DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE
Thursday, March 18, 2004
Mahendra S. Rao, M.D., Ph.D., Chair
Gail Dapolito, Executive Secretary
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
Jeffrey S. Borer, M.D.
Susanna Cunningham, Ph.D.
Jeremy N. Ruskin, M.D.
Michael E. Schneider, M.D.
Michael Simons, M.D.
John F. Neylan, M.D.
GUEST HEALTH CANADA REPRESENTATIVE
Norman Viner, M.D.
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.
Richard O. Cannon, M.D.
Stephen M. Rose, Ph.D.
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
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
Overview Cardiomyopathy and Ischemic Heart
Emerson Perin, M.D., Ph.D. 35
Clinical Experience of Autologous Myoblast
Philippe Menasch, M.D. 85
Bone Marrow Cell Therapy for Angiogenesis:
Present and Future
Steven Epstein, M.D. 128
Cellular Therapies for Cardiac Disease
Richard McFarland, Ph.D., M.D. 159
Myoblasts: The First Generation Cells for
Cardiac Repair: What Have We Learned?
Doris Taylor, Ph.D. 169
Preclinical Models - Hematopoietic and
Mesenchymal Cell Therapies for Cardiac Diseases
Silviu Itescu, M.D. 219
C O N T E N T S (Continued)
From Mouse to Man: Is it a Logical Step for
Doris Taylor, Ph.D. 257
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
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
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
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
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
University of Minnesota, Center for Cardiovascular
1 Repair. She receives consultant fees from a firm
2 that could be affected by the committee
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
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
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
7 DR. RAO: If we can go down the table, Dr.
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
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
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
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
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
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
Perin. I am an interventional
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
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.
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,
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.
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
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
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.
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.
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
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
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
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.
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
intended to regenerate and/or augment disease
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.
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
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
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.
24 A little over 10 years ago, FDA clarified
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.
24 As previously noted, the keystone
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.
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
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
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
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.
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.
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
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
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
catheters by the cellular product, and the safety
1 concerns associated with manipulation of the
2 catheters in the heart.
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
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.
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
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
6 Secondly, we have noted the regulatory
7 precedent for the cellular products.
8 Finally, we come to the questions.
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
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
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.
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
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
description of the types of manufacturing
1 information that needs to be submitted with an IND
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
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
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.
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
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
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,
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
16 come across people like this all the time in the
17 hospital every day.
18 This is a patient who was 41 years old, he
19 had bypass, he stopped up all his vein grafts and
20 his memory artery, and he had ejection fraction of
21 20 percent, very similar to the one that I showed
22 you, and Class IV congestive heart failure.
23 This gentleman was really delightful. He
24 was actually a pilot for a major airline, and
because of his bypass, he had to be put off the
1 flying, and he was actually in charge of all the
2 simulators, and he was the guy that graded all the
3 pilots when they had to come in and do the
4 simulation testing.
5 Basically, here, we have a 41-year-old
6 guy, very active man who has gone bypass, he has
7 lost his graft, he obviously has very aggressive
8 disease, and why I hear the talk about why some
9 people have more aggressive coronary disease than
11 You see this is his right coronary, it is
12 completely blocked up, X's mean that you can't see
13 anything on angiography, so this kind of fills from
14 the other side by collaterals, see these little
15 twigs down here.
16 Then, the circumflex is completely
17 occluded. This is a floating marginal branch.
18 This is supposed to be connected, but this is
19 totally occluded, as well. The only artery he has
20 got left is the one down the front of his heart,
21 but this is very much infarcted, and has a very
22 significant blockage here, as well as the takeoff
23 of this.
24 So, this patient, there is really nothing
to do, and we are faced with this a lot every day.
1 This patient, as I have shown you these curves of
2 mortality, this patient at our hospital wound up
3 going for an LVAD type procedure and died, and that
4 is what we see again and again, so this is a very
5 serious problem.
6 So, looking of an overview of treatment of
7 heart failure, let's see, we have medical-based
8 therapy, on one hand, we have device-based therapy,
9 on the other.
10 On the medical side, we need neurohumoral
11 blockade, we can have a hemodynamic approach and
12 also antiarrhythmic approach, so we are going to
13 use these drugs, ACE inhibitors, aldosterones,
14 diuretics, beta blockers, and then antiarrhythmics,
15 such as amiodarone, and then we are going to use
16 more potent i.v. inotropes that improve
17 hemodynamics, and asaratide [ph], which is
18 basically similar to BNP, it is like giving the
19 patient BNP.
20 On the other hand, we are going to have a
21 device-based approach using resynchronization
22 therapy. It really hasn't shown a benefit in
23 survival, but in combined endpoints. We are going
24 to put defibrillators into people, and I will show
you how that has improved survival.
1 Then, we will have ventricular assist
2 devices, and when all this fails, we have an option
3 of heart transplant, that is very little available
4 actually, and as you saw, it is a very little
5 sliver of what we are able to do.
6 But as you cumulatively add these
7 therapies, you are able to impact on survival and
8 make patients live longer. Here, you see sort of
9 adding digoxin and diuretic, adding an ACE
10 inhibitor, and then adding a beta blocker, we get
11 progressive improvement. So, this is pretty well
12 established in terms of medical therapy.
13 When we look at defibrillators, here is a
14 curve. This is from the MADA-2. This is primary
15 prevention, defibrillator in patients, previous MI,
16 LVF less than 30 percent, a very significant
17 survival difference in the patients that get a
18 defibrillator, so treating the arrhythmias is also
20 Back to our schema of the different
21 classification of stages of heart failure. You see
22 that we can gradually, we start with ACE inhibitors
23 and gradually add different medications, but
24 everybody kind of goes up these stairs and ends up
here at the top, and that is why we have increasing
1 mortality from heart failure, because we are
2 getting people to get to this point where before
3 they really didn't reach that stage.
4 Then, we get to a stage of basically
5 refractory symptoms, so they have been bypassed,
6 they have had stents, everything has been done for
7 them, and they have that bad heart, it doesn't pump
8 well, they have a lot of symptoms, they can't
9 breathe very well. Many of them have angina. I
10 want to want to give you a little bit of my own
11 perspective on that.
12 If we look at current trends, this was
13 published last week in JACC, very interesting.
14 Heart failure treatment--this is the survival
15 curves--heart failure treatment in 1994 to 1997.
16 Here is a survival curve. We have improved the
17 treatment of heart failure.
18 1999 to 2001, gee, we are doing a lot
19 better, and this is comparable actually to
20 transplant from 1993 to 2000, and it really raises
21 the question if transplant, with the modern
22 management in medical management of heart failure,
23 how important is it and what the role of transplant
24 really is.
25 Really, there is a gap between a very
1 invasive transplant or LVAD and the medical
2 therapy, there really is, and we are here to talk
3 about stem cell therapy. There is a gap of
4 something that could be done that is not quite as
5 invasive and traumatic as an LVAD or transplant,
6 and that can improve the patient significantly
7 since we are doing so well with medical therapy.
8 I want to talk to you a little bit about
9 my perspective on end-stage ischemic heart disease.
10 Basically, as I have told you, we have improved the
11 medical management, so we have longer survival, we
12 have improved the vascularization treatments of
13 coronary disease, we have improved the survival
14 following a heart attack, and that is why we have
15 more patients, and now we are using widely
16 defibrillators, and that is why people are living
18 So, this is sort of my understanding of
19 this end-stage patient. You progress with coronary
20 disease until you get to the Stage III and Stage
21 IV, Class III/Class IV heart failure.
22 If we look at these patients, sometimes
23 there will be a little surprise, because some
24 patients really just have shortness of breath, so
this is a variable. This may
occupy the whole
1 square or angina may occupy the whole square.
2 So, some patients predominantly have heart
3 failure, and these patients that predominantly have
4 heart failure probably weren't very good at forming
5 collaterals when they had heart attacks and
6 developed a lot of scar tissue, and have a very low
7 ejection fraction. These are the sickest patients
8 and the patients that are going to have a very high
10 On the other hand, but also in the Class
11 III or Class IV, and sometimes we pool these people
12 together in trials and that is why I am making this
13 distinction, some people have angina more than they
14 have heart failure. These probably have a much
15 better collateral formation when they had these
16 events, so their ejection fraction is a little more
18 I have had many patients that have lived
19 on one artery. Their whole heart is beating okay.
20 That one artery feeds everything by collaterals,
21 but they are in really bad shape. I mean it's an
22 illusion that they are doing okay, but they do have
23 a preserved ejection fraction, and their
24 manifestation is a lot of chest pain.
25 So, symptoms can vary from one side to the
1 other and some patients have a balance here, and I
2 think we need to keep this in mind when we are
3 designing these trials.
4 So, there is a predominant angina, and
5 this is the kind of patient that got, let's say,
6 these TMR type procedures. That is the kind of
7 population you are dealing with. The predominant
8 aspect is disabling angina, preserved EF, 100- to
9 200,000 new cases per year, and constitute about 5
10 percent of the patients undergoing angiography at
11 tertiary referral centers. This has been studied
12 in this particular case at the Cleveland Clinic.
13 One year mortality is still very high.
14 Then, that other group, predominantly heart failure
15 symptoms, very low EF, myocardial ischemia, though,
16 is still present, but with more scar. No option
17 really for any kind of revascularization. One year
18 mortality, 20 to 50 percent. I have shown you one
19 curve where it is up to 80 percent, I mean it can
20 be really bad.
21 Here, we have ICD therapy trials. If we
22 look at secondary prevention trials, very sick
23 patients in this study, treated with amiodarone,
24 you see here one year mortality 44 percent. I mean
heart failure can be worse than cancer.
1 Here is the REMATCH trial. This is an
2 LVAD. This is the impact of LVAD, and there is an
3 impact of survival, but again you are dealing, in
4 this case, with Class IV patients that are
5 unresponsive to medical therapy, so these very sick
6 patients, but again an invasive, costly, not widely
7 available kind of therapy, but it does have an
8 impact on failure.
9 I want to finish now talking a little bit
10 then, hopefully, I have given you an overview of
11 the problems with heart failure, and how are we
12 going to look at adverse events.
13 Well, what are the things that are going
14 to drive the adverse events here, are going to be
15 arrhythmia, ejection fraction, and symptoms, and I
16 think if we focus here, we can pretty much decide
17 what we need to look at in these patients over time
18 as we use new therapy towards these patients.
19 Let's look at low ejection fraction, how
20 are we going to monitor that? Well, we need to
21 look at cardiac function, cardiac size, and the
22 perfusion status of the ventricle. We can do that
23 very simply, if you take a simplistic approach,
24 with echocardiography.
25 I empirically have placed this here based
1 on my own limited experience here, but I read in
2 the document that you wanted some more practical
3 advice, so I will give you my own sort of practical
4 feel for what I would do.
5 If we did echocardiogram on these
6 patients, we could do it monthly for the first
7 three months and then at six months follow-up. We
8 can do SPECT, we know that we don't need it too
9 early, and that is a very simple way of doing it,
10 three to six months. Clinical visits, which will
11 be very frequent, and I will talk about that, and
12 BNP can be done for that, as well.
13 Now, we can get fancy and use alternative
14 imaging strategies, we can use MRI,
15 electromechanical mapping, PET, depending on the
16 institution, and depending on what we are really
17 looking for and want to find.
18 Cardiac arrhythmias, it is important to
19 monitor cardiac rhythm. Holter monitoring is very
20 simple, probably should be done after the
21 procedure, one, three, six months later. Q-T
22 interval when the patient comes in for his clinic
23 visit is a strong predictor of survival, just a
24 plain-old, good-old 12-lead EKG, and that should
always be looked at.
1 In the patients I guess that are getting
2 myoblast therapy, there may be a little bit more
3 concern about this, and this is really not my area
4 of expertise, but these patients, many of them
5 already entering with an AICD, that have sort of a
6 built-in little computer that is already monitoring
7 their rhythm as it is. If they don't, you might
8 want to consider event monitoring.
9 For symptoms, well, clinical visits
10 biweekly for 8 weeks, monthly up to 6 months. We
11 are going to look at heart class, we are going to
12 look at EKG, CBC, CRP, look for inflammation.
13 Exercise capacity, ramp treadmills, as you know, if
14 you put a patient that has end-stage heart failure
15 on a graded treadmill test, every time the
16 treadmill bumps up and goes a little faster, he
17 just may not be able to exercise at that point.
18 So, the advantage of a ramp treadmill
19 protocol is that you have a gradual continuous
20 increase, so these people that really can't do very
21 much at all, they will be able to tolerate the
22 exercise and probably get further than they could
23 in any other kind of exercise test.
24 There is a very simple way of evaluating
an exercise test, a 6-minute walk test.
1 define a distance, walk the patient walk for 6
2 minutes, see how fast he can go. You can do that
3 at a clinic visit, and it is very simple to do.
4 So, you can do something like this at one, three,
5 and six months.
6 Rehospitalization. We look at the
7 rehospitalization rates. It is important to look
8 at the use of i.v. medications that are used to
9 control symptoms, because this is, as you saw, the
10 biggest part of the pie in terms of costs, and is a
11 real problem in the end-stage patients.
12 Quality of life, it is important to assess
13 quality of life, for example, SF36, Minnesota
15 Just some suggestions. I want to wrap
16 this up and saying I hope I have given you a
17 general idea and scope of this problem. We deal
18 with a very, very serious problem, which is heart
19 failure, specifically, that which is ischemic heart
20 failure and specifically, end-stage ischemic heart
22 I hope I have given you a flavor of this
23 and set the stage for the discussions.
24 Thank you very much.
1 DR. RAO: Thank you, Dr. Perin.
2 There is time for questions, and we can
3 open it up to the committee.
5 DR. SCHNEIDER: Emerson, one of the things
6 that you did very nicely was lay out the clinical
7 spectrum for people who may not be familiar with it
8 in this context.
9 I wanted to follow up on that point
10 because work presented at international meetings
11 recently by the Frankfurt group of Andreas Sire and
12 Stephanie Dimler suggests that bone marrow derived
13 cells and circulating progenitor cells from
14 patients with established heart failure may be
15 deficient relative to the performance of bone
16 marrow derived and circulating progenitor cells
17 from patients with an acute infarct.
18 So, while it is not quite an apples and
19 oranges comparison to envision cardiac cell
20 grafting immediately post infarction or in the
21 first week post infarction in patients without
22 severe ventricular dysfunction versus patients,
23 let's say, two to four months out with mild or no
24 ventricular dysfunction versus the end-stage heart
failure patients who have been a focus in your talk
1 this morning, it does seem to me that that clinical
2 heterogeneity introduces a couple of problems.
3 I am curious to know how you have worked
4 those through in your own work. One of them is
5 because what we are discussing today and tomorrow,
6 is autologous cell therapy, I believe that there is
7 a serious issue of patient-to-patient cell
8 heterogeneity which has been relatively little
9 discussed in the field except in these still
10 unpublished or perhaps one paper has come out in a
11 secondary journal from Stephanie and Andreas about
12 the defects.
13 So, one question is what kinds of
14 standards should a proposed production center be
15 required to meet in terms of their ability to
16 generate cells that perform in accordance with some
17 standard when there is patient-to-patient variation
18 of this kind.
19 Secondly, if you are envisioning putting
20 cells of different kinds into a so severely an
21 ischemic background as the 41-year-old former pilot
22 that you mentioned, doesn't it become important to
23 clearly distinguish, as the prefatory remarks did,
24 between mechanisms of action for proposed donor
cells that are aimed at regeneration specifically
1 versus benefits that are achieved through entire
2 different mechanisms, such as angiogenesis?
3 If you put new cells into an ischemic
4 background, they will surely die, and if the goal
5 is to achieve angiogenesis in a background where
6 the native coronary circulation has failed and the
7 graft has failed, then, it seems to me we need a
8 clearer resolution of the problem of which cells do
9 which things well, and really fine-tune much better
10 than the field has to date, you know, which are the
11 cells that we want where the spectrum is normal
12 vasculature, insufficient muscle cells versus the
13 hypothetical ischemic patient that you described
14 where revascularization is the major goal.
15 DR. PERIN: Well, that's fantastic.
17 DR. PERIN: I think the basic answer to
18 your question is I don't know, but, you know, these
19 are all very good points, starting with the cell
20 type, we really don't know.
21 Actually, we have submitted a manuscript
22 in which we have had the pathology of one or our
23 patients in our study in Brazil who received
24 autologous bone marrow, died 11 months later, and I
really can't preempt I guess our publication, but I
1 think we will be seeing some evidence of myogenesis
2 and angiogenesis from autologous bone marrow cells,
3 but we really don't know what we are getting when
4 we are putting, let's say, autologous bone marrow,
5 and even in that patient that has, let's say he has
6 predominantly ischemia, if we want to
7 revascularize, can we get a predominantly
8 angiogenic effect, so we really don't know, and we
9 need to define that.
10 Mononuclear fraction of the bone marrow is
11 a very simple approach, the one that we have taken,
12 and it seems to initially, and we haven't really
13 done efficacy studies and we are continuing on, but
14 there is a suggestion that it does, so I think that
15 we need to take every step that we take should be
16 put one foot in front of the other, and if the
17 mononuclear cell fraction works, I think we can go
18 from there and keep investigating that.
19 Now, the average age in our trial was
20 about 58, and you mentioned the problem--
21 DR. RAO: Can I interrupt? These are
22 really important questions, but they discuss data
23 which was not presented in the talk right now. I
24 would like to at least focus the questions
initially on the issues that relate to the
1 presentation right now.
2 We should really come back to these
3 questions tomorrow when we discuss exactly these
4 sorts of issues.
5 Do you think that that would be okay with
6 you, Dr. Schneider?
7 DR. SCHNEIDER: We will certainly return
8 to them tomorrow, but I was discussing issues that
9 were raised in this talk, which was clinical
11 DR. RAO: Let's then focus, not on the
12 cells per se, and the choice of cells, because none
13 of the presentation was related to the production
14 facility or how the cells would be, or the quality
15 would be, or how you would choose the mechanism,
16 but maybe how do you choose patients for a trial or
17 is there some reasonable way of selecting patients,
18 that there would be consensus on.
19 DR. PERIN: Okay. So, we will get back to
20 your first question and really, that is something
21 that actually, we are working on trying to
22 understand, is there a thumbprint or is there a
23 profile in the study by Dimler and their colleagues
24 looking at the characteristics of cells in certain
patients, and obviously, they may not be the same
1 in a diabetic, in a severe heart failure, we don't
2 know, so there is another important we don't know.
3 Age obviously is a very important thing,
4 so harvesting cells from a 75-year-old may be very
5 different than doing that in a 55-year-old, so
6 these are all questions that need to be answered.
7 DR. RAO: Dr. Mul.
8 DR. MULE: Given the slides you showed of
9 the steps toward progression of heart failure, and
10 given the current interventions along that pathway,
11 from your perspective, where would you see
12 cell-based therapy intervention falling into that
13 step toward complete heart failure?
14 DR. PERIN: Right now, at close to the
15 last few steps, I think ethically, we are propelled
16 to really study the problem in the patients that
17 really don't have a proven conventional option for
18 treatment. In brief, I would say in the patients
19 who can't be revascularized, because really medical
20 therapy, we are going to apply to everyone, so then
21 we are left with revascularization.
22 Well, can we revascularize? Well, we do,
23 and we do it again and again, and there is a point
24 where you are out of revascularization options, and
think that is one place we are
1 then, you could think about applying this kind of
3 DR. HARLAN: Building upon what Dr. Rieves
4 mentioned when he gave his introductory comments, I
5 want to just congratulate you on, it seems like our
6 task is to weigh the risk-benefit, and you have
7 outlined very clearly the risk, and I accept that
8 it is severe, and I also want to congratulate you
9 on mentioning the JACC paper that was just
10 published, that showed how dangerous it is to look
11 at historical controls, because we are making such
12 rapid progress.
13 My question is along those lines, not in
14 this field, I just read in the journal, the
15 Washington Post, about the great advance that has
16 been made in super-high statin therapies, and I
17 wonder if you could comment on that study, that
18 these super-physiologic statin doses seem to have a
19 major impact on mortality.
20 DR. PERIN: I really don't have an
21 expertise in a lot of things, and that is not one
22 of them, so it is really hard for me to comment on
23 that. I know that it looks like giving people HDL
24 in the future may be a very exciting thing, and we
25 may be able to finally find our liquid
1 of solution for people.
2 Then, again, statins are just--more and
3 more if you study statins, you have probably come
4 to the conclusion it should be in the water pretty
5 soon, I mean the patient benefit is on every single
6 aspect of cardiovascular disease.
7 DR. RAO: Dr. Kurtzberg.
8 DR. KURTZBERG: You mentioned some
9 practice-based methods to evaluate outcomes and
10 function in these patients, but I think the
11 challenge is to determine what the cells are doing,
12 you know, are they differentiating into other kinds
13 of cells, are they mediating inflammation, are they
14 mediating angiogenesis, and I don't see how you can
15 sort that out by clinical-based study.
16 Do you know of other technologies that are
17 on the horizon that may help with that, that are
18 non-invasive, or would you consider serial biopsies
19 in patients like this to answer those questions?
20 DR. PERIN: That is a good question. I
21 don't know that serial biopsies would be a very
22 efficient way of evaluating that. You would have
23 to have a very precise way of being able to
24 identify where you put the cells and be able to go
exactly to that same spot.
1 We do have that technology. Dr. Lederman
2 is going to follow me eventually here. The MRI
3 field, I think is very promising in that regard in
4 terms of labeling and following cells.
5 Now, I really don't know that even
6 labeling a cell, even if it died, if the label
7 stays there, you still see the label, so I think
8 that we have to even go a step further and be able
9 to prove the functionality of the cell that is
10 alive and was implanted.
11 That can be done on an experimental basis,
12 so we figure ways out to do that, but this is a
13 very intriguing problem and a very difficult
14 problem to evaluate. I think you have put your
15 finger on something that is going to be hard to
17 DR. DINSMORE: Jonathan Dinsmore from
19 I just had a question on your angina heart
20 failure continuum. I was confused because most
21 heart failure patients present without angina, with
22 symptoms of fatigue, so what percentage of heart
23 failure patients actually experience angina?
24 DR. PERIN: If we are talking about
ischemic heart failure, we are not talking about
1 other kinds of heart failure, actually, idiopathic
2 heart failure, you kind of get the same remodeling
3 and everything except you didn't have that infarct
4 in the beginning, but you go through the same sort
5 of pathophysiologic processes.
6 So, we are talking about ischemic heart
7 failure. People that have ischemic heart failure
8 have coronary disease. Coronary disease is
9 narrowing of your coronary arteries.
10 Depending on what your response is, you
11 will or will not have angina, but angina is one of
12 the manifestations of coronary disease, and it is
13 really not a good thing to base a lot on, because
14 the expression of angina is very variable.
15 It depends on your pain threshold. I mean
16 if you are a diabetic, you may not have as much
17 pain. It is a subjective thing subject to
18 interpretation by the actual patient, so it is
19 something that is very difficult to evaluate, and
20 that is why I put the continuum, because it is all
21 there and you really shouldn't take a patient
22 population based on angina or based on shortness of
24 I think you have got to bring both of
these things together to understand they are sort
1 of in the spectrum of a similar underlying
2 pathophysiologic process.
3 DR. SIMONS: I would like to come back to
4 the issues of the differences among the patients
5 having these kind of therapies. We have learned
6 from a number of trials of growth factor therapies
7 that there is a very large difference in how the
8 patients respond.
9 This issue that there are different
10 subgroups that we are not defining is fairly
11 critical to the field. You mentioned one or two
12 biomarkers, but there seemed to be a general
13 association of markers as opposed to really
14 identifying which patients respond in which manner.
15 What would you suggest as a way of trying
16 to sort of stratify these patient groups? Not
17 suggest ejection fraction, that is probably in a
18 way sort of crude measure, but in terms of
19 biological responses.
20 DR. PERIN: If we look at the trials of
21 devices, I think that probably a common way to look
22 at these patients is exercise capacity.
23 I think that probably is one of the
24 unifying parameters that we cannot only use at
entry, but also you are able to follow as a patient
1 goes along, and if he has a response to therapy, he
2 will have a positive response in terms of what he
3 is able to do in terms of function.
4 That has a very practical translation into
5 quality of life and people feeling better. I would
6 say in a broad sense, that exercise capacity, peak
7 oxygen consumption might be something that I might
8 consider an important thing to follow in these
9 patients, and not just ejection fraction, which is
10 dependent on a lot of things, how much loading the
11 ventricle has that day, the amount of mitral
12 regurgitation, et cetera, so there is a lot of
13 things that will make that extremely variable.
14 DR. RAO: As an extension of that, it's a
15 very general question. Is there any problem with
16 many of these studies which are in high-risk
17 patients enrolling people for the placebo arm of
18 the trial? Not in cell therapy, but maybe when you
19 do devices or you do assists, has this been
20 historically a problem for the cardiovascular
22 DR. PERIN: Well, it has been done as you
23 can see, so I have showed you a bunch of studies
24 where it has been done, and it can be done.
25 Personally, the way I like to see it is I
1 want to offer patients that get in the placebo arm
2 some kind of a treatment, so in our future upcoming
3 study, what I am going to do is I will tell a
4 patient you are going to get randomized to maybe
5 not getting treatment, but if you don't get that
6 treatment at an X period of time, six months, you
7 will cross over to get the treatment.
8 I think that is a humane way of doing it,
9 in which these patients are very ill and desperate
10 to get something to help, so again, if you can
11 cross over, sometimes these placebo patients at
12 some point after you have achieved your assessment,
13 then that makes it a more palatable or fair way to
14 do things maybe.
15 DR. RAO: Dr. Cunningham.
16 DR. CUNNINGHAM: I just wonder, in your
17 data, if you see any difference by either
18 socioeconomic status or by gender, or by any way of
19 culture, dividing populations, whether it would be
20 race or ethnicity or any other factor like that?
21 DR. PERIN: You mean in our own--
22 DR. CUNNINGHAM: Yes, reading the JACC
23 data, was there anything by gender, for instance,
24 or by subpopulation?
25 DR. PERIN:
Females, there are some
1 differences in the female population in which there
2 are some differences. There is the catch-up
3 phenomenon in the end, but socioeconomic
4 differences, I am not aware that it would have an
5 impact on that, as well, but maybe gender
6 differences, yes.
7 DR. RAO: One question to sort of follow
8 on Dr. Simons' question, in at least the way I
9 understood it, it is really kind of difficult to
10 stratify patients or to extrapolate from one class
11 of patients to the other. Historically, that has
12 always been a problem.
13 Again, it's a general feeling when one
14 conducts studies in the cardiovascular field, is
15 there some consensus that everybody says that,
16 well, if you measure by ejection fraction, and we
17 take patients, which is what it seemed like a lot
18 of studies have done, that that is a reasonable
19 criteria that you can extrapolate from one
20 classification of that kind to the next, or one
21 cannot? Just as a general statement.
22 DR. PERIN: It has been done, and it is a
23 general way of separating--there is definitely a
24 correlation with your ejection fraction and your
survival, so it is probably not the most refined
1 way of dividing patients, and it depends where you
2 make the cutoff, so if you make a fairly high
3 cutoff, let's say, patients that had ejection
4 fraction less than 40 percent, then, you are
5 including most of the population of patients that
6 have heart failure, so it's a general way to divide
8 If you start decreasing that number of
9 that cutoff, then, you are really selecting out
10 more I think subpopulations we were talking about,
11 maybe some different kind of subpopulations of
12 patients with heart failure.
13 DR. RAO: Dr. Borer.
14 DR. BORER: Dr. Rao, a few minutes ago you
15 made a point, and I would like to restate it in
16 another way, because what Dr. Perin did, as I see
17 it, is very well present an overview as an outline,
18 was a scaffold upon which we can conduct subsequent
19 more specific discussions.
20 I think that right now we are getting into
21 a series of questions that are way beyond the data
22 that exist, and you couldn't expect Dr. Perin to
23 respond to them in a meaningful way because the
24 data don't exist.
25 In specific response to your question,
1 which was a very fundamental one, I think we are at
2 a point now with this form of therapy where if we
3 could define any group in which we saw a response
4 which seemed credible, which was statistically
5 valid, we would then have a series of hypotheses
6 that would have been generated that would allow one
7 to move further, but I think that is the level we
8 are at.
9 The idea of defining a general population
10 in which to test therapy the way we do with drugs,
11 we are not there yet, so I think the specific
12 questions have to come a little later in this
14 DR. RAO: I just wanted to get it clear to
15 people that that was the case, but your point is
16 very well taken.
17 Dr. Neylan.
18 DR. NEYLAN: Thank you.
19 That was a very nice clinical overview,
20 and I wanted to ask you from your perspective as a
21 clinician, there are obviously many parameters
22 whose relief or improvement would be significant in
23 terms of the lives of individual patients, and many
24 of these could be utilized as endpoints for proof
1 But ultimately, what do you believe is the
2 most relevant clinical endpoint for defining
3 registration criteria for this form of therapy, is
4 it patient mortality or something else?
5 DR. PERIN: I don't know if we are going
6 to be impacting patient mortality. That is a very
7 difficult question. I would go back and what I had
8 said earlier, and use an endpoint, I would use
9 something like the LV02 as an endpoint.
10 I think that is a little bit more
11 palpable, and obviously, looking at mortality, this
12 is such an initial incipient field in which we have
13 barely treated any patient, so to think about
14 looking at mortality, which involves a much larger
15 number of patients, I think that is probably
16 getting ahead of ourselves a little bit.
17 We need to first verify if this is
18 efficacious and if there is some objective
19 improvement in these patients, and one of those
20 objective ways of doing that would be something
21 like exercise capacity, like I mentioned.
22 DR. RAO: Dr. Ruskin.
23 DR. RUSKIN: Just two quick comments on
24 Dr. Perin's very nice presentation.
25 One is that we have learned from drug and
1 device trials that both ejection fraction and heart
2 failure classification are critically important
3 predictors, but that they are not necessarily fully
4 interactive, that is, they are independent, so
5 using both, I think in any classification with
6 regard to these kinds of interventions would be
7 critical because the outcomes are very, very
8 different in Class III and IV even with the same
10 The other relates to a question that Dr.
11 Rao raised about recruitment and controls. I think
12 that given the excitement in this area, but the
13 unknown issues that have already been raised, doing
14 trials that have adequate controls perhaps is more
15 important here than anywhere else one can imagine
16 given the severity of the illness that we are
17 dealing with and the kinds of outcomes that Dr.
18 Perin has described.
19 As someone who recruits for device trials,
20 though, I can tell you that it is not easy, and
21 randomizing patients to acceptable controls in this
22 kind of illness is going to be a huge challenge,
23 but I think it is important for this group to
24 emphasize that there is no place where this could
be more important, otherwise, we will never get an
1 answer, and I think that mortality ultimately will
2 have to be a critical part of any trial that is
4 DR. RAO: Go ahead, Dr. Borer.
5 DR. BORER: I agree completely with Jeremy
6 that controls are essential in this kind of
7 research and really in any clinical research, but I
8 think again to put this whole area in context, and
9 in response to Dr. Neylan's point and question, we
10 are at the point now of looking at physiological
11 variables and what we would call in drug
12 development "surrogates," to see whether cardiac
13 performance, cardiac perfusion, this, that, and the
14 other thing, is affected in one way or another, so
15 that one could extrapolate to the point where it
16 would be legitimate to define hypotheses about
17 clinical outcome.
18 We are not there yet, and the clinical
19 outcome, just to put it in context from the drug
20 world, is perfectly legitimate in the view of most
21 people who deal with this area and these agents to
22 think of a therapy as being approvable if it makes
23 people feel better, but doesn't make them live
25 If it makes people feel better, even if it
1 makes them live a little bit shorter, as long as
2 you know how much shorter that is, and if it makes
3 people live longer while not making them feel too
4 much worse.
5 I don't think we are at a point yet again
6 to define what the outcomes variables should be. I
7 think we are at the point of defining physiological
8 and pathophysiological surrogates, and that is what
9 is being done in the studies to date, and then we
10 can decide what the outcomes are, clinically
11 important for registration.
12 DR. RAO: I guess that leads us to the
13 fact that many of these things should be discussed
14 tomorrow, just like you pointed out.
15 If there are no critical questions
16 remaining, I will thank Dr. Perin.
18 DR. RAO: We are going to take a short
21 DR. RAO: We are really extremely
22 fortunate in having Dr. Menasch here to present
23 his findings, and I look forward to a really
24 interesting talk.
25 Clinical Experience of Autologous
1 Myoblast Transplantation
2 DR. MENASCHE: Good morning. First of
3 all, I would like really to thank you for the
4 privilege of this invitation and this unique
5 opportunity of sharing some data on the clinical
6 myoblast transplantation.
7 What I would like to do in this talk is
8 first to briefly touch on the preclinical data
9 which have paved the way for these early clinical
10 trials, and then, as requested by Dr. Grant, to
11 focus on the various aspects of the clinical
12 experience which has accumulated so far before
13 drawing some perspectives which may have clinical
14 relevance in the near future.
15 Now, I think just to make things clear,
16 that the basic assumption is fairly
17 straightforward, and the objective of this therapy
18 is really to try to repopulate areas of dead
19 myocardium with new contractile cells with the hope
20 that these areas can regain some function, and
21 given the close relationship between function and
22 survival, which has been already mentioned, the
23 ultimate hope is obviously that it can have a
24 significant impact on clinical outcomes.
25 The reason why we initially started with
1 the skeletal myoblasts are actually listed here.
2 These cells are not really stem cells, they are
3 better termed precursor cells for muscular fibers
4 in that they are very committed to their skeletal
5 muscle phenotype as you will see.
6 The first advantage of the myoblasts is
7 that they can be very easily retrieved from the
8 patient himself, thus overcoming any problem
9 associated with rejection and immunosuppressive
11 These cells feature a very great expansion
12 potential which is important given the relationship
13 which exists between the number of cells which are
14 injected and the ultimate functional outcome.
15 As I have just said, they are pretty well
16 committed to their myogenic lineage, and the risk
17 of tumor development is virtually negligible.
18 Finally, they are pretty resistant to ischemia, and
19 although unfortunately, many of them die shortly
20 after the injections, fortunately, some of them
21 will survive and may positively affect function.
22 So, this is type of animal model which has
23 been used initially in rodents. You see here the
24 heart and the needle injecting the cells. I just
would like to mention that it took us seven years,
1 seven years of preclinical work before I did
2 operate on the first patient June 15, 2000.
3 During the seven years, we moved from the
4 rodent models to the large animal models, which I
5 think is absolutely necessary before arriving to
6 clinical trials.
7 Just to summarize the bulk of this data,
8 we can say, number one, that when you inject
9 skeletal myoblasts into an infarcted area, they
10 retain the possibility of differentiating into
11 typical myotubes. Here is a typical myotube,
12 elongated structure, and this is a sheep heart and
13 this is a human heart.
14 This is an autopsy specimen. One patient
15 of our Phase I trial died 18 months after his
16 surgery from stroke, and we had permission for the
17 autopsy. You will appreciate the striking
18 similarity of these two slides. Here you find in
19 this human heart, a typical myotube embedded in
20 scar tissue.
21 At closer magnification, you can
22 appreciate the typical cross-striations, and I
23 think two observations are important to be made at
24 this point. Number one, these cells really remain
committed to their skeletal muscle phenotype. In
1 other words, there is virtually no evidence that
2 they can ever turn to cardiomyocytes. They will
3 not become cardiac cells.
4 Number two, they remain electrically
5 insulated from the surrounding myocardium, which
6 obviously raises major mechanistic questions
7 regarding the underlying mechanisms by which they
8 can improve function, but the fact is that there is
9 no real evidence that they develop connections with
10 the neighboring cardiomyocytes.
11 Nevertheless, when you subject them to
12 strong depolarizing currents, they show excitable
13 properties, and you see here, this is a fluorescent
14 myotube which has been grafted in a myocardial
15 scar. This is an in vivo study and definitely they
16 can respond to currents by generating action
17 potentials followed by contractions.
18 This translates into an improvement in
19 function, both regional function here in the sheep
20 model, and global function, the LV ejection
21 fraction. This improvement, as you can see, seems
22 to be sustained over time until one year in our rat
23 studies, and basically, these kinds of observations
24 have been made by several other investigators
already past 10 years.
1 So, there is a fairly good consistency
2 showing that these myoblasts can, to some extent,
3 improve function at least in animal models, and
4 obviously, the gap with the humans is a wide one.
5 So, if we now move to the clinical
6 experience, so far there are 44 patients who have
7 been included in early Phase I trials, and 34
8 patients currently included in our ongoing
9 randomized, multi-centered Phase II study .
10 This list is by far not exhaustive. I
11 have not tabulated anecdotal case or me-too cases.
12 I have just kept those studies which have been
13 published in peer-reviewed journals.
14 Basically, the inclusion criteria have
15 been fairly straightforward across all these
16 studies. Patients with low ejection fractions,
17 usually below 35 percent, patients with a history
18 of myocardial infarct, and obviously, patients
19 requiring concomitant coronary bypass surgery since
20 for ethical reasons, it is difficult to open the
21 chest just for injecting a product we don't really
22 know whether it is effective or not.
23 If we try to summarize the main results,
24 we can say, number one, that multiple epicardial
injections look to be safe. I
have never seen any
1 bleeding from the needle holes, and overall, this
2 experience has been shared by the other surgeons
3 who have practiced the operation.
4 Number two, it is possible--and we will
5 come back on that--that the procedure increases the
6 risk of arrhythmia postoperatively, at least in the
7 early post-op period.
8 Number three, I will be extremely careful
9 and cautious about that, there are some data
10 suggesting that maybe function can improve, but it
11 is clear that until we have the results of the
12 ongoing randomized, placebo-controlled study, we
13 cannot make any meaningful conclusion.
14 This is the list of the studies and of the
15 patients. I have just added the last one a few
16 days ago. Professor Siminiak presented at the
17 American College of Cardiology another series of 10
18 patients who got the cells through a percutaneous
19 catheter using the coronary sinus route. I will
20 come back on that catheter in a few minutes, but I
21 will rather concentrate on the surgical
22 implantations listed here.
23 Dr. Smits also injected cells through a
24 catheter using the interventricular approach
similar to the one alluded to by Dr. Perin.
1 This goes back to the inclusion criteria
2 which have previously been mentioned. I think it
3 is important to look at all words, because as you
4 will see, differences in definition may really be
5 confounders in the interpretation of the results.
6 It is important to look at akinetic areas
7 that is really dead myocardium, not simply
8 ipokinetic or dyskinetic, really akinetic
9 myocardium, which are not amenable to
10 revascularization and obviously, it is also
11 important that the bypass surgery be done in other
13 For example, you will see that in one
14 study, the area which was transplanted with cells
15 was also revascularized, so when the authors
16 conclude that cell therapy improves function, it is
17 clearly meaningless since the same area has got
18 simultaneous revascularization.
19 For those of you who are not familiar with
20 the procedure, I just would like briefly to show
21 you this three-step operation. It starts with a
22 muscular biopsy. We take it at the thigh. It is a
23 very simple procedure under local anesthesia.
24 We remove a chunk of muscle, which is then
cut into small pieces, put in this sheeping medium
1 and sent to the cell culture lab where a multiple
2 tri-cell factory is being designed to allow for
3 large-scale cell production.
4 Then, there are regular morphological
5 controls. Obviously, the key point is to inject the
6 cells before they reach confluence. What you would
7 like to do is that confluence occurs in vivo
8 following the engraftment, not before, so it is
9 important to check the morphological state of the
10 cells on a regular basis.
11 This is how human myoblasts look like
12 during the cell culture process, and this is how
13 the cells look like when they are back in the
14 operating room.
15 Then, with the curved needle, we inject
16 the cells all across the infarcted area including
17 the borders. It's a time-consuming, I would say
18 10, 12, 15 minute procedure, rather tedious and
19 boring procedure, by the way, where you have to
20 mentally construct the grids and then go with the
21 needle from side to side, so we are working on the
22 multiple shot device, but it is more tricky than we
23 initially thought.
24 So, right now we have the requirement for
these multiple injections all across.
1 another view of the injections.
2 So, if we start by feasibility, I think it
3 is quite well established that this technique is
4 perfectly feasible. In other words, it does
5 demonstrate that provided you have the appropriate
6 techniques, you can take a small piece of muscle
7 which contains, say, 3- 4 million skeletal
8 myoblasts initially and expand it over two to three
9 weeks until approximately 1 billion cells.
10 These are the results of our cultures
11 during the Phase I trial, during which the target
12 numbers which have been prespecified have
13 consistently been obtained and even overshoot it.
14 You will note that you can get up to 90
15 percent of skeletal myoblasts in that--and this is
16 an important point--you really end up with a pretty
17 well defined cell therapy product. You really know
18 what you are injecting.
19 Importantly, what we have seen is that
20 heart failure does not prevent skeletal myoblasts
21 to differentiate into myotubes, and this was a
22 question because when we did preclinical rounds, I
23 got pieces of tissue from orthopedic colleagues,
24 but often these patient were young, and the
question was are the myoblasts from this Class
1 III/IV heart failure patients going to
2 differentiate normally, and the answer is yes, so
3 far we have had no failure.
4 The only thing is that it may take a
5 little bit more time for some patients until we get
6 the target number of cells, but at the end of the
7 day, it has always been possible to achieve the
8 prespecified target number of cells in myoblasts.
9 What about safety now? These are the
10 different adverse events we were concerned with by
11 the time we started the trial, and fortunately, I
12 must say that none of them has occurred except--and
13 we are going to discuss that--possibly the
14 arrhythmias, but it is important to emphasize that,
15 for example, there was never any particular
16 bleeding from these multiple puncture sites.
17 There was no unusual complication in the
18 postoperative course of these patients, and when
19 the cells were injected in newt immunocompromised
20 mice, there was never any evidence for tumor
22 Obviously, before we started the study, we
23 had to go through a lot of regulatory constraints,
24 indeed, what I did is to discuss with the French
FDA and ask them what was approved or not, and the
1 game was not so easy because as previously
2 mentioned, there was no precedent.
3 So, they told us, well, this is what you
4 are allowed to do. This is the kind of culture
5 medium, ancillary product additives which are
6 permitted for human use, so we immediately from the
7 onset designed our cell culture in accordance to
8 the prespecified instructions, and obviously, it
9 was timesaving because when we came back with the
10 process, there was nothing else than to accept it.
11 Well, what about the V-tachs? In the
12 initial series we had 4 patients with sustained
13 episodes of ventricular tachycardia.
14 All of them occurred during the early
15 post-op period, the early three first week,
16 postoperative weeks, and there was virtually no
17 recurrence later on because these patients had a
18 defibrillator put on and only one of them
19 experienced firing of the defibrillator one year
20 later, so it really appears to be a relatively
21 early post-op event.
22 Now, there are different mechanisms which
23 could account for these arrhythmias, in particular,
24 the differences in electrical membrane properties
between the grafted cells and the neighboring
1 cardiomyocytes. Obviously, other mechanisms can
2 also be considered, but we really favor the first
3 one because we did an EP study in which we looked
4 at the different membrane properties of the cells.
5 Here, you see a typical action potential
6 of a muscular fiber and here of a cardiomyocyte.
7 Now, if you graft skeletal myoblasts back into a
8 muscle, these cells retain a typical skeletal
9 muscle phenotype, and this is also true for
10 myotubes which grow in culture.
11 The question is how does it look like when
12 you graft the skeletal myoblasts into the heart.
13 Well, definitely it remains very similar to what it
14 was initially and different from the action
15 potential of the cardiomyocyte.
16 If you expressed it graphically, you would
17 see that the action potential duration is quite
18 different between the cardiomyocyte and the
19 myotube, and this heterogeneity might account for
20 some of these arrhythmias.
21 Now, having said that, the picture is
22 probably more complex and the reason, as you know,
23 and it has been mentioned by Dr. Perin in his talk,
24 is that heart failure by itself predisposes
patients to arrhythmias.
1 So, I think that as long as we don't have
2 the results of the randomized trial in which all
3 patients have been instrumented with a
4 defibrillator, it will be difficult to conclusively
5 establish a causal relationship between grafting of
6 cells and the occurrence of arrhythmia.
7 I can also tell you that we currently have
8 randomized 34 patients in the Phase II trial and
9 the incidence of arrhythmia has been strikingly
10 low, much lower than in the initial study we had
11 done, so things are probably less clear than they
12 were initially, and once again we have to wait for
13 the results of the randomized trial before we can
14 definitely say yes, there is no relationship
15 between myoblast transplantation and arrhythmia.
16 Anyway, these patients or most of them
17 would require at one point a defibrillator, so it
18 was not a big issue for us to implant those
19 defibrillators in all the Phase II patients.
20 Now, what about efficacy? Now, we have to
21 be extremely careful in the interpretation of the
22 results which are presented because of the
23 multiplicity of the confounding factors.
24 The culture conditions, for example, the
Spanish group has used a culture medium which
1 contains the patient's own serum, and the
2 conclusion is we had no arrhythmia, so if you use
3 the patient's own serum instead of fetal calf
4 serum, you prevent arrhythmia.
5 I think it is really a simplistic
6 conclusion based on 12 patients, but it can
7 introduce an additional bias. There is currently
8 no evidence that fetal calf serum is really
9 responsible for the arrhythmias.
10 Dosing has been extremely different and
11 variable from one study to the other, as well as
12 the kinetics of the grafted area.
13 Once again, any kinetic area is different
14 from a dyskinetic area, which features a
15 paradoxical motion, and, for example, in the U.S.
16 trial, some patients were included who had
17 hypokinesia, which we know can improve just because
18 of the revascularization even if revascularization
19 is not targeted at this particular area.
20 The same for bypasses. In the Spanish
21 study, for example, the cell grafted areas were
22 also bypassed, which makes the interpretation of
23 results impossible.
24 Type of surgery has also been different.
In the U.S. study, for example, some patients had
1 additional reconstructions of the left ventricle in
2 addition to the bypass surgery, which make things
3 still more complicated.
4 Finally, the method of outcome assessment,
5 in some studies, the assessment has been
6 centralized at one side, in others, each center has
7 made its own assessment, which obviously makes big
9 This is just to illustrate the variability
10 in the number of cells which have been injected. I
11 don't have the figures for the initial surgical
12 study from Professor Siminiak, but as you can see,
13 there is a wide variability.
14 The U.S. study of Dr. Dib was, as you
15 know, was a dose escalating study accounting for
16 this variability in the numbers. Dosing is
17 probably important. This is one study among others
18 showing that there seems to be a tight relationship
19 between the number of injected cells and the
20 functional outcomes.
21 This is the reason why, in our early Phase
22 I trial, we have targeted a high number of cells,
23 800 million. In the Phase II, we have two arms with
24 two different doses of cells, but the number
probably makes a big difference given the high rate
1 of early cell death.
2 The characteristics of the grafted
3 segments, as I previously mentioned, have also been
4 different from one study to the other, as well as
5 the method for assessing viability, usually,
6 dobutamine echocardiography, occasionally MRI or
7 PET scan.
8 Same variability in the characteristics
9 of injections, but you see that you can go up to
10 almost 60 injections without any concern related to
11 bleeding, and obviously, the number of injections
12 depends on the extent of the area of infarction.
13 It is also important to look at the cell
14 concentration. We extensively studied that before
15 I started doing patients. You have to find a
16 tradeoff because if you use a large needle, then,
17 you can have large holes and some bleeding
19 If you use a too small needle, you will
20 eliminate the bleeding problems, but the cells may
21 be packed and damaged through their passage, so we
22 ended with a 27-gauge needle which gave an
23 acceptable rate of cell viability.
24 The concentration of cells is important,
and probably still more important when you are
1 using a long catheter. We are using a short needle
2 with directly the serum hooked to the needle, but
3 if you are using a long catheter, concentration may
4 make a big difference.
5 Finally, revascularization is occasionally
6 being done in the same area as the area where cells
7 were put in, which completely confuses the results.
8 This is, for example, the Spanish study,
9 what you see is that, what they call the untreated
10 segments, that it is segments which had just
11 bypassed, the wall motion score went from 1.2 to
12 1.1 and 1, but really, this is almost normal
13 motion, so obviously, it makes it easier to
14 demonstrate that in the other segments which have
15 bypass surgery and cells, the improvement was
17 This is a summary of our data from the
18 Phase I trial. We had an improvement in the
19 functional status and an increase in ejection
20 fraction. These results are meaningless because
21 these patients had associated bypass surgery.
22 So, we rather looked at the number of
23 scarred segments, and I remind you these were
24 akinetic segments without viability on dobutaminic
echocardiography without any possibility for
1 revascularization. So, we looked at the changes in
2 the contractions of these segments which have been
3 grafted with cells.
4 So, initially, obviously, there was no
5 motion since it was one of the inclusion criteria,
6 and afterwards we had, at two different time
7 points, approximately 60 percent of segments
8 regaining some function.
9 I am not saying that these segments were
10 normally contracting, they were not. There was a
11 slight and modest improvement. This was a blinded
12 assessment, in other words, we blinded the dates of
13 the echo tapes and asked independent
14 echocardiographers to review them and to grade
15 them. There was a modest improvement, not normal
16 contraction, but it was sufficient to push us to
17 move forward to the Phase II study.
18 I just show you a couple of examples.
19 This is a flat exterior wall, no motion at all, and
20 this is the same wall with the systolic thickening
21 following myoblast transplantation. This is the
22 MRI study which does not project on the screen. I
23 have it on the computer, but not on the screen.
24 You see here the interior infarct which
has been grafted, and you can appreciate an
1 improvement in wall motion in the postoperative
2 period. This is an exterior infarct. You see the
3 thin wall here, which has been grafted, and this is
4 the post-op pattern with a thickening of the wall.
5 I add intentionally that these patients
6 also had bypasses in the left system. I don't like
7 the slides where you see pre-transplantation,
8 post-transplantation, just omitting that in
9 addition, there was either bypass surgery or
10 balloon angioplasty.
11 This is another example of an interior
12 infarct pre-transplantation and bypass to the
13 posterior descending coronary artery and the
14 post-op, with an improvement in the wall motion.
15 So, now, can it be due to the
16 revascularization of the PDA? It is unlikely, but
17 it cannot be eliminated.
18 So, basically, this is the design of the
19 MAGIC, the Phase II trial which has been initiated
20 now in Europe, in different countries in Europe.
21 It is targeted to include 300 patients in different
22 countries, and to emphasize what Dr. Ruskin was
23 mentioning earlier, it is a placebo-controlled
24 study. In other words, patients following
randomization have a muscular biopsy and they have
1 eventually injection of a placebo solution in
2 addition to their bypass surgery.
3 There are three arms, one control and two
4 treated groups, one having 400 million, the other
5 having 800 million cells. The production of cells,
6 and this is probably important, has been
7 centralized in two sites, one in Paris and one in
8 Boston, and it is exactly the same technology which
9 is used in the two sites.
10 The primary endpoint is the improvement in
11 the contractility of the segments which have been
12 grafted with cells in the core lab and in a blinded
13 fashion. In addition to that, we are obviously
14 looking at major adverse cardiovascular events at
15 the one-year follow-up time.
16 I would like to move on now before
17 finishing to some clinically relevant perspectives
18 which may have really clinical implications in the
19 near future.
20 First of all, so far we have been talking
21 primarily of ischemia cardiomyopathy, but as
22 mentioned by Dr. Perin, there are other causes of
23 heart failure in particular non-ischemic, globally
24 dilated cardiomyopathy.
25 So, we have been interested in assessing
1 myoblast transplantation in this particular
2 context, and use a particular genetic strain of
3 hamsters which develop a non-ischemic dilated
4 cardiomyopathy, and randomize the animals to
5 receive either autologous skeletal myoblasts,
6 because phenotypically, these myoblasts are free
7 from the disease, or culture medium.
8 To make a long story short, you see that
9 there is a definite improvement in function which
10 correlates with a major engraftment of cells in
11 this non-ischemic myocardium. I think it just
12 brings another piece of evidence that maybe
13 something good is occurring.
14 The second problem is cell death.
15 Regardless of the cell type, cell death is
16 extremely high, 80, 90 percent of cells are dying
17 shortly after the injections for a variety of
18 causes, in particular, apoptosis, but also
19 ischemia. It makes sense since we are injecting
20 cells in scar areas which receive very little
21 vascularization. So, even if myoblasts are fairly
22 resistant, they die nevertheless.
23 So, now there are several studies
24 suggesting that the co-induction of angiogenesis
may be an effective means of improving survival of
1 the cells, and ultimately, of improving function of
2 the animals.
3 This is a study comparing transplantation
4 of fetal cardiomyocytes, injection of fibroblast
5 growth factor, or a combination of both. As you
6 can see, function is improved when you combine the
7 two therapies.
8 Recently, we have duplicated this study
9 except that we used myoblasts and another growth
10 factor, and we found exactly similar results.
11 So, there are different ways of inducing
12 angiogenesis, and I know Dr. Epstein is going to
13 discuss that, but the point I wanted to make, this
14 is, you know, the difference in cell survival
15 between myoblasts alone and myoblasts plus an
16 angiogenic growth factor.
17 The point I would like to make is that
18 probably in the future, you will have to deal with
19 proposal of studies trying to combine cell
20 transplantation with some form of angiogenesis just
21 to optimize cell survival and potentiate the
22 benefits of the intervention.
23 A third point regards cycling. This is
24 the muscular biopsy of the patient who died. I
previously talked about this patient who died from
1 a stroke. Initially, in this biopsy, and this is