1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
BIOLOGICAL RESPONSE MODIFIERS
ADVISORY COMMITTEE
MEETING #37
Thursday, March 18,
2004
8:30 a.m.
Hilton Hotel
Silver Spring,
Maryland
2
PARTICIPANTS
Mahendra S. Rao, M.D., Ph.D., Chair
Gail Dapolito, Executive Secretary
MEMBERS
Jonathan S. Allan, D.V.M.
Bruce R. Blazar, M.D.
David M. Harlan, M.D.
Katherine A. High, M.D.
Joanne Kurtzberg, M.D.
Alison F. Lawton
James J. Mul, Ph.D.
Thomas H. Murray, Ph.D.
Anastasios A. Tsiatis, Ph.D
CONSULTANTS
Jeffrey S. Borer, M.D.
Susanna Cunningham, Ph.D.
Jeremy N. Ruskin, M.D.
Michael E. Schneider, M.D.
Michael Simons, M.D.
INDUSTRY REPRESENTATIVE
John F. Neylan, M.D.
GUEST HEALTH CANADA REPRESENTATIVE
Norman Viner, M.D.
GUEST SPEAKERS
Stephen Epstein, M.D.
Silviu Itescu, M.D.
Robert J. Lederman, M.D.
Philippe Menasch, M.D.
Emerson C. Perin, M.D., F.A.C.C.
Doris A. Taylor, Ph.D.
NIH PARTICIPANTS
Richard O. Cannon, M.D.
Stephen M. Rose, Ph.D.
FDA PARTICIPANTS
Jesse L. Goodman, M.D., M.P.H.
Philip Noguchi, M.D.
Dwaine Rieves, M.D
Stephen Grant, M.D.
Richard McFarland, Ph.D., M.D.
Donald Nick Jensen, D.V.M., M.S.E.E.
3
C O N T E N T S
PAGE
Call to Order
Mahendra Rao, M.D., Ph.D., Chair 5
Conflict of Interest Statement
Gail Dapolito, Executive
Secretary 5
Introduction of Committee 9
FDA Opening Remarks
Presentation of Certificate of
Appreciation
to Retiring Member
Jesse Goodman, M.D., M.P.H. 14
Philip Noguchi, M.D. 16
Open Committee
Discussion
Cellular Therapies for Cardiac Disease
FDA Introduction and Perspectives
Dwaine Rieves, M.D. 18
Guest Presentations
Overview Cardiomyopathy and Ischemic
Heart
Disease
Emerson Perin, M.D., Ph.D. 35
Q&A 65
Clinical Experience of Autologous
Myoblast
Transplantation
Philippe Menasch, M.D. 85
Q&A 115
Bone Marrow Cell Therapy for
Angiogenesis:
Present and Future
Steven Epstein, M.D. 128
Q&A 148
Cellular Therapies for Cardiac Disease
Richard McFarland, Ph.D., M.D. 159
Guest Presentations
Myoblasts: The First Generation Cells for
Cardiac Repair: What Have We Learned?
Doris Taylor, Ph.D. 169
Q&A 202
Preclinical Models - Hematopoietic and
Mesenchymal Cell Therapies for Cardiac
Diseases
Silviu Itescu, M.D. 219
Q&A 245
4
C O N T E N T S
(Continued)
From Mouse to Man: Is it a Logical Step for
Cardiac Repair?
Doris Taylor, Ph.D. 257
Q&A 275
Cardiac Catheters for Delivery of Cell
Suspension
Donald Nick Jensen, D.V.M.,
M.S.E.E. 292
Transcatheter Myocardial Cell
Delivery: Questions
and Considerations from the Trenches
Robert Lederman, M.D. 307
Q&A 333
Open Public Hearing 343
5
1 P R O C E E D I N G S
2 Call to Order
3 DR. RAO: Good
morning. Welcome to the
4
37th meeting of the Biological Response Modifiers
5
Advisory Committee.
6 Today's topic, as you all know, is related
7
to use of cells in cardiovascular disorders, and we
8
have a pretty full schedule for the next couple of
9
days, but before we can start the meeting, we have
10
to have a few sort of committee stuff that needs to
11
be gotten through, so I will turn the mike over to
12
Gail, so that she can make the mandatory
13
announcements.
14 Conflict of Interest Statement
15 MS. DAPOLITO:
Good morning.
16 The following announcement addresses
17
conflict of interest issues associated with this
18
meeting of the Biological Response Modifiers
19
Advisory Committee on March 18 and 19, 2004.
20 Pursuant to the authority granted under
21
the Committee Charter, the Associate Commissioner
22
for External Relations, FDA, appointed Drs. Jeffrey
23
Borer and Susanna Cunningham as temporary voting
24
members.
25 In addition, the Director of FDA's Center
6
1
for Biologics Evaluation and Research, appointed
2
Drs. Jeremy Ruskin, Michael Schneider, and Michael
3
Simons as temporary voting members.
4 Based on the agenda, it was determined
5
that there are no specific products considered for
6
approval at this meeting. The
committee
7
participants were screened for their financial
8
interests. To determine if any
conflicts of
9
interest existed, the agency reviewed the agenda
10
and all relevant financial interests reported by
11
the meeting participants.
12 The Food and Drug Administration prepared
13
general matters waivers for participants who
14
required a waiver under 18 U.S.C. 208.
Because
15
general topics impact on many entities, it is not
16
prudent to recite all potential conflicts of
17
interest as they apply to each member.
18 FDA acknowledges that there may be
19
potential conflicts of interest, but because of the
20
general nature of the discussions before the
21
committee, these potential conflicts are mitigated.
22 We note for the record that Dr. John
23
Neylan is participating in this meeting as a
24
non-voting industry representative acting on behalf
25
of regulated industry. Dr.
Neylan's appointment is
7
1
not subject to 18 U.S.C. 208. He
is employed by
2
Wyeth Research and thus has a financial interest in
3
his employer.
4 With regards to FDA's invited guest
5
speakers and guests, the agency determined that
6
their services are essential.
The following
7
disclosures will assist the public in objectively
8
evaluating presentations and/or comments made by
9
the participants.
10 Dr. Stephen Epstein is the Executive
11
Director, Cardiovascular Research Institute,
12
Washington Hospital Center. He
receives research
13
support, is a consultant to and has financial
14
interests with, firms that could be affected by the
15
committee discussions.
16 Dr. Philippe Menasch is employed at the
17
George Pompidou Hospital in Paris, France. He has
18
an association with a firm that could be affected
19
by the committee discussions.
20 Dr. Emerson Perin is employed by the Texas
21
Heart Institute. He receives
consultant fees from,
22
and is a scientific advisor to, firms that could be
23
affected by the committee discussions.
24 Dr. Doris Taylor is employed by the
25
University of Minnesota, Center for Cardiovascular
8
1
Repair. She receives consultant
fees from a firm
2
that could be affected by the committee
3
discussions.
4 Dr. Norman Viner is employed by the
5
Biologics and Radiopharmaceuticals Evaluation
6
Centre, Biologics and Genetic Therapies
7
Directorate, Health Canada, in Ottawa, Canada.
8 FDA participants are aware of the need to
9
exclude themselves from the discussions involving
10
specific products or firms for which they have not
11
been screened for conflicts of interest. Their
12
exclusion will be noted for the public record.
13 With respect to all other meeting
14
participants, we ask in the interest of fairness
15
that you state your name, affiliation, and address
16
any current or financial involvement with any firm
17
whose product you wish to comment upon.
18 Waivers are available by written request
19
under the Freedom of Information Act.
20 Thank you, Dr. Rao.
21 DR. RAO: Now
you know why I always have
22
Gail read that statement.
23 Before we start any committee work, I
24
would like to welcome two new members to the
25
committee, Dr. Murray and Dr. James Mul. We
9
1
generally introduce everyone on the committee
2
first, and we generally go in alphabetical order,
3
but this time I will try and start with the new
4
members, so that they can tell us a little bit
5
about themselves before we have the others
6
introduce themselves.
7 Introduction of Committee
8 DR. MULE: I am
Dr. Jim Mul. I am
9
currently the Associate Center Director for the H.
10
Lee Moffitt Cancer Center in Tampa.
I oversee all
11
translational research at the Center including all
12
cell-based therapies for the treatment of cancer as
13
it applies to the clinical treatment of patients
14
with advance tumors.
15 Prior to being in Tampa since September of
16
last year, I was at the University of Michigan
17
Cancer Center for 10 years, and prior to that, the
18
NCI for another 10 years, and I am delighted to be
19
here.
20 DR. MURRAY:
Good morning. I am Tom
21
Murray. I am President of the
Hastings Center,
22
which is celebrating its 35th years as the world's
23
first research institute devoted to ethics in
24
medicine and the life sciences.
25 I spent 15 years as professor at medical
10
1
schools including 12 at Case Western Reserve
2
University School of Medicine.
My interests are
3
fairly broad. I write a lot
about ethics and
4
ethics in the life science and science policy.
5 Thank you. I
am delighted also to be
6
here.
7 DR. RAO: If we
can go down the table, Dr.
8
Tsiatis.
9 DR. TSIATIS:
Hi. I am Butch Tsiatis. I
10 am
from the Department of Statistics at North
11
Carolina State University.
12 DR. BORER: My
name is Jeff Borer. I am a
13
cardiologist. I work at Weill
Medical College of
14
Cornell University in New York City.
I run a
15 division
and an institute at Cornell and, relevant
16
to this meeting, I am the Chairman of the
17
Cardiorenal Drugs Advisory Committee of the FDA.
18 DR. CUNNINGHAM:
Good morning. My name is
19
Susanna Cunningham. I am a professor
in the School
20
of Nursing at the University of Washington in
21
Seattle, and I am the consumer representative for
22
the Cardiovascular Renal Advisory Committee.
23 DR. SCHNEIDER:
I am Michael Schneider. I
24
co-direct the Center for Cardiovascular Development
25
at Baylor College of Medicine, and our interests
11
1
are in the molecular genetics of cardiac muscle
2
formation, cardiac growth, cardiac cell apoptosis
3
and its relation to heart failure, and, relevant to
4
this meeting, cardiac progenitor cells of different
5
kinds.
6 DR. SIMONS:
Hi. I am Michael Simons. I
7
am Chief of Cardiology at Dartmouth Medical School.
8 I
work in the area of vascular biology, gene and
9
cell therapy.
10 DR. RUSKIN:
Good morning. I am Jeremy
11
Ruskin. I am a cardiologist and
12
electrophysiologist, and I direct the
Cardiac
13 Arrhythmia
Service at Massachusetts General
14
Hospital.
15 DR. NEYLAN:
Good morning. I am John
16
Neylan. I am a nephrologist and
an organ
17
transplanter by training. Currently, I am Vice
18
President of Clinical Research and Development at
19
Wyeth, and I serve as a industry representative to
20
the committee.
21 DR. KURTZBERG:
Hi. I am Joanne
22
Kurtzberg. I am a pediatric
oncologist. I direct
23
the Pediatric Bone Marrow and Stem Cell Transplant
24
Program at Duke University and the Carolinas Cord
25
Blood Bank at Duke.
12
1 DR. ALLAN:
Hi. I am Jon Allan. I am a
2
virologist at the Southwest Foundation for
3
Biomedical Research. My area is
nonhuman primate
4
models for AIDS pathogenesis.
5 DR. CANNON:
Good morning. I am Richard
6
Cannon. I am at the National
Heart, Lung, and
7
Blood Institute. I am Clinical
Director of NHLBI,
8
and I am representing NHLBI at this meeting.
9 DR. ROSE: Good
morning. I am Stephen
10
Rose. I am Deputy Director for
the Recombinant DNA
11
Program in the Office of Biotechnology Activities
12
in the NIH.
13 DR. JENSEN:
Good morning. My name is
14
Nick Jensen. I am a reviewer in
the Center for
15
Devices and Radiological Health.
I am a
16
veterinarian and an engineer.
17 DR. McFARLAND:
Good morning. I am
18
Richard McFarland. I am a
reviewer in the
19
Pharm/Tox Branch in the Center for Biologics in the
20
Office of Cellular, Tissue and Gene Therapies.
21 DR. RIEVES:
Good morning. My name is
22
Dwaine Rieves. I am a medical
officer in FDA's
23
Center for Biologics Evaluation and Research.
24 DR. GOODMAN:
Good morning. I am Jesse
25
Goodman. I am the Center
Director of the Center
13
1
for Biologics. I would just like
to join in
2
welcoming especially the new members.
My
3
background is as an infectious disease physician in
4
academic medicine for many years.
5 DR. NOGUCHI: I
am Phil Noguchi, Acting
6
Director of the Office of Cellular, Tissue and Gene
7
Therapies in CBER.
8 DR. RAO: Thank
you, everyone.
9 We are very fortunate in having some
10
really leaders in the field come and present some
11
of the data which will be the basis of where we can
12
address some of the questions that have been raised
13
by the FDA.
14 I am going to ask them to just briefly
15
introduce themselves, as well.
16 DR. EPSTEIN: I
am Steve Epstein, a
17
cardiologist. I am head of the
Cardiovascular
18
Research Institute at the Washington Hospital
19
Center. We are involved in
vascular biology, gene,
20
and cell therapy.
21 DR. MENASCHE:
I am Philippe Menasch. I
22
am cardiac surgeon at the Hospital European George
23
Pompidou in Paris, France.
24 DR. PERIN:
Good morning. I am Emerson
25
Perin. I am an interventional
cardiologist and
14
1
Director of Interventional Cardiology at Texas
2
Heart Institute in Houston.
3 DR. TAYLOR:
Hi. I am Doris Taylor. I am
4 a
scientist. I just moved from Duke
University to
5
the University of Minnesota to head the Center for
6
Cardiovascular Repair.
7 DR. ITESCU:
Hi. I am Silviu Itescu. I
8
am Director of Transplantation Immunology at
9
Columbia Presbyterian, New York.
10 DR. RAO: I
would also like to welcome Dr.
11
Viner who is from Health Canada.
Health Canada has
12
been following a lot of what the FDA has been doing
13
and it is nice to have them there.
14 I would like to invite Dr. Goodman to make
15 a
statement.
16 FDA Opening Remarks
17
Presentation of Certificate of Appreciation
18 to Retiring Member
19 DR. GOODMAN:
My main purpose is to thank
20
Joanne Kurtzberg for I guess about four years of
21
service to the BRMAC. We really
appreciate that
22
tremendously. She has also
interacted with CBER
23
before that.
24 One of the reasons I really wanted to come
25
by this morning. Joanne is
rotating off this
15
1
committee. I know from
interactions both within
2
this committee and outside, and from all the
3
leadership and staff within CBER, just what a
4
tremendous advisor and asset Joanne has been for
5
FDA and for your various fields here.
6 Of course, she has mostly contributed very
7
extensively in her areas of hematopoietic stem
8
cells, et cetera, but she has also been a very
9
important thinker and discussant and contributor on
10
the whole range of other cellular therapies and
11
even gene therapy.
12 Please join me in thanking Joanne for her
13
service over these years. Also,
we like to say,
14 particularly CBER, that we are a family and that
15
nobody ever leaves it, and that we, just like a
16
family, we will keep asking for favors in the
17
future and probably causing grief in return.
18 Thanks so much, Joanne. We have a plaque
19
for her, of course.
20 [Applause.]
21 DR. GOODMAN: I
guess I will just turn it
22
over to Phil to just give a brief introduction for
23
the meeting, but just to say that, as I mentioned a
24
little while back about the islet cell therapies,
25
we, at FDA, are extremely excited about cellular
16
1
therapies and their potential, and I think nowhere
2
is some of that potential clearer, but also perhaps
3
more difficult to evaluate and help move forward
4
than in the area of cardiovascular disease whether
5
it is for ischemic disease or heart muscle disease
6
or trauma, et cetera, some of the uses where there
7
have been some very promising reports.
8 So, we think this is a very timely
9
meeting. It is very important to
get input about
10
how to go forward with efficient development of
11
those products, how to address some of the clinical
12
and safety issues, and how to hopefully make this
13
field positioned to realize its successes in the
14
most efficient manner and also help FDA get that
15
right to the extent that we all can based on
16
incomplete information.
17 Again, we really look forward to this. I
18
apologize, my usual schedule means I will be in and
19
out, but I really appreciate it.
20 Phil.
21 DR. NOGUCHI:
Thank you, Jesse, and, of
22
course, Dr. Kurtzberg, our sincere thanks for the
23
many years of service. Jesse is
absolutely right,
24
don't be surprised if the next meeting, you get a
25
funny call early in the morning.
17
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
18
1
do, because we have such a full schedule, is now
2
turn it over to Dr. Rieves for the introduction.
3 DR. RAO: As
Dr. Rieves comes up to the
4
mike, I just want to remind people of a few simple
5
rules. Remember that when you
want to ask a
6
question, make sure that you are recognized. Use
7
the button. You will see that
the light comes on.
8
When you are done, just hit the button again to
9
switch it off, because otherwise, there is sort of
10 a
feedback loop and noise. Make sure you
identify
11
yourself when you ask questions.
12 Cellular Therapies for Cardiac Disease
13 FDA Introduction and Perspectives
14 DR. RIEVES:
Good morning. My name is
15
Dwaine Rieves. I am a medical
officer within FDA's
16
Center for Biologics Evaluation and Research. This
17
morning I am going to present a brief overview of
18
FDA's perspective on cellular products used in the
19
treatment of cardiac diseases.
20 As will be covered in a subsequent
21
presentation, certain cellular products, when
22
either perfused into the heart or directly injected
23
into heart muscle, are thought to be capable of
24
regenerating heart tissue and/or augmenting heart
25
function.
19
1 Consequently, these products may have
2
special utility in the treatment of heart failure
3
and certain other cardiac diseases.
Today and
4
tomorrow, we will discuss issues in the early
5
clinical development of these products.
6 [Slide.]
7 This talk is divided into three major
8
sections. First, I will cite the purpose in
9
convening this advisory committee.
Secondly, I
10
will provide a regulatory background on FDA's
11
understanding and activities within the realm of
12
clinical development of these products.
Finally, I
13
will introduce the major questions we have proposed
14
for discussion.
15 [Slide.]
16 Unlike many advisory committees where the
17
topics center around assessment of data associated
18
with a specific product or data related to a
19
specific regulatory concern, our purpose in
20
convening this committee is not to obtain
21
definitive regulatory advice, instead, FDA has
22
convened this committee to listen to, and learn
23
from, the voiced thoughts and perspectives with the
24
understanding that this information will enhance
25
our ability to promote the safe clinical
20
1
development of these products.
2 As you are aware, the clinical development
3
of cellular products is in its infancy and many
4
questions surround the very early stages of product
5
development. Consequently, our purpose today and
6
tomorrow is to stimulate a solid scientific
7
discussion of the major facets associated with the
8
very early clinical development of these products.
9 As noted here, we will focus upon three
10
major areas: manufacturing
aspects of the cellular
11
product, preclinical testing of the products, and
12
finally, items related to the early clinical
13 studies.
14 [Slide.]
15 What are the cellular products we will be
16
discussing? These products may
be broadly grouped
17
into two categories.
18 Firstly, those manufactured without
19
ex-vivo culture methodology, that is, the cells are
20
harvested from humans, processed, and then
21
delivered to a recipient without maintaining the
22
cells in culture for a period of time.
23 In general, these cells consist of bone
24
marrow mononuclear cells and certain peripheral
25
blood mononuclear cells, hematopoietic progenitor
21
1
cells that are variously referred to as stem cells,
2
cells thought to be capable of assuming phenotypic
3
characteristics of non-hematopoietic cells.
4 The second category consists of cells
5
that, following harvesting, are maintained in ex
6
vivo culture for a period of time before final
7 processing
and administration.
8 In general, these cells consist of those
9
derived from skeletal muscle tissue, cells
10
frequently referred to as myoblasts, and certain
11
bone marrow stromal cells, cells also referred to
12
as mesenchymal cells. Whether
these cultured cells
13
should be regarded as forms of stem cells is more
14
questionable than that for the hematopoietic
15
progenitor cells.
16 Lastly, as the slide notes, most of the
17
cellular products we will be discussing today and
18
tomorrow are of autologous origin.
19 [Slide.]
20 The many questions surrounding the
21
scientific basis for cellular product development
22
illustrate the very nascent nature of the field.
23
As we are probably all aware, there is almost no
24
precedent for the clinical development of products
25
intended to regenerate and/or augment disease
22
1
tissue.
2 The scientific data surrounding this field
3
are relatively new, such that the data are limited
4
in depth and the extent of replication.
Hence we
5
come to the table of clinical development with many
6 hypothetical
considerations and some, but
7
relatively limited background supportive data.
8 [Slide.]
9 Given these limitations, our discussions
10
today and tomorrow assume a scientific focus in
11
which certain insights and perspectives are
12
presented, and you, the committee members, will be
13
asked to share your thoughts.
Three points are
14
cited here.
15 First, we acknowledge that these thoughts
16
are all tentative and susceptible to revision based
17
on accumulating data.
18 Secondly, we are not requesting any
19
definitive assessment of data, and we note that the
20
data presented here today are within the public
21
arena, and have not undergone FDA vetting.
22 Finally, I reiterate an earlier comment,
23
that no specific cellular product discussed here is
24
under review with respect to regulatory
25
decisionmaking.
23
1 [Slide.]
2 This slide illustrates the
3
interconnectedness of clinical research and
4
regulatory paradigms. The
connecting link between
5
the two fields is the science.
Clinical research
6
generates the scientific background for clinical
7
development of cellular products and the scientific
8
background forms the major basis for our regulatory
9
paradigms.
10 [Slide.]
11 FDA is charged with many responsibilities,
12
but as cited here, two are especially relevant to
13
this discussion. Specifically, FDA's mission is to
14
promote and protect the public health by optimizing
15
pre-market product development and ensuring
16
sufficient post-marketing product monitoring.
17 The key word in these two statements is
18
"product." A notation that whereas we frequently
19
hear the terms transplant, graft, and procedure, we
20
need to think in terms of a cellular product, a
21
product that is manufactured, labeled, and
22
potentially marketed.
23 [Slide.]
24 A little over 10 years ago, FDA clarified
25
the regulatory basis for oversight of clinical
24
1
development programs for cellular products. In
2
general, this regulatory framework is the same as
3
that for the drugs and biologic products we
4
commonly recognize as marketed products.
5 Hence, the commonly cited biologic
6
product, drug, and device regulations applied to
7
the clinical development of these cellular
8
products, and the clinical studies must be
9
conducted under the purview of submission of a
10
investigational new drug application.
11 The last bullet on this slide reminds us
12
that clinical development programs may be divided
13
into early and late stages, with the late stages
14
focused upon the ascertainment of data definitive
15
to safety and efficacy, and the early stage, what
16
we are talking about today and tomorrow, focused
17
upon the ascertainment of exploratory safety and
18
bioactivity data.
19 That is, we hope to examine the nature and
20
extent of background data necessary to introduce
21
the cellular products into small, sample size,
22
Phase I clinical studies.
23 [Slide.]
24 As previously noted, the keystone
25
consideration in early clinical development is
25
1
safety. Specifically, we need to
ensure that the
2
tripod of product development is solid. That tripod
3
consists of manufacturing control and testing
4
information, sufficient preclinical testing
5
information, especially information that may inform
6
the design of a clinical study, and finally, the
7
clinical study itself.
8 The next few slides will cite each of
9
these three components.
10 [Slide.]
11 Cellular products must be manufactured in
12
some manner, that is, the cells must be harvested
13
and processed prior to administration to a
14
recipient. Manufacturing aspects
may be divided
15
among four major areas, three being shown on this
16
slide.
17 The top bullet notes that documents should
18
describe the cell source and reagents used in the
19
manufacturing process, such as growth factors,
20
sera, salt solutions and additives.
We need to be
21
confident that all the reagents used in the
22
manufacturing are of clinical or pharmaceutical
23
grade, or that if they are not pharmaceutical
24
grade, they are sufficient for human use.
25 One may envision many potential concerns
26
1
with these materials, such as the use of sera that
2
may contain infections agents, or the use of only
3
partially purified reagents that contain harmful
4
excipients.
5 Secondly, documents should describe the
6
procedures used in manufacturing, specifically
7
describing how cells are aseptically harvested,
8
isolated, and potentially selected.
9 For example, a distinct population of
10
cells may be selected based upon the presence of
11
certain cell surface markers, such as the CD34
12
antigen with the selection process involving
13
incubation with an antibody to CD34.
14 As we know, many investigational
15
antibodies have been developed to target cell
16
surface antigens, and we need to be confident that
17
these selection techniques are performed in a
18
reproducible and safe manner.
19 Additionally, documents should describe
20
the storage and tracking of the cellular products,
21
this being of special concern because certain
22
cellular products may be patient-specific products.
23 For example, measures must be in place to
24
ensure that for autologous products, the cellular
25
product is returned to the correct donor. Of
27
1
course, the cellular product needs to be labeled as
2
one for investigational use only.
3 The bullet at the bottom of this slide
4
emphasizes the importance of testing the cellular
5
product, an especially important concern since
6
cellular products cannot be sterilized in the same
7
manner as one might sterilize a drug product or a
8
device. Notable aspects of
testing include tests
9
for sterility, endotoxin, viability, enumeration,
10
or cell counting.
11 [Slide.]
12 The fourth component of manufacturing
13
information is product characterization as
14
highlighted here. When one
speaks of product
15
characterization, we are generally talking about
16
cellular phenotype and/or functional
17
characterization and the characteristics of the
18
product's final formulation.
19 For example, a product containing solely
20
CD34 positive cells in saline with no preservatives
21
or media. Product characterization is especially
22
important from a clinical perspective, because
23
failure to consistently manufacture a product makes
24
the clinical data virtually uninterpretable.
25 As noted here, the major aspects of
28
1
product characterization consist of a description
2
of identity, purity, and potency of the final
3
cellular product.
4 [Slide.]
5
Pre-clinical testing is the
second major
6
component of product development, and the major
7
aspects of this testing are cited here.
The top
8
bullet notes that consistent with the science, the
9
extent and depth of preclinical testing necessary
10
to support a clinical study is an evolving paradigm
11
and is a major topic for discussion at this
12
meeting. However, we generally
take the stance
13
that this preclinical testing paradigm should be
14
consistent with that used for other biological
15
products.
16 The last bullet notes another important
17
aspect of preclinical testing, the testing of the
18
product administration procedure.
19 This is especially important because many
20
cellular products involve injection directly into
21
heart muscle either through the epicardial surface
22
or the endocardial surface.
These techniques
23
represent inherent safety concerns that may be best
24
evaluated in animals prior to their use in humans.
25 As noted, all available catheters, whether
29
1
marketed or not, are regarded as investigational
2
with respect to administration of cellular
3
products.
4 [Slide.]
5 This slide highlights three aspects of
6
preclinical testing that will be the focus of the
7
preclinical questions tomorrow.
8 Firstly, the choice of the relevant
9
species is central to designing preclinical studies
10
with the major choices being between large animals,
11
such as pigs, versus small animals, such as mice,
12
as well as the choice between immunocompetent
13
animals where, for autologous products, the
14
cellular products would be the animal cells, not
15
human cells, or immunocompromised animals, where
16
the actual human cellular product may be tested.
17 Secondly, designing preclinical studies
18
raise questions of the choice of model, that is, a
19
disease model, such as ischemic heart disease
20
induced in the pig versus a healthy animal.
21 Lastly, preclinical concerns relate to
22
testing of the administration procedure itself,
23
such items as the impact of the catheter materials
24
upon cells, the potential for occlusion of
25
catheters by the cellular product, and the safety
30
1
concerns associated with manipulation of the
2
catheters in the heart.
3 [Slide.]
4 The third component of the clinical
5
development program for cellular products is the
6
clinical study. There are many
aspects of clinical
7
study design that could be discussed, but at this
8
meeting, we are focusing upon two, the first shown
9
here, that is, adverse event detection.
10 This slide highlights two aspects of
11
clinical study design that are frequently
12
engineered to optimize adverse event detection, the
13
evaluation plan with attention to the duration of
14
clinical follow-up, the frequency of evaluations,
15
and the extent or nature of these evaluations.
16 Secondly, the clinical study safety
17
monitoring plan may be optimized through the use of
18
close scrutiny of each study subject based upon the
19
sequential, not simultaneous, enrollment and
20
treatment of the subjects, as well as the
21
prespecifications of the types and numbers of
22
adverse events that should prompt interruption of
23
the study, that is, the study stopping rules.
24 Tomorrow, the committee will be asked to
25
discuss potential adverse events in these early
31
1
clinical studies, both the nature of the events and
2
ways to optimize the safety of the studies.
3 [Slide.]
4
This slide illustrates an
additional
5
clinical study design item that we will bring to
6
the committee, that is, a discussion of the
7
analysis of adverse events.
8 Exploratory clinical studies are, by their
9
nature, small sample size studies in which it is
10
often difficult or impossible to distinguish
11
treatment-related events from adverse events that
12
might occur in the natural history of the disease,
13
potential study design mechanisms that might help,
14
but certainly not resolve this issue are cited in
15
the bullets, design features that incorporate
16
randomization of subjects among groups, such that
17
comparisons may be made, the use of controls,
18
especially placebo controls, to make comparisons,
19
the use of masking or blinding to help lessen the
20
bias associated with concomitant therapies or
21
clinical care.
22 Tomorrow, the committee will be asked to
23
discuss mechanisms that might aid in adverse event
24
attribution.
25 [Slide.]
32
1 In this presentation, we have covered
2
three major topics. Firstly, we
have noted that
3
the focus of this meeting is upon a discussion of
4
the scientific aspects of early cellular product
5
development.
6 Secondly, we have noted the regulatory
7
precedent for the cellular products.
8 Finally, we come to the questions.
9 [Slide.]
10 This slide highlights the four major areas
11
of tomorrow's questions.
Specifically, questions
12
related to manufacturing, we will request a
13
discussion of the extent of safety testing and
14
characterization that should be performed prior to
15
the release of a cellular product for
16
administration to humans.
17 The second and third discussion areas are
18
especially critical and may consume the bulk of our
19
time, that is, the extent and nature of preclinical
20
testing necessary to support the introduction of a
21
cellular product into humans, testing that involves
22
questions related to the product itself, as well as
23 the delivery mechanism, the catheter.
24 Finally, we will pose clinical questions
25
centered around adverse event detection and
33
1
analysis with a discussion of the pros and cons
2
associated with the use of controls in these
3
studies.
4 [Slide.]
5 Our agenda is summarized on this slide.
6
As you can see, today, we have a series of invited
7
presentations by FDA staff and leading
8
investigators in the field, as well as the
9
opportunity for public presentations.
10 Tomorrow, we will have another opportunity
11
for public presentations followed by a discussion
12
of the questions.
13 [Slide.]
14 In closing, listed here are some documents
15
that are especially pertinent to our discussions.
16
All these documents are available at www.fda.gov
17
under the CBER sites, specifically the guidance
18 section.
19 The first document is entitled "Draft
20
Guidance for CMC Reviewers: Human Somatic Cell
21
Therapy Investigational New Drug Applications."
22
This document describes the types of information
23
FDA reviewers will examine following the submission
24
of an IND. Consequently, it
provides a very clear
25
description of the types of manufacturing
34
1
information that needs to be submitted with an IND
2
application.
3 The second document is from the
4
International Conference on Harmonization of
5
Regulatory Practices, and it is entitled "
6
Preclinical Safety Evaluation of
7
Biotechnology-derived Pharmaceutics," the S6
8
document.
9 This document is cited because it contains
10 a
paradigm that one may apply to cellular products.
11 Finally, the last bullet cites one of the
12
most useful guidances to sponsors and
13
investigators, the ICH Guideline on Good Clinical
14
Practice.
15 This guideline provides detailed
16
information on how to design and conduct a clinical
17
study, information presented in a simple to read,
18
yet relatively comprehensive format.
19 This concludes my presentation and I thank
20
you for your attention.
21 [Applause.]
22 DR. RAO:
Before we continue with the rest
23
of the presentations, I would like to just welcome
24
Dr. Harlan and ask him to introduce himself.
25 DR. HARLAN: I
apologize for being late,
35
1
but I am David Harlan, NIDDK. I
study
2
transplantation of islets and immunotherapies.
3 DR. RAO: Our
first speaker will be Dr.
4
Perin, whom you already were introduced to.
5 Guest Presentations
6
Overview Cardiomyopathy and Ischemic Heart Disease
7 DR. PERIN: I
want to thank you for the
8
invitation to be here to present to you today,
9
especially Dr. Grant, who has helped me put this
10
together in a way.
11 So, what I want to do here this morning,
12
the task that has been laid before me is that of in
13 a
way setting the stage or giving you a general
14
idea of the kinds of patients that we are treating.
15 Obviously, this is fundamental if we are
16
thinking about doing clinical trials.
It is very
17
important to understand the nature of the disease
18
in which these kind of therapies will frequently be
19
applied.
20 What I plan to do is talk about the
21
following topics. First, we will
start from the
22
beginning, define what heart failure is, look at
23
the scope of heart failure, talk a little bit about
24
the pathophysiology, look at some prognostic
25
markers, talk about the treatment to some extent
36
1
and that is important in terms of monitoring, and
2
then really work our way towards end stage heart
3
failure because that is where I think the focus of
4
most of the future clinical trials will likely be
5
initially, and finally, talk about adverse events,
6
which I think is a major concern, and the
7
monitoring of there adverse events.
8 Now, I know many of you are not
9
cardiologists, so hopefully, I can go from a level
10
where we are not getting too complicated, but not
11
too simple.
12 Starting with the definition of what heart
13
failure is. Firstly, heart
failure is a clinical
14
syndrome very simply defined by certain symptoms
15
and certain signs that come together.
These
16
symptoms are fatigue, shortness of breath, and
17
congestion, and these are translated on a physical
18
exam by being able to hear a third heart sound, the
19
patient manifesting peripheral edema, and jugular
20
venous distention.
21 If we start looking at this problem and
22
have a broad overview of this, first, I want to
23
show you a graph from the HOPE trial.
This is a
24
trial that was conducted in thousands of patients,
25
as you can see here, over 9,000 patients. It was a
37
1
study primarily of ramipril and vitamin E in
2
patients with hypertension over a long period of
3
time, involved a five-year follow-up.
4 But it is just very interesting, as we
5
start out looking at heart failure, to look at this
6
patient population, and here we have over 500 days,
7
so here is about a year out, and if we look at this
8
population, who is not primarily designated as
9
particularly sick or harboring heart failure, that
10
identified the patients that did have heart failure
11
and we look at their survival, you will see the
12
mortality.
13 It separates from the beginning, and when
14
we get out to about a year, you have got a 10
15
percent mortality in the group that has heart
16
failure compared to less than 4 percent mortality
17 in the general population.
So, you can see that
18
the problem that we are dealing with seems to be
19
very serious.
20 If we go here and let's just look at the
21
placebo arms of some very large heart failure
22
trials, these are trials pretty much aimed at
23
evaluating different forms of therapy now in heart
24
failure patients, and looking at different severity
25
of heart failure patients, for example, in the
38
1
V-HeFT trial, inclusion criteria might be an
2
ejection fraction less than 40 percent.
3 If we look at PRAISE, which evaluated
4
amlodipine in more severe heart failure, an
5
ejection fraction was less than 30 percent,
6
comparing this with Class III and Class IV
7
patients, very sick patients.
8 So, you can see here if we look at just
9
the placebo arms of all these trials, a very
10
striking mortality as we go along.
If we look at 1
11
year here, this will vary from 10 percent down to
12
around 30 percent.
13 If we go out to 2 years in the very sick
14
patients, we see that half of the patients are
15
dead. So, heart failure,
depending on the
16
presentation, carries a very ominous prognosis.
17 It is a very broad problem, 5 million
18
Americans are living with heart failure now,
19
550,000 new cases are diagnosed each year.
20 From 1979 to 2000, heart failure deaths
21
increased by 148 percent. Now,
what is
22
interesting, over this period of time, we have
23
actually gotten a lot better at treating heart
24
failure, and we do treat it. I will get into this a
25
little later, and I will show you the modern treat
39
1
of heart failure and how much better we are doing,
2
but at the same time that we are treating heart
3
failure better, we are also treating the patients
4
that have coronary disease, which is a very
5
dominant problem in this country and around the
6
world, we are treating those
patients better, too,
7
so what happens is we are getting more patients
8
with heart disease that normally would have died
9
earlier, to live longer, and as we are able to
10
bypass and stent and do all these revascularization
11
procedures and come up with better treatments, we
12
are getting people that go further down the road,
13
that otherwise would have succumbed a long time
14
ago.
15 So, despite our improvements in treatment
16
of coronary disease, we are dealing with an
17
increasing amount of heart failure deaths.
18
In individuals diagnosed with
heart
19
failure, cardiac death occurs at 6 to 9 times the
20
rate in the general population.
If you are more
21
than 40 years old, you have a 1 in 5 chance of
22
developing heart failure, and 22 percent of men and
23
46 percent of women that have heart attacks will be
24
disabled within 6 years with heart failure.
25 So, as you can imagine, the high
40
1
prevalence and multiple complications have an
2
implication in terms of health costs.
If we look
3
at the costs, and these numbers vary, and it
4
depends on what you are looking at and what year
5
you are looking at, but this is a very significant
6
financial burden on the country, over 5 percent of
7
the total health care costs.
8 You can see that most of the cost involved
9
is really involved in inpatient care, and as I will
10
show you hopefully, that really translates to the
11
sickest portions of these patients, that as you get
12
sicker with heart failure, you start coming into
13
the hospital more, and that is what runs up the
14
cost of treating these patients.
It is interesting
15
that transplant is just a little sliver out of the
16
pie here.
17 So, let's look at the causes of heart
18
failure, and I am not going to get into all the
19
little minor details, but let's look at the major
20
causes of what brings on heart failure.
21 Seventy-five percent of people that go on
22
to develop heart failure had hypertension
23
previously. Valvular heart
disease is a big
24
contributor and also heart failure engenders
25
valvular heart disease, mitral regurgitation
41
1
further contributes to the problem.
2 Coronary artery disease, you are all
3
familiar with this, the number one problem in this
4 country, and this is
really what we are going to
5
focus majorly on in terms of causing heart failure
6
and the specific kind of heart failure that this
7
engenders.
8 In cardiomyopathy, there is many different
9
kinds of things that get a heart to perform poorly,
10
all the way from an idiopathic cardiomyopathy to
11
such things as iron overload, et cetera, which are
12
not as common.
13 Now, what I want to talk about here is
14
really systolic heart failure.
There is something
15
called diastolic heart failure, and that really has
16 a
lot to do with compliance problems of the
17
ventricle, and in these patients, we are going to
18
see a normal ejection fraction.
19 So, this is really a different
animal and
20
it is really not what we are focusing on, so what I
21
am going to be talking about today is systolic
22
heart failure, and as I will show you, with the
23
hallmark being a low left ventricular ejection
24
fraction.
25 This is just to give you a practical
42
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
43
1
and Class IV together, you see the division is
2
about a third for each of these pieces of the pie
3
here.
4 Now, if somebody comes in with Class IV
5
heart failure, they are very short of breath at
6
rest, you can give them some diuretics and they
7
will feel better. They are not
Class IV anymore,
8
they are Class III.
9 So, it is interesting, there has been a
10
want in development of a little different way of
11
looking at heart failure, and a staging or
12
classification put out by joint AHA and ACC shows
13
four different stages, and really looks at heart
14
failure more like a disease like cancer.
15 So, where we can identify patients that
16
are at high risk of developing it, we can screen
17
patients, and then we can start treating patients
18
before they really manifest symptoms of the
19
disease.
20 Again, this is a progressive disease and
21
we are going to end up with people that are
22
refractory even to all kinds of treatment. I am
23
going to go over this a little bit more in detail a
24
little later.
25 So, in defining what heart failure is, I
44
1
hope I have given you a general idea of the scope
2
of the problem, just talk a little bit about what
3
causes it because it is important to understand
4
that to be able to know how we treat it and how we
5
monitor these patients.
6 Usually, we are talking about ischemic
7
heart disease and we are dealing with a myocardial
8
insult, which is usually a heart attack, so that
9
heart attack causes damage to the heart muscle, and
10
that is going to result in dysfunction of that
11
heart muscle.
12 Well, the body is going to try to
13
compensate this dysfunction and especially in two
14
major ways. One is neurohumoral
activation, so we
15
will talk a little bit about this in more detail,
16
but essentially, these compensatory mechanisms are
17
going to make the heart change its shape and its
18
size. It is something we call
remodeling. It
19
involves hypertrophy of the myocytes and then it
20
involves fibrosis and dilatation.
21 So, these mechanisms that the body helps,
22
to try to help to reverse what is going on,
23
actually wind up causing toxicity, hemodynamic
24
alterations that all lead to remodeling, and
25
remodeling really is the hallmark.
45
1 You saw that big heart. Well, remodeling
2
is how you get from a normal small heart, which you
3
have, to a big boggy heart that doesn't contract.
4
That is the problem of heart failure.
5 This was very simply put by Doug Mann in a
6
nice editorial a few years ago.
Basically, here is
7 the
heart over time, as we have an index event, and
8
basically, remodeling occurs, the heart gets
9
bigger, the ejection fraction goes down as time
10
goes by and symptoms occur as time progresses, as
11
well.
12 So, I have told you we have a myocardial
13
insult. This leads to LV dysfunction and
14
remodeling, and this really instigates a
15
neurohumoral response. In
return, this is going to
16
have an impact on remodeling again.
17 So, what are these neurohumoral things
18
that happen? Well, first of all,
most importantly,
19
is the renin- angiotensin-aldosterone system, and
20
there are several points in which the body
21
upregulates the system and ultimately, it acts on
22 the AT-1 receptor, which will cause
23
vasoconstriction, proteinuria, again LV remodeling.
24 As you can identify, here are several
25
sites in which medications, the mainstay of some of
46
1
the therapy for heart failure works, namely ACE
2
inhibitors that work at this point, ARBs that work
3
at this point, beta blockers have a role in
4
inhibiting renin, as well. So,
some of the
5
mainstay of therapy is actually directed at one of
6
these mechanisms of compensation.
7 On the other side, we have sympathetic
8
activation. We have increased sympathetic activity
9
that again leads to myocardial toxicity and
10 arrhythmias,
and then on the other side, with the
11
sympathetic outflow, we get vasoconstriction. This
12
impacts negatively on the kidney, sodium retention,
13
more vasoconstriction, and progression of the
14
disease.
15 Just to get a slightly little bit more
16
complicated, just to mention that it is really not
17
all that simple, there are other things involved,
18
and we have cytokines, TNF-alpha, IL-6,
19
inflammation that actually progresses with the
20 progression of heart failure.
21 Endothelin is a potent vasoconstrictor.
22
All these things lead to apoptosis and unfavorable
23
effects upon the myocyte, but then lead to LV
24
remodeling, which I have told you is one of the
25
mainstays of reasons for heart failure.
47
1 Now, natruretic peptides are important,
2
as well. It's another compensatory mechanism that
3
the body has. I am sure you are
familiar with
4
these BNP, it's a B-type natruretic protein that
5
actually comes from the ventricle, the A types
6
comes from the atrium. We will
just focus on the B
7
type.
8 What this does, basically, in response to
9
elevated pressure inside the heart, we secrete BNP.
10
This suppresses the renin-angiotensin-aldosterone
11
system and suppresses endothelin.
It helps with
12
peripheral vascular resistances, decreases
13
vasodilatation, and it increases natruresis.
14 So, if we go on to understand now that
15
there is an interplay between LV dysfunction and
16
remodeling, and that basically, this will lead to
17
low ejection fraction, and that is what we see in
18
the patients.
19 On the other hand, as a result of this, we
20
will start getting a constellation of symptoms, and
21
it is the combination of having a low ejection
22
fraction and symptoms that defines heart failure.
23 Let's look a little bit at the prognostic
24
markers. I just talked a little bit about BNP.
25
Well, it is very interesting. If
we divide BNP in
48
1
quartiles here, depending on the amount of BNP that
2
you have circulating, your survival will go down.
3
It is a prognostic marker, as well as a treatment.
4
Norepinephrine, the same way.
So, these are
5
markers of prognosis.
6 It is very interesting. These are levels
7
of BNP, and if you can decrease them, decrease to a
8
less degree, or here, we have an increase. So,
9
depending on which direction your BNP goes, your
10
survival varies as well, and that is an important
11
concept.
12 Let's look at another different kind of
13
marker. Exercise capacity, peak oxygen consumption.
14
In the transplant world, this is very important.
15
Here you see the number 14, so a peak oxygen
16 consumption greater than 14 or less than 14 has
17
very different prognostic indicators and in many
18
centers, this serves as a marker threshold for one
19
of the criteria for entering the patient into a
20
transplant program.
21
You can see here a
difference in mortality
22
from 53 percent mortality over two years in
23
patients that have an NVO2 of less than 14, to that
24
of 11 with greater than 14, so this is another
25
important number in patients with heart failure.
49
1 Then, if we look overall and look at
2
symptoms and hospitalizations, here is a New York
3
Heart Class I to IV, and this is fairly intuitive,
4
but as we get more symptomatic, we have an impact
5
on survival, and as we are getting more
6
symptomatic, we have an increase in
7
rehospitalization.
8 What about ejection fraction? I just
9
talked about ejection fraction, and you can see
10
here, similarly to NVO2, ejection fraction can
11
divide prognostically how patients will do. Here
12
we see more than 20 percent, less than 20 percent.
13
Here you see a two-year survival, 54 percent, so
14 half
the people dying that have an ejection
15
fraction less than 20 percent.
At one year, that
16
is a little over 20 percent.
17 The same thing, this is a large randomized
18
clinical trial, ejection fraction less than 40
19 percent. Over time,
people die more frequently.
20 Now, let's add a little arrhythmia to
21
this. Looking at different
levels, the first two
22
are greater than 30 percent ejection fraction, here
23
less than 30 percent, so that stratifies that out,
24
but then if we just add the amount of extra
25
ventricular beats to this, and if we have less than
50
1
10 per hour, more than 10 per hour, and then with a
2
poorly contractile ventricle, your survival goes
3
down as we add extra ventricular beats.
4 One attempt that has been made to sort of
5
graph this problem, because now I have shown you
6
many different prognostic markers and different
7
things we can use to classify these patients to
8
decide what to do and how to follow them.
9 One of them is a heart failure survival
10
score. There is an invasive
model, there is a
11
non-invasive model. So, things
like cause of heart
12
failure, resting heart rate, EF, mean blood
13
pressure, if there is a conduction delay
14
electrically in the heart, oxygen consumption, and
15
serum sodium can enter into a risk classification.
16 Here, you just basically have a graph that
17
shows according to low, medium, and high, your
18
survival will vary according to the risk.
19 In our little schema here, that leads
20
symptoms and low ejection fraction to heart
21
failure, what are really the things, though, that
22
are driving mortality? They are
going to be pump
23
failure, on the one hand, and arrhythmia, on the
24
other, because sudden death, as I talked to you
25
about before, is a very prominent problem in people
51
1
that have heart failure.
2 So, it is the combination of these three
3
things that will pretty much drive patients to a
4
lethal exit.
5 Let's talk a little bit about treatment
6
now. What are the goals of
treatment of heart
7
failure? You want to delay the
progression or
8
reverse remodeling, which you can do in some
9
patients, and delay the progression and reverse
10
myocardial dysfunction.
11 You want to reduce mortality, relieve the
12
symptoms, improve functional capacity, and reduce
13
disability, also decrease the intensity of medical
14
care and hopefully reduce economic cost.
15 I have shown you we go from initial
16
injury, initial infarct, we suffer remodeling, we
17
get a remodeled heart that now has a low ejection
18
fraction, and over this course of time, we have a
19
worsening of symptoms, so how are we going to
20
impact this in terms of treatment?
21 Well, the two mainstays are neurohumoral
22
blockade, we have kind of gone over some of the
23
things that we can do, and we will look at those,
24
and the other is revascularization.
So, many times
25
with the use of medication or with the use of
52
1
revascularization, we can reverse some of this
2 remodeling
in some patients, and in some patients
3
we don't.
4 One thing that is very important in terms
5
of being able to recover patients that have
6
remodeled hearts, and that are in this road of
7
heart failure, is identification of viable
8
myocardium.
9 Myocardial viability has clearly been
10
shown to influence the prognosis of people that are
11
undergoing revascularization procedures, so if you
12
have a viable myocardium, you are going to do
13
better. You have a chance of
improving more than
14
someone who doesn't.
15 Just to shift gears for just a second
16
here, these are electromechanical maps.
These are
17
representations of the left ventricle. This is
18
from a patient in our Brazil stem cell study.
19 This is an electrical map, this is a
20
mechanical map. Let's just look
at the electrical
21
map because I just talked to you about viability.
22
Very simply, if your cells are alive, they have an
23
electrical signal that is high.
If you have a big
24
scar with no cells, you have no electricity, you
25
have a low electrical signal.
53
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