1
1
AThis transcript has not been edited or corrected,
but appears as received from the commercial transcribing service. Accordingly, the FDA makes no representation
to its accuracyY@
2
3
4 FOOD AND DRUG ADMINISTRATION
5 CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
6
7
8
9 BIOLOGICAL RESPONSE MODIFIERS
10 ADVISORY
COMMITTEE (BRMAC)
11 Meeting 36
12 DAY TWO
13
14
15
16
17
18
19
20
21 Gaithersburg, Maryland
22 Friday, October 10, 2003
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1
PARTICIPANTS:
2 BRMAC MEMBERS:
3 MAHENDRA S. RAO, Acting Chair
National Institute on
Aging
4
JONATHAN S. ALLAM
5 Southwest Foundation for Biomedical Research
6 BRUCE R. BLAZAR
University of Minnesota
7
DAVID M. HARLAN
8 National Institute of Diabetes and Digestive
and Kidney Disease
9
KATHERINE A. HIGH
10 University of Pennsylvania
11 JOANNE KURTZBERG
Duke University Medical
Center
12
ALISON F. LAWTON
13 Genzyme Corporation
14 RICHARD C. MULLIGAN
Harvard Medical School
15
ANASTASIOS A. TSIATIS
16 North Carolina State University
17 ALICE J. WOLFSON
Wolfson &
Schlichtmann
18
TEMPORARY VOTING MEMBERS:
19
JAMES F. CHILDRESS
20 University of Virginia
21 LYNNE L. LEVITSKY
Harvard Medical School
22
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1 PARTICIPANTS
(CONT'D):
2 TEMPORARY VOTING MEMBERS (CONT'D):
3 ABBEY S. MEYERS
National Organization for
Rare Disorders
4
CAROLE B. MILLER
5 St. Agnes Healthcare
6 W. MICHAEL O'FALLON
Mayo Clinic
7
DANIEL R. SALOMON
8 The Scripps Research Institute
9 ROBERT S. SHERWIN
Yale University School of Medicine
10
JANET H. SILVERSTEIN
11 University of Florida College of Medicine
12 CONSULTANTS:
13 JOHN J. O'NEIL JR.
LifeScan, Inc.
14
CAMILLO RICORDI
15 University of Miami School of Medicine
16 GUESTS/GUEST SPEAKERS:
17 BERNARD J. HERING
University of Minnesota
18
JAMES SHAPIRO
19 University of Alberta
20 THOMAS L. EGGERMAN
National Institute of
Diabetes and Digestive
21 and Kidney Diseases
22
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PARTICIPANTS (CONT'D):
2 GUESTS/GUEST SPEAKERS (CONT'D):
3 JAMES BURDICK
Health Resources and
4 Services Administration
5 FRANCISCA AGBANYO
Health Canada
6
FOOD & DRUG ADMINISTRATION
(FDA) PARTICIPANTS:
7
JESSE L. GOODMAN
8 Center for Biologics Evaluation
and Research
9
KATHRYN CARBONE
10 Center for Biologics Evaluation
and Research
11
RAJ PURI
12 Center for Biologics Evaluation
and Research
13
CAROLYN WILSON
14 Center for Biologics Evaluation
and Research
15
ANDREW BYRNES
16 Center for Biologics Evaluation
and Research
17
NANCY MARKOWITZ
18 Center for Biologics Evaluation
and Research
19
STEVEN BAUER
20 Center for Biologics Evaluation
and Research
21
22
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PARTICIPANTS (CONT'D):
2 FDA PARTICIPANTS (CONT'D):
3 AMY ROSENBERG
Center for Drug
Evaluation
4 and Research (CDER)
5 EMILY SHACTER
Center for Drug
Evaluation
6 and Research
7 GAIL DAPOLITO
Executive Secretary
8 Center for Biologics Evaluation
and Research
9
ROSANNA L. HARVEY
10 Committee Management Specialist
Center for Biologics Evaluation
11 and Research
12 BRMAC #36 FDA PLANNING COMMITTEE MEMBERS:
13 PHILIP NOGUCHI
Center for Biologics
Evaluation
14 and Research
15 CYNTHIA
RASK
Center for Biologics
Evaluation
16 and Research
17 DARIN WEBER
Center for Biologics
Evaluation
18 and Research
19 DWAINE RIEVES
Center for Biologics
Evaluation
20 and Research
21 KEITH M. WONNACOTT
Center for Biologics
Evaluation
22 and Research
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PARTICIPANTS (CONT'D):
2 BRMAC #36 FDA PLANNING COMMITTEE MEMBERS
(CONT'D):
3
NICHOLAS I. OBIRI
4 Center for Biologics Evaluation
and Research
5
RICHARD McFARLAND
6
STEPHEN GRANT
7
SUSAN LEIBENHAUT
8
JOHN ELTERMANN JR.
9
JOHN FINKBOHNER
10
SARAH KIM
11
SUSAN ELLENBERG
12
GHANSYAM GUPTA
13
ROBERT MISBIN
14
15 C O N T E N T S
16
AGENDA SESSION: PAGE
17 Current Status of Clinical Islet 7
Transplantation
18
Allocation of Pancreata for
Whole 65
19 Organ and Islet Transplantation
20 Ethical Considerations in Allogeneic 115
Islet Transplantation
21
Clinical Development of
Islet Products 151
22
* *
* * *
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1 P R O C E E D I N G S
2 (8:13 a.m.)
3 DR. SHAPIRO:
Good morning. On
4
behalf of Dr. Camillo Ricordi, and
5
Dr. Bernhard Hering, and myself, and many
6
other members involved with total islet
7
transplant activity. It is a
great pleasure
8
to provide this information today to the FDA
9
as we consider moving forward with a
10
possibility of a BLA.
11 I'd like to emphasize that we come
12
to you today with a long history of research
13
and progress in islet transplantation over
14
now three decades. With the
first
15
successful islet transplantation and
16
reversal of diabetes in rodent models by
17
Dr. Paul Lacy and his colleagues back in the
18
early 1970s.
19 The success at the University of
20
Minnesota with islet auto‑transplants in
21
the 1970s, and in fact it's worth mentioning
22
that today there are islet autografts that
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are functional beyond 18 years maintaining
2
insulin independence with no concerns
3
regarding the health of those patients
4
receiving islet autografts ‑‑
5 (Power plug pulled)
6 DR.
SHAPIRO: As I was saying,
7
the 30 years of research and then the 18
8
years of success with islet
9
auto‑transplants, and then the development
10
of the automated method by Dr. Camillo
11 Ricordi
introduced and published in 1989,
12
and then the first series of patients
13
receiving allo transplants using the
14
automated method in 1990; the success at
15
Giessen and more recently in Minnesota by
16
Dr. Bernhard Hering and his group, and also
17
in Geneva and Milan, with 50 percent insulin
18
independence rates reported in the
19
mid‑1990s.
20 The introduction of the low
21
antitoxin liberase soclazinaes (?) enzyme;
22
and then the work from Edmonton, the
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multi‑center trial, and now with subsequent
2
refinements and techniques and periodicals
3
including the use of culture and the
4
two‑layer method for perforlodectorine (?)
5
transportation and oxygenation of pancreases
6
during transportation.
7 So with this recent success that
8
clearly, and the FDA's aware of this,
9 there's been an
enormous interest and a
10
large number of new institutions moving
11
forward with islet transportation.
We are
12
aware now of at least 75 new centers across
13
the world trying to develop processes for
14
islet isolation or clinical transplant
15
programs.
16 So if we lay on the map the
17
current activity in islet transplantation up
18
to the present time, and we look at the
19
centers involved with islet transplantation
20
North America and in Europe now, within the
21
Edmonton Protocol and beyond the Edmonton
22
Protocol now, there are over 300 patients
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treated since 1990 with clinical islet alone
2
transplantation, or with islet after kidney
3
transplantation, too.
4 Now what is common between the
5
three of us and our data at three
6
institutions and a number of institutions as
7
well is that we have common protocols.
We
8
have identical patient selection criteria
9
for islet‑alone transplants.
We have common
10
methods for patient evaluation and the
11
schedule of testing.
12 We have common methods, as you
13
heard yesterday, for islet processing using
14
the Ricordi method across centers.
We have
15
common methods for maintaining islets in
16
culture. We have common methods
for
17
transplant techniques; standard
18
anti‑coagulation protocols for
19
peri‑transplant management; standard
20
post‑transplant screening for complications,
21
including bleeding and thrombosis.
Standard
22
post‑transplant monitoring; and standard
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definitions of what we regard as being
2
success and failure with an islet
3
transplantation.
4 We have common criteria for
5
patient selection. We pick
patients for
6
islet‑alone transplantation who have Type 1
7
diabetes for more than five years.
Where
8
there is independent evidence that a patient
9
is failing despite total compliance with
10
maximum alternative medical therapy, in
11
other words, insulin.
12 The process for patient selection
13
is typically in layers, with a primary
14
screen, a secondary screen, two
15
diabetologists involved independently with
16
islet programs completing a review prior to
17
acceptance by an islet program for further
18
work‑up; and generally, a multi‑disciplinary
19
team approach for assessments so that a
20
patient who ends up being listed for islet
21
transplantation clearly has been through
22
many separate screenings to get to that
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point.
2 Our inclusion criteria for
3
islet‑alone transplantation generally
4
include an age between 18 and 65, c‑peptide
5
negative, capable of understanding risks and
6
benefits of treatments including evidence of
7 good compliance.
8 We only take patients who have
9
complications of Type 1 diabetes that
10
include frequent hypoglycemia, metabolic
11
lability, or very occasionally, evidence of
12 progressive
secondary complications. We
13
have a large number of exclusion criteria.
14
I won't go through these in detail except
15
just to point out maybe body mass index
16
greater than 28; insulin requirements
17
greater than .7 units per kilogram per day;
18
untreated prolific retinopathy or evidence
19
where there is inadequate insulin
20
compliance. In other words, with
a
21
hemoglobin A1C greater than 12 percent; or
22
untreated Addison's disease or untreated
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sialic disease that might confirm the
2
interpretation of hypoglycemic unawareness.
3 So how do we select our patients
4
with hypoglycemia or metabolic lability?
5
Our patients have to have Type 1 diabetes,
6
as mentioned, with insulin therapy that's
7
essentially failed, where patients have
8
reduced awareness of hypoglycemia, as
9 defined by an absence
of adequate autonomic
10
symptoms and a plasma glucose level at 58
11
milligrams per deciliter, indicated by two
12
or more episodes of hypoglycemia requiring
13
third‑party assistance within 12 months.
14 Or patients who have metabolic
15
instability, characterized by erratic
16
glucose levels that interfere with daily
17
activities, and/or requiring two or more
18 hospital visits
for diabetic ketoacidosis
19
over the proceeding 12 months.
20 Intensive insulin management is
21
defined as monitoring glucose values at home
22
at no less than four times each day, and by
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the administration by three or more insulin
2
injections each day. This has to
be
3
monitored in close cooperation with an
4
endocrinologist or primary care physician.
5 More recently, we've tried to
6 develop more
objective criteria for
7
assessment of both hypoglycemia and
8
lability. Dr. Edmond Ryan, a
diabetologist
9
and medical director of our program at
10
Edmonton has really developed this Ryan
11
index, which is hypoglycemic score, and a
12
lability index that replaces the former
13
scoring system that we used, which was
14
called the mean aptitude of glycemic
15
excursion.
16 Just to show you very briefly, the
17
hypoglycemic score sheet is essentially
18
filled out by the patient, and we record the
19
number of episodes and how this interferes
20
with the patient's activities;
whether they
21
become confused, whether the patient had
22
developed seizures, whether they have to
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require outside help to treat.
Essentially
2
a score is developed from this.
3 Really just to emphasize here,
4
here is a population of a control cohort in
5
Edmonton who have Type 1 diabetes in the
6
general diabetes clinic. Here
are pre‑islet
7
transplant patients that have a much higher
8 hypoglycemia
score. Just to make the point
9
that islet transplantation is successful,
10
one year after the islet transplant, you can
11
see that this hypo score is brought down to
12
zero.
13 With
regard to assessment to
14
metabolic lability, it's too early in the
15
morning for me to fully explain the
16
mathematical approach to the lability index.
17
But just to say this does provide robust
18
data, and again, to illustrate to you how
19
the lability index demonstrates.
Here again
20
is our Type 1 diabetes controls.
Here are
21
our patients before an islet transplant that
22
have a much higher index of lability
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compared to the normal Type 1 diabetic
2
populations. So these are again
a highly
3
selected subset of patients.
Then after
4
islet transplantation, the lability index is
5
corrected down to zero at one year.
6 How do we define insulin
7
independence? I know this was
one issue
8
that was raised in some of the questions
9
that were passed to us before the meeting.
10 Essentially, we
regard the sustained graft
11
function with adequate endocrine metabolic
12
reserve after complete discontinuation of
13
exogenous insulin, while maintaining a
14
normal hemoglobin A1C.
15 There has to be independence from
16
insulin, and this is defined by adequate
17
control of glucose when a patient is not
18
using insulin; where the hemoglobin A1C is
19
less than 6.5 percent; where
the fasting
20
blood glucose level does not exceed 140
21
milligrams per deciliter more than three
22
times a week using the morning fasting
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glucose level; where the two‑hour
2
post‑prandial glucose levels using any
3
post‑meal glucose value does not exceed 180
4
milligrams per deciliter more than four
5
times in any one week.
6 A participant may occasionally
7
have elevated blood sugars in response to an
8
intercurrent illness, or when the tacrolimus
9
level is high, but this period has to be
10
less than the total of 14 days in order to
11
calculate this as a patient who is
12
insulin‑dependent.
13 To emphasize, in our program at
14
Edmonton, we've transitioned from research
15
to being regarded to as clinical standard of
16
care. Our non‑research
program is funded as
17
of April 2001 by the same mechanism that
18
funds hearts, lungs, or livers for
19
transplantation in Alberta by the government
20
of Alberta through the Providence‑wide
21
Services Committee, after a full independent
22
and critical appraisal committee review of
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the program data.
2 So we are regarded as a clinical
3
standard of care in Edmonton.
This covers
4
only the non‑research transplants. We do of
5 course continue
to do research funded by the
6
Juvenile Diabetes Research Foundation, by
7
the NIH, and by other organizations, too.
8 The standards for non‑research
9
islet processing are currently in evolution
10
with Health Canada, and we're working
11
closely with Health Canada, just as the
12
process is moving forward with the FDA in
13
the U.S. to try to get similar standards in
14
place.
15 The immune protocols are generally
16
based on sirolimus, low‑dose tacrolimus and
17
diclisimap (?), but we are willing to vary
18
this and we can vary this for our
19
non‑research patients since the
20
immunosuppression protocol's, just like with
21
heart, lung, or liver transplant, are
22
individualized as needed by the patient.
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This is not specifically restricted or
2
mandated by the government. So
we are able
3
to used approved or off‑label drugs as
4
appropriate for the management of our
5
clinical islet patients.
6 We accept referrals from across
7
Canada. You can see, again, just
to
8
emphasize the point that we're very
9
selective in who we pick for an islet
10
transplant. Ten percent of the
patients
11
referred for islet transplant, no more
12
than 10 percent, end up on the islet
13
transplant list. Just to show
you the
14
distribution between the three indications,
15
hypoglycemia, and hypoglycemic unawareness
16
forms the bulk of the referrals at 70
17
percent, lability 25 percent.
18 So at the University at Alberta
19
now, we've moved on from the first seven
20
patients we've transplanted now.
We now
21
have a consecutive cohort of 58 patients
22
treated. This just shows you the
follow‑up
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for these patients; with a median follow‑up
2
now of 21.5 months. There are
now five
3
patients beyond four years after transplant.
4
You can see here the first 15 patients
5
received fresh islet transplants.
Working
6
together with Dr. Ricordi and Dr. Hering, we
7
then switched our program from fresh
8
transplants to cultured islet transplants.
9 So you can
see we have data on
10
patients receiving cultured, with a total
11
of 35 patients, versus 20 patients receiving
12
fresh transplants. Most of our
patients
13
require two procedures to provide insulin
14
independence. So 24 patients
here you can
15
see had two islet procedures.
There are
16
five patients that have had a third islet
17
infusion.
18 So how can we compare the data
19
between fresh and cultured clinical islet
20
preparations? I know we covered
some of
21
this yesterday, so I'll be brief.
Improved
22
safety and reduce pac cell (?) volume is one
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clear advantage of the use of islet culture.
2
Together with the enhanced opportunity for
3
completion of product‑released criteria, as
4
you heard from Dr. Hering yesterday.
5
Certainly from the patient's perspective,
6
this increases the practicality of the
7
procedure. Not only does it
allow islets to
8
be shipped between centers, but it also
9
means that the patient does not have to live
10
in the transplant center while they're
11
listed.
12 Data that Dr. Camillo Ricordi and
13
his group in Miami shared with us is
14
reporting insulin dependence following
15
cultured islet transplants, where they have
16
either been transplanted in Miami or shipped
17
to the beta group in Houston.
Here, their
18
survival rate for insulin independence is 80
19
percent at one year, for a total of 19
20
patients transplanted.
21 If we compare our data in Edmonton
22
with the first 16 patients with the next 35
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patients treated with cultured islet
2
preparations, we see no difference in
3
outcome at one year. With
cultured patients
4 receiving cultured
first islet
5
transplants, 90 percent of these patients
6
are insulin‑free at the one‑year time point.
7
Whereas with the non‑cultured first
8
transplants, 95 percent of patients are
9
insulin‑free at the one‑year time point,
10
with no statistical difference between
11
these two groups; again indicating that
12
culture is certainly not detrimental to
13
outcome.
14 Our outcome at two years, 79
15
percent are insulin‑free at two years with
16
cultured islets. Four years ‑‑
and these
17
are fresh islet. Two of the
first three
18
patients are still insulin‑free at the last
19
analysis. Four‑year graft
survival by
20
c‑peptide secretion shows for our entire
21
series that 88 percent of patients remain
22
c‑peptide positive at four years.
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1 Data again from the University of
2
Miami shows that islet after kidney
3
transplantation can be equally successful.
4
Here's an example of three patients
5
receiving islets after kidney transplants,
6
all three of whom are completely
7
insulin‑free with the complete absence of
8
hypoglycemia.
9 So if we pool our data at the
10
three sites, Miami, Minneapolis, and
11
Edmonton, for cultured islets, we now have a
12
cumulative total of 75 patients treated.
13
Ninety‑nine percent of these patients
14
demonstrate primary islet graft function.
15 One‑year C‑peptide secretion is
16
evident in 96 percent of patients.
One‑year
17
insulin independence rates are evident in 85
18
percent of these patients. These
outcomes
19
clearly match the current success rate of
20
the pancreas alone transplantation across
21
the U.S.
22 Complications including main
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portal vein thrombosis have not been seen in
2
this series of patients. There
is no main
3
portal vein thrombosis. We have
seen the
4
left portal vein branched on, but only at
5
our site in Edmonton, not in Miami or
6
Minnesota in three cases. So the
risk
7
overall is at 4 percent. There
have been no
8
deaths, no cancers, no lymphomas, no CMV, no
9
EBV infections to date.
10 Again, showing the collaboration
11
between the three centers, we routinely now
12
use the transplant bag rather than the
13
syringe for islet delivery, to make sure
14
that we have uniformed product that is not
15
exposed to additional risks in the radiology
16
department. We can show you
sustained
17
evidence of graft function over time, really
18
evidenced by normalization of hemoglobin
19
A1C.
20 This shows our cohort of islet
21
transplant patients at one, two and three
22
years data showing normalization of
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hemoglobin A1C less than 6.1 percent.
If we
2 compare this to
consecutive patients
3
undergoing pancreas transplantation at our
4
own institution, we see virtually identical
5
hemoglobin A1C function out to three years.
6 If we compare the hemoglobin A1C
7
in our non‑cultured versus cultured islet
8
preparations, again we see no difference in
9
outcome, with normalization of hemoglobin
10
A1C in both transplant groups.
11 We see
evidence of sustained
12
C‑peptide secretion over time.
So these
13
patients are generally not losing C‑peptide
14
secretion. If you look here,
these are the
15
fasting C‑peptide levels.
These are the
16
stimulated C‑peptide levels.
Again, showing
17
stable data shown here across three years of
18
follow‑up.
19 We're currently in the process of
20
working with Miami and Minnesota to complete
21
prospective quality of live and cost utility
22
studies. These are in evolution
of the
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present time. Just to show you
one example,
2
the hypoglycemia fear score is significantly
3
reduced after islet transplantation and
4
remains stable over time.
5 Complications after islet
6
transplantation can occur despite this being
7
a minimally invasive procedure.
Here's a
8
list of complications encountered at our own
9
site the University of Alberta.
We've had
10
an unusually high incidence of liver bleeds,
11
at 14 percent. This has been
entirely due
12
to the fact that we were giving a loading
13
dose of aspirin just before the patient
14
received their percutaneous procedure, to
15
try to improve islet engraftment.
16 Since we've recognized this
17
complication, the use of aspirin has been
18
withdrawn from our protocols.
Other
19
complications that occur commonly include
20
mouth ulceration, in 87 percent of patients;
21
dyslipidemia, in 44 percent of patients that
22
respond to statin therapy; transient rises
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in liver function tests. And we
do see
2
changes on the MRI scan, with steatosis in
3
the liver in about 23 percent of patients.
4
Again, no deaths, no cancer, no lymphomas,
5 no CMV.
6 I mentioned the bleeds that have
7
occurred after transplant.
Here's a patient
8
having a laparoscopy for a bleed that
9
occurred at the site of puncture in the
10 liver. This is a preventable complication.
11
We believe this is the technique developed
12
at the University of Miami where a
13
collagen‑thrombin plug is placed in the
14
catheter tract.
15 The
University of Miami has had no
16
further bleeding using that approach.
In
17
Edmonton we've been developing a Nd:YAG
18
Laser for a very similar approach really to
19
ablate the liver. This is in a
large animal
20
model, but we've been using this in patients
21
to seal the catheter tract.
22 At the University of Minnesota,
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also, in a consecutive series of 20
2
consecutive patients there, not a single
3 bleed when the
combination of coils and
4
gelfoam are used to mechanically and
5
physically ablate the catheter tract.
So
6
this is a preventable complication, in our
7
opinion.
8 Data from the International
9
Multicenter Trial of the Edmonton Protocol,
10
I'm showing you data that has been presented
11
and has been in the public forum since May
12
of this year, when this data was presented
13
at the American Society of Transplantation
14
meeting, ATC meeting. The
objectives of the
15
ITN trial was to replicate the Edmonton
16
Protocol at multiple sites; provide a base
17
of qualified islet centers for future ITN
18
tolerance trails; and really to define the
19
challenges of applying one common protocol
20
for patient selection, islet preparation,
21
and immunosuppression across multiple
22
centers.
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1 Also with the ITN to potentially
2
explore mechanisms of islet acceptance and
3
rejection in collaboration with the
4
tolerance assay subgroup.
5 A total of nine sites moved
6
forward with this trial. This is
three
7
sites in Europe and the five sites in North
8
America. We look at the success,
it
9
certainly has been variable by site, but
10
what we can say very clearly from this data
11
is the Edmonton Protocol has been
12
successfully replicated by a number of
13
sites. Not by everybody.
14 But this really illustrates the
15
challenges involved with preparation of
16
islets and with the clinical care of
17
patients. Now this data shown
here with
18
four sites not delivering insulin
19
dependence; again, I would emphasize this is
20
data reported in May 2003. This
data has
21
not been subsequently updated, and there's
22
no question this data has improved since
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then. But subsequent analyses
are pending.
2
I'd also draw your attention to a letter in
3 correspondence in
today's issue of "The
4
Lancet," and I'll just read it to you.
5 "As co‑principal investigators of
6
the ITN Multicenter trial, we wish to
7
clarify the importance of the preliminary
8
analysis. A 90 percent insulin‑free
rate
9
was noted in three centers with longstanding
10
expertise in islet preparation and in
11
clinical use of immunosuppression, not only
12 at the Edmonton
site where the protocol
13
originated.
14 The average rate of insulin
15
independence among the remaining six
16
clinical sites was 23 percent, including one
17
site with an interim success rate of 67
18
percent. Thus, the Edmonton
Protocol has
19
been replicated successfully at other
20
clinical sites, and in some cases with a
21
high degree of success. Although
this data
22
is preliminary, we view this result as a
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positive one, which confirms the great
2
benefits to patients of islet
3
transplantation and provides additional
4
justification for continued investigation of
5
islet transplantation as a treatment for
6
brittle forms of Type 1 diabetes."
7 Finally, I draw your attention to
8
data emerging from the University of
9
Minnesota, with truly a remarkable series of
10
now 20 patients treated with successful
11
single donor islet transplants for Type 1
12
diabetes. Dr. Hering may address
this
13
further in discussion. But
essentially, in
14
order to achieve single donor islet
15
transplant success, there were seven
16
strategies implemented, including excluding
17
pancreas organs from donor organs aged 50 or
18
higher; limited ischemic injury of islets by
19
processing within eight hours, sometimes
20
quite a bit less than that time, to optimize
21
islet function; avoiding islet toxic
22
reagents during the islet processing, using
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culture of islets as we've mentioned to
2
allow pre‑transplant initiation of
3
immunosuppression; providing potent
4
prophylactic anticoagulation and aggressive
5
insulin therapy prior to transplant; and
6
increasing the immunosuppressive and
7
anti‑inflammatory potency of the induction
8
of immunosuppression while avoiding
9
calcineural (?) inhibitors in maintenance of
10
immunosuppression.
11 This shows the remarkable success
12
of these patients undergoing this form of
13
transplant. Here's a patient
with a single
14
donor islet transplant at the University of
15
Minnesota with totally normal oral glucose
16
tolerance test and perfect glycemic control
17
across one year of follow‑up.
18 Thank you for your attention.
19 DR. RAO:
Thank you, Dr. Shapiro.
20
Any questions for Dr. Shapiro?
21 DR. RIEVES:
Hi there. My name is
22
Dwaine Rieves. Could you very
briefly
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provide a perception, share some of your
2
thinking regarding some of the clinical
3
benefit in your studies, in your procedures,
4
beyond perhaps the avoidance of exogenous
5
insulin? You've touched on
improvement in a
6
fear index, and I suspect that you also have
7
thoughts about other clinical outcomes that
8
these patients may have achieved.
Can you
9
comment on that?
10 DR. SHAPIRO:
Certainly. I would
11
say that most patients who come to us for an
12
islet transplant, their aim isn't to attain
13
insulin independence. It may be
the
14
program's aims, but it's certainly not many
15
of the patient's aim, sort of suffering from
16
severe hypoglycemia. Most
patients have no
17
problem staying on a small amount of insulin
18
if needed in order to rid themselves of the
19
day‑to‑day difficulties and challenges of
20
recurrent hypoglycemias.
21 I would emphasize to you that
22
these patients are at quite high risk when
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they face recurrent hypoglycemias.
For
2
example, at our three sites, there have been
3
in fact three deaths in patients that were
4
listed for islet transplant from
5
hypoglycemia. I mentioned to
you, we
6
haven't had any deaths after an islet
7
transplant. So clearly these
patients are
8
at added risk because of their recurrent
9
hypoglycemias.
10 In other words, in our sense, even
11
with just one islet transplant, as long as
12
the patient's maintained c‑peptide
13
secretion, their risk of hypoglycemia is
14
completed obviated, so they have very much
15
more stable glucose control, and in fact
16
rapid correction of hemoglobin A1C even
17
though they're requiring at that point small
18
doses of insulin. So from the
patient's
19
perspective, there clearly is a benefit from
20
that.
21 If you're asking about what are
22
the longer‑term benefits of a successful
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islet transplant in terms of secondary
2
complications, I think that is a harder one
3
to answer right now. We
currently use the
4
surrogate endpoint of correction of the
5
hemoglobin A1C; we would expect that if
6
patients maintain a hemoglobin A1C within a
7
normal range over time, they will enviably
8
have reduced progression and maybe reversal
9
of some of the secondary complications in
10
exactly the same way as that's been shown
11
with successful whole pancreas
12
transplantation.
13
But we don't have long‑term
data
14
really to prove that at the present time.
15
That will emerge, but I suspect just like in