunocompetent

13 animals where, for autologous products, the

14 cellular products would be the animal cells, not

15 human cells, or immunocompromised animals, where

16 the actual human cellular product may be tested.

17 Secondly, designing preclinical studies

18 raise questions of the choice of model, that is, a

19 disease model, such as ischemic heart disease

20 induced in the pig versus a healthy animal.

21 Lastly, preclinical concerns relate to

22 testing of the administration procedure itself,

23 such items as the impact of the catheter materials

24 upon cells, the potential for occlusion of

25 catheters by the cellular product, and the safety

1 concerns associated with manipulation of the

2 catheters in the heart.

3 [Slide.]

4 The third component of the clinical

5 development program for cellular products is the

6 clinical study. There are many aspects of clinical

7 study design that could be discussed, but at this

8 meeting, we are focusing upon two, the first shown

9 here, that is, adverse event detection.

10 This slide highlights two aspects of

11 clinical study design that are frequently

12 engineered to optimize adverse event detection, the

13 evaluation plan with attention to the duration of

14 clinical follow-up, the frequency of evaluations,

15 and the extent or nature of these evaluations.

16 Secondly, the clinical study safety

17 monitoring plan may be optimized through the use of

18 close scrutiny of each study subject based upon the

19 sequential, not simultaneous, enrollment and

20 treatment of the subjects, as well as the

21 prespecifications of the types and numbers of

22 adverse events that should prompt interruption of

23 the study, that is, the study stopping rules.

24 Tomorrow, the committee will be asked to

25 discuss potential adverse events in these early

1 clinical studies, both the nature of the events and

2 ways to optimize the safety of the studies.

3 [Slide.]

4 This slide illustrates an additional

5 clinical study design item that we will bring to

6 the committee, that is, a discussion of the

7 analysis of adverse events.

8 Exploratory clinical studies are, by their

9 nature, small sample size studies in which it is

10 often difficult or impossible to distinguish

11 treatment-related events from adverse events that

12 might occur in the natural history of the disease,

13 potential study design mechanisms that might help,

14 but certainly not resolve this issue are cited in

15 the bullets, design features that incorporate

16 randomization of subjects among groups, such that

17 comparisons may be made, the use of controls,

18 especially placebo controls, to make comparisons,

19 the use of masking or blinding to help lessen the

20 bias associated with concomitant therapies or

21 clinical care.

22 Tomorrow, the committee will be asked to

23 discuss mechanisms that might aid in adverse event

24 attribution.

25 [Slide.]

1 In this presentation, we have covered

2 three major topics. Firstly, we have noted that

3 the focus of this meeting is upon a discussion of

4 the scientific aspects of early cellular product

5 development.

6 Secondly, we have noted the regulatory

7 precedent for the cellular products.

8 Finally, we come to the questions.

9 [Slide.]

10 This slide highlights the four major areas

11 of tomorrow's questions. Specifically, questions

12 related to manufacturing, we will request a

13 discussion of the extent of safety testing and

14 characterization that should be performed prior to

15 the release of a cellular product for

16 administration to humans.

17 The second and third discussion areas are

18 especially critical and may consume the bulk of our

19 time, that is, the extent and nature of preclinical

20 testing necessary to support the introduction of a

21 cellular product into humans, testing that involves

22 questions related to the product itself, as well as

23 the delivery mechanism, the catheter.

24 Finally, we will pose clinical questions

25 centered around adverse event detection and

1 analysis with a discussion of the pros and cons

2 associated with the use of controls in these

3 studies.

4 [Slide.]

5 Our agenda is summarized on this slide.

6 As you can see, today, we have a series of invited

7 presentations by FDA staff and leading

8 investigators in the field, as well as the

9 opportunity for public presentations.

10 Tomorrow, we will have another opportunity

11 for public presentations followed by a discussion

12 of the questions.

13 [Slide.]

14 In closing, listed here are some documents

15 that are especially pertinent to our discussions.

16 All these documents are available at www.fda.gov

17 under the CBER sites, specifically the guidance

18 section.

19 The first document is entitled "Draft

20 Guidance for CMC Reviewers: Human Somatic Cell

21 Therapy Investigational New Drug Applications."

22 This document describes the types of information

23 FDA reviewers will examine following the submission

24 of an IND. Consequently, it provides a very clear

25 description of the types of manufacturing

1 information that needs to be submitted with an IND

2 application.

3 The second document is from the

4 International Conference on Harmonization of

5 Regulatory Practices, and it is entitled "

6 Preclinical Safety Evaluation of

7 Biotechnology-derived Pharmaceutics," the S6

8 document.

9 This document is cited because it contains

10 a paradigm that one may apply to cellular products.

11 Finally, the last bullet cites one of the

12 most useful guidances to sponsors and

13 investigators, the ICH Guideline on Good Clinical

14 Practice.

15 This guideline provides detailed

16 information on how to design and conduct a clinical

17 study, information presented in a simple to read,

18 yet relatively comprehensive format.

19 This concludes my presentation and I thank

20 you for your attention.

21 [Applause.]

22 DR. RAO: Before we continue with the rest

23 of the presentations, I would like to just welcome

24 Dr. Harlan and ask him to introduce himself.

25 DR. HARLAN: I apologize for being late,

1 but I am David Harlan, NIDDK. I study

2 transplantation of islets and immunotherapies.

3 DR. RAO: Our first speaker will be Dr.

4 Perin, whom you already were introduced to.

5 Guest Presentations

6 Overview Cardiomyopathy and Ischemic Heart Disease

7 DR. PERIN: I want to thank you for the

8 invitation to be here to present to you today,

9 especially Dr. Grant, who has helped me put this

10 together in a way.

11 So, what I want to do here this morning,

12 the task that has been laid before me is that of in

13 a way setting the stage or giving you a general

14 idea of the kinds of patients that we are treating.

15 Obviously, this is fundamental if we are

16 thinking about doing clinical trials. It is very

17 important to understand the nature of the disease

18 in which these kind of therapies will frequently be

19 applied.

20 What I plan to do is talk about the

21 following topics. First, we will start from the

22 beginning, define what heart failure is, look at

23 the scope of heart failure, talk a little bit about

24 the pathophysiology, look at some prognostic

25 markers, talk about the treatment to some extent

1 and that is important in terms of monitoring, and

2 then really work our way towards end stage heart

3 failure because that is where I think the focus of

4 most of the future clinical trials will likely be

5 initially, and finally, talk about adverse events,

6 which I think is a major concern, and the

7 monitoring of there adverse events.

8 Now, I know many of you are not

9 cardiologists, so hopefully, I can go from a level

10 where we are not getting too complicated, but not

11 too simple.

12 Starting with the definition of what heart

13 failure is. Firstly, heart failure is a clinical

14 syndrome very simply defined by certain symptoms

15 and certain signs that come together. These

16 symptoms are fatigue, shortness of breath, and

17 congestion, and these are translated on a physical

18 exam by being able to hear a third heart sound, the

19 patient manifesting peripheral edema, and jugular

20 venous distention.

21 If we start looking at this problem and

22 have a broad overview of this, first, I want to

23 show you a graph from the HOPE trial. This is a

24 trial that was conducted in thousands of patients,

25 as you can see here, over 9,000 patients. It was a

1 study primarily of ramipril and vitamin E in

2 patients with hypertension over a long period of

3 time, involved a five-year follow-up.

4 But it is just very interesting, as we

5 start out looking at heart failure, to look at this

6 patient population, and here we have over 500 days,

7 so here is about a year out, and if we look at this

8 population, who is not primarily designated as

9 particularly sick or harboring heart failure, that

10 identified the patients that did have heart failure

11 and we look at their survival, you will see the

12 mortality.

13 It separates from the beginning, and when

14 we get out to about a year, you have got a 10

15 percent mortality in the group that has heart

16 failure compared to less than 4 percent mortality

17 in the general population. So, you can see that

18 the problem that we are dealing with seems to be

19 very serious.

20 If we go here and let's just look at the

21 placebo arms of some very large heart failure

22 trials, these are trials pretty much aimed at

23 evaluating different forms of therapy now in heart

24 failure patients, and looking at different severity

25 of heart failure patients, for example, in the

1 V-HeFT trial, inclusion criteria might be an

2 ejection fraction less than 40 percent.

3 If we look at PRAISE, which evaluated

4 amlodipine in more severe heart failure, an

5 ejection fraction was less than 30 percent,

6 comparing this with Class III and Class IV

7 patients, very sick patients.

8 So, you can see here if we look at just

9 the placebo arms of all these trials, a very

10 striking mortality as we go along. If we look at 1

11 year here, this will vary from 10 percent down to

12 around 30 percent.

13 If we go out to 2 years in the very sick

14 patients, we see that half of the patients are

15 dead. So, heart failure, depending on the

16 presentation, carries a very ominous prognosis.

17 It is a very broad problem, 5 million

18 Americans are living with heart failure now,

19 550,000 new cases are diagnosed each year.

20 From 1979 to 2000, heart failure deaths

21 increased by 148 percent. Now, what is

22 interesting, over this period of time, we have

23 actually gotten a lot better at treating heart

24 failure, and we do treat it. I will get into this a

25 little later, and I will show you the modern treat

1 of heart failure and how much better we are doing,

2 but at the same time that we are treating heart

3 failure better, we are also treating the patients

4 that have coronary disease, which is a very

5 dominant problem in this country and around the

6 world, we are treating those patients better, too,

7 so what happens is we are getting more patients

8 with heart disease that normally would have died

9 earlier, to live longer, and as we are able to

10 bypass and stent and do all these revascularization

11 procedures and come up with better treatments, we

12 are getting people that go further down the road,

13 that otherwise would have succumbed a long time

14 ago.

15 So, despite our improvements in treatment

16 of coronary disease, we are dealing with an

17 increasing amount of heart failure deaths.

18 In individuals diagnosed with heart

19 failure, cardiac death occurs at 6 to 9 times the

20 rate in the general population. If you are more

21 than 40 years old, you have a 1 in 5 chance of

22 developing heart failure, and 22 percent of men and

23 46 percent of women that have heart attacks will be

24 disabled within 6 years with heart failure.

25 So, as you can imagine, the high

1 prevalence and multiple complications have an

2 implication in terms of health costs. If we look

3 at the costs, and these numbers vary, and it

4 depends on what you are looking at and what year

5 you are looking at, but this is a very significant

6 financial burden on the country, over 5 percent of

7 the total health care costs.

8 You can see that most of the cost involved

9 is really involved in inpatient care, and as I will

10 show you hopefully, that really translates to the

11 sickest portions of these patients, that as you get

12 sicker with heart failure, you start coming into

13 the hospital more, and that is what runs up the

14 cost of treating these patients. It is interesting

15 that transplant is just a little sliver out of the

16 pie here.

17 So, let's look at the causes of heart

18 failure, and I am not going to get into all the

19 little minor details, but let's look at the major

20 causes of what brings on heart failure.

21 Seventy-five percent of people that go on

22 to develop heart failure had hypertension

23 previously. Valvular heart disease is a big

24 contributor and also heart failure engenders

25 valvular heart disease, mitral regurgitation

1 further contributes to the problem.

2 Coronary artery disease, you are all

3 familiar with this, the number one problem in this

4 country, and this is really what we are going to

5 focus majorly on in terms of causing heart failure

6 and the specific kind of heart failure that this

7 engenders.

8 In cardiomyopathy, there is many different

9 kinds of things that get a heart to perform poorly,

10 all the way from an idiopathic cardiomyopathy to

11 such things as iron overload, et cetera, which are

12 not as common.

13 Now, what I want to talk about here is

14 really systolic heart failure. There is something

15 called diastolic heart failure, and that really has

16 a lot to do with compliance problems of the

17 ventricle, and in these patients, we are going to

18 see a normal ejection fraction.

19 So, this is really a different animal and

20 it is really not what we are focusing on, so what I

21 am going to be talking about today is systolic

22 heart failure, and as I will show you, with the

23 hallmark being a low left ventricular ejection

24 fraction.

25 This is just to give you a practical

1 example. This is an angiogram from one of the

2 patients that we treated with stem cell therapy in

3 Brazil, who all had an ejection fraction that

4 averaged about 20 percent. This patient has an

5 ejection fraction of 10 percent.

6 You can see the coronaries are calcified.

7 This is a catheter in the left ventricle. This

8 heart is supposed to be pumping this contrast we

9 just put into the aorta. As you can see, it is not

10 doing that very well at all. Only 10 percent of

11 what is in here gets out with each beat.

12 So, you can tell this is a dilated big

13 heart that just doesn't contract well. That is the

14 picture of severe heart failure right there, and

15 this is what I want to talk about.

16 Now, when we talk about heart failure, I

17 think everybody is aware of the classification.

18 There is Class I, II, III, IV, which are commonly

19 used, but it is important to acknowledge this.

20 Class I involves no limitation of physical

21 activity, Class II slight limitations, Class III

22 marked limitations, you can't walk up a flight of

23 stairs without getting short of breath, and Class

24 IV, you have symptoms at rest.

25 If we look at this, if we put Class III

1 and Class IV together, you see the division is

2 about a third for each of these pieces of the pie

3 here.

4 Now, if somebody comes in with Class IV

5 heart failure, they are very short of breath at

6 rest, you can give them some diuretics and they

7 will feel better. They are not Class IV anymore,

8 they are Class III.

9 So, it is interesting, there has been a

10 want in development of a little different way of

11 looking at heart failure, and a staging or

12 classification put out by joint AHA and ACC shows

13 four different stages, and really looks at heart

14 failure more like a disease like cancer.

15 So, where we can identify patients that

16 are at high risk of developing it, we can screen

17 patients, and then we can start treating patients

18 before they really manifest symptoms of the

19 disease.

20 Again, this is a progressive disease and

21 we are going to end up with people that are

22 refractory even to all kinds of treatment. I am

23 going to go over this a little bit more in detail a

24 little later.

25 So, in defining what heart failure is, I

1 hope I have given you a general idea of the scope

2 of the problem, just talk a little bit about what

3 causes it because it is important to understand

4 that to be able to know how we treat it and how we

5 monitor these patients.

6 Usually, we are talking about ischemic

7 heart disease and we are dealing with a myocardial

8 insult, which is usually a heart attack, so that

9 heart attack causes damage to the heart muscle, and

10 that is going to result in dysfunction of that

11 heart muscle.

12 Well, the body is going to try to

13 compensate this dysfunction and especially in two

14 major ways. One is neurohumoral activation, so we

15 will talk a little bit about this in more detail,

16 but essentially, these compensatory mechanisms are

17 going to make the heart change its shape and its

18 size. It is something we call remodeling. It

19 involves hypertrophy of the myocytes and then it

20 involves fibrosis and dilatation.

21 So, these mechanisms that the body helps,

22 to try to help to reverse what is going on,

23 actually wind up causing toxicity, hemodynamic

24 alterations that all lead to remodeling, and

25 remodeling really is the hallmark.

1 You saw that big heart. Well, remodeling

2 is how you get from a normal small heart, which you

3 have, to a big boggy heart that doesn't contract.

4 That is the problem of heart failure.

5 This was very simply put by Doug Mann in a

6 nice editorial a few years ago. Basically, here is

7 the heart over time, as we have an index event, and

8 basically, remodeling occurs, the heart gets

9 bigger, the ejection fraction goes down as time

10 goes by and symptoms occur as time progresses, as

11 well.

12 So, I have told you we have a myocardial

13 insult. This leads to LV dysfunction and

14 remodeling, and this really instigates a

15 neurohumoral response. In return, this is going to

16 have an impact on remodeling again.

17 So, what are these neurohumoral things

18 that happen? Well, first of all, most importantly,

19 is the renin- angiotensin-aldosterone system, and

20 there are several points in which the body

21 upregulates the system and ultimately, it acts on

22 the AT-1 receptor, which will cause

23 vasoconstriction, proteinuria, again LV remodeling.

24 As you can identify, here are several

25 sites in which medications, the mainstay of some of

1 the therapy for heart failure works, namely ACE

2 inhibitors that work at this point, ARBs that work

3 at this point, beta blockers have a role in

4 inhibiting renin, as well. So, some of the

5 mainstay of therapy is actually directed at one of

6 these mechanisms of compensation.

7 On the other side, we have sympathetic

8 activation. We have increased sympathetic activity

9 that again leads to myocardial toxicity and

10 arrhythmias, and then on the other side, with the

11 sympathetic outflow, we get vasoconstriction. This

12 impacts negatively on the kidney, sodium retention,

13 more vasoconstriction, and progression of the

14 disease.

15 Just to get a slightly little bit more

16 complicated, just to mention that it is really not

17 all that simple, there are other things involved,

18 and we have cytokines, TNF-alpha, IL-6,

19 inflammation that actually progresses with the

20 progression of heart failure.

21 Endothelin is a potent vasoconstrictor.

22 All these things lead to apoptosis and unfavorable

23 effects upon the myocyte, but then lead to LV

24 remodeling, which I have told you is one of the

25 mainstays of reasons for heart failure.

1 Now, natruretic peptides are important,

2 as well. It's another compensatory mechanism that

3 the body has. I am sure you are familiar with

4 these BNP, it's a B-type natruretic protein that

5 actually comes from the ventricle, the A types

6 comes from the atrium. We will just focus on the B

7 type.

8 What this does, basically, in response to

9 elevated pressure inside the heart, we secrete BNP.

10 This suppresses the renin-angiotensin-aldosterone

11 system and suppresses endothelin. It helps with

12 peripheral vascular resistances, decreases

13 vasodilatation, and it increases natruresis.

14 So, if we go on to understand now that

15 there is an interplay between LV dysfunction and

16 remodeling, and that basically, this will lead to

17 low ejection fraction, and that is what we see in

18 the patients.

19 On the other hand, as a result of this, we

20 will start getting a constellation of symptoms, and

21 it is the combination of having a low ejection

22 fraction and symptoms that defines heart failure.

23 Let's look a little bit at the prognostic

24 markers. I just talked a little bit about BNP.

25 Well, it is very interesting. If we divide BNP in

1 quartiles here, depending on the amount of BNP that

2 you have circulating, your survival will go down.

3 It is a prognostic marker, as well as a treatment.

4 Norepinephrine, the same way. So, these are

5 markers of prognosis.

6 It is very interesting. These are levels

7 of BNP, and if you can decrease them, decrease to a

8 less degree, or here, we have an increase. So,

9 depending on which direction your BNP goes, your

10 survival varies as well, and that is an important

11 concept.

12 Let's look at another different kind of

13 marker. Exercise capacity, peak oxygen consumption.

14 In the transplant world, this is very important.

15 Here you see the number 14, so a peak oxygen

16 consumption greater than 14 or less than 14 has

17 very different prognostic indicators and in many

18 centers, this serves as a marker threshold for one

19 of the criteria for entering the patient into a

20 transplant program.

21 You can see here a difference in mortality

22 from 53 percent mortality over two years in

23 patients that have an NVO2 of less than 14, to that

24 of 11 with greater than 14, so this is another

25 important number in patients with heart failure.

1 Then, if we look overall and look at

2 symptoms and hospitalizations, here is a New York

3 Heart Class I to IV, and this is fairly intuitive,

4 but as we get more symptomatic, we have an impact

5 on survival, and as we are getting more

6 symptomatic, we have an increase in

7 rehospitalization.

8 What about ejection fraction? I just

9 talked about ejection fraction, and you can see

10 here, similarly to NVO2, ejection fraction can

11 divide prognostically how patients will do. Here

12 we see more than 20 percent, less than 20 percent.

13 Here you see a two-year survival, 54 percent, so

14 half the people dying that have an ejection

15 fraction less than 20 percent. At one year, that

16 is a little over 20 percent.

17 The same thing, this is a large randomized

18 clinical trial, ejection fraction less than 40

19 percent. Over time, people die more frequently.

20 Now, let's add a little arrhythmia to

21 this. Looking at different levels, the first two

22 are greater than 30 percent ejection fraction, here

23 less than 30 percent, so that stratifies that out,

24 but then if we just add the amount of extra

25 ventricular beats to this, and if we have less than

1 10 per hour, more than 10 per hour, and then with a

2 poorly contractile ventricle, your survival goes

3 down as we add extra ventricular beats.

4 One attempt that has been made to sort of

5 graph this problem, because now I have shown you

6 many different prognostic markers and different

7 things we can use to classify these patients to

8 decide what to do and how to follow them.

9 One of them is a heart failure survival

10 score. There is an invasive model, there is a

11 non-invasive model. So, things like cause of heart

12 failure, resting heart rate, EF, mean blood

13 pressure, if there is a conduction delay

14 electrically in the heart, oxygen consumption, and

15 serum sodium can enter into a risk classification.

16 Here, you just basically have a graph that

17 shows according to low, medium, and high, your

18 survival will vary according to the risk.

19 In our little schema here, that leads

20 symptoms and low ejection fraction to heart

21 failure, what are really the things, though, that

22 are driving mortality? They are going to be pump

23 failure, on the one hand, and arrhythmia, on the

24 other, because sudden death, as I talked to you

25 about before, is a very prominent problem in people

1 that have heart failure.

2 So, it is the combination of these three

3 things that will pretty much drive patients to a

4 lethal exit.

5 Let's talk a little bit about treatment

6 now. What are the goals of treatment of heart

7 failure? You want to delay the progression or

8 reverse remodeling, which you can do in some

9 patients, and delay the progression and reverse

10 myocardial dysfunction.

11 You want to reduce mortality, relieve the

12 symptoms, improve functional capacity, and reduce

13 disability, also decrease the intensity of medical

14 care and hopefully reduce economic cost.

15 I have shown you we go from initial

16 injury, initial infarct, we suffer remodeling, we

17 get a remodeled heart that now has a low ejection

18 fraction, and over this course of time, we have a

19 worsening of symptoms, so how are we going to

20 impact this in terms of treatment?

21 Well, the two mainstays are neurohumoral

22 blockade, we have kind of gone over some of the

23 things that we can do, and we will look at those,

24 and the other is revascularization. So, many times

25 with the use of medication or with the use of

1 revascularization, we can reverse some of this

2 remodeling in some patients, and in some patients

3 we don't.

4 One thing that is very important in terms

5 of being able to recover patients that have

6 remodeled hearts, and that are in this road of

7 heart failure, is identification of viable

8 myocardium.

9 Myocardial viability has clearly been

10 shown to influence the prognosis of people that are

11 undergoing revascularization procedures, so if you

12 have a viable myocardium, you are going to do

13 better. You have a chance of improving more than

14 someone who doesn't.

15 Just to shift gears for just a second

16 here, these are electromechanical maps. These are

17 representations of the left ventricle. This is

18 from a patient in our Brazil stem cell study.

19 This is an electrical map, this is a

20 mechanical map. Let's just look at the electrical

21 map because I just talked to you about viability.

22 Very simply, if your cells are alive, they have an

23 electrical signal that is high. If you have a big

24 scar with no cells, you have no electricity, you

25 have a low electrical signal.

1 We put it on a little color scale. Red is

2 dead or red is very little voltage. Purple is

3 high. Here, you see on this electromechanical map,

4 an area of myocardial viability. Again, just as it

5 is important to understand viability when you are

6 vascularizing patients that have heart failure,

7 that have coronary disease, it is also going to be

8 important, in my view, to understand myocardial

9 viability when we are applying some of these

10 therapies, and I think there will be differences in

11 bone marrow therapies and myoblast therapy, but

12 that is something to keep in mind.

13 I just wanted to show you an example of

14 the very common things that we deal with, so this

15 is not some esoteric difficult patient to find. We