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
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
25
because of his bypass, he had to be put off the
54
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
10
others.
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
25
to do, and we are faced with this a lot every day.
55
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
25
you how that has improved survival.
56
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
19
important.
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
25
here at the top, and that is why we have increasing
57
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
58
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
17
longer.
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
25
this is a variable. This may
occupy the whole
59
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
9
mortality.
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
17
preserved.
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
60
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
25
heart failure can be worse than cancer.
61
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
62
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
25
always be looked at.
63
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
25
an exercise test, a 6-minute walk test.
You just
64
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
14
Questionnaire.
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
21
failure.
22 I hope I have given you a flavor of this
23
and set the stage for the discussions.
24 Thank you very much.
25 [Applause.]
65
1 DR. RAO: Thank
you, Dr. Perin.
2 There is time for questions, and we can
3
open it up to the committee.
4 Q&A
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
25
failure patients who have been a focus in your talk
66
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
25
cells that are aimed at regeneration specifically
67
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.
16 [Laughter.]
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
25
really can't preempt I guess our publication, but I
68
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
25
initially on the issues that relate to the
69
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
10
heterogeneity.
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
25
patients, and obviously, they may not be the same
70
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
25 I
think that is one place we are
initially now,
71
1
then, you could think about applying this kind of
2
treatment.
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
plumber kind
72
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
25
exactly to that same spot.
73
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
16
know.
17 DR. DINSMORE:
Jonathan Dinsmore from
18
GenVec.
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
25
ischemic heart failure, we are not talking about
74
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
23
breath.
24
I think you have got to
bring both of
25
these things together to understand they are sort
75
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
25
entry, but also you are able to follow as a patient
76
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
21
field?
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
77
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
78
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
25
survival, so it is probably not the most refined
79
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
7
things.
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,
80
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
13
forum.
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
25
of concept.
81
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
82
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
9
EF.
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
25
be more important, otherwise, we will never get an
83
1
answer, and I think that mortality ultimately will
2
have to be a critical part of any trial that is
3
done.
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
24
longer.
25 If it makes people feel better, even if it
84
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.
17 [Applause.]
18 DR. RAO: We
are going to take a short
19
break.
20 [Break.]
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
85
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
86
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
10
therapies.
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
25
would like to mention that it took us seven years,
87
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
25
committed to their skeletal muscle phenotype. In
88
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
25
already past 10 years.
89
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
25
injections look to be safe. I
have never seen any
90
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
25
similar to the one alluded to by Dr. Perin.
91
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
12
areas.
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
25
cut into small pieces, put in this sheeping medium
92
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
25
these multiple injections all across.
This is
93
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
25
question was are the myoblasts from this Class
94
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
21
formation.
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
25
FDA and ask them what was approved or not, and the
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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
25
between the grafted cells and the neighboring
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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
25
patients to arrhythmias.
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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
25
Spanish group has used a culture medium which
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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.
25
In the U.S. study, for example, some patients had
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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
8
differences.
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
25
probably makes a big difference given the high rate
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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
18
problems.
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,
25
and probably still more important when you are
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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
16
greater.
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
25
echocardiography without any possibility for
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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
25
has been grafted, and you can appreciate an
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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
25
randomization have a muscular biopsy and they have
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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
105
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
25
may be an effective means of improving survival of
106
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
25
previously talked about this patient who died from
107
1 a
stroke. Initially, in this biopsy, and
this is