DEPARTMENT OF HEALTH AND
HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY
COMMITTEE
MEETING
OPEN SESSION
FRIDAY, MAY 2, 2008
The meeting came to order at 8:30 a.m. in the Plaza Meeting
rooms of the Hilton Washington DC Rockville, 1750 Rockville Pike,
PRESENT:
FREDERICK P. SIEGAL, MD,
CHAIRMAN
MARK BALLOW, MD, MEMBER
HENRY M. CRYER III, MD, PHD,
MEMBER
ADRIAN M. DI BISCEGLIE, MD,
MEMBER
MAUREEN A. FINNEGAN, MD,
MEMBER
SIMONE A. GLYNN, MD, MSC,
MPH, MEMBER
MATTHEW J. KUEHNERT, MD,
MEMBER
ROSHNI KULKARNI, MD, MEMBER
CATHERINE S. MANNO, MD,
MEMBER
KATHERINE A. MCCOMAS, PHD,
MEMBER
FRANCISCO J. RENTAS, PHD,
MEMBER
ANDREA B. TROXEL, SCD,
MEMBER
ANN B. ZIMRIN, MD, MEMBER
This transcript has not been
edited or corrected, but appears as received from the commercial transcribing
service. Accordingly, the Food and Drug Administration makes no representation
as to its accuracy.
PRESENT: (CONT.)
JUDITH R. BAKER, MHSA,
CONSUMER
REPRESENTATIVE
THOMAS P. ATKINSON, MD,
TEMPORARY VOTING
MEMBER
ANDREA J. APTER, MD,
TEMPORARY VOTING MEMBER
THOMAS R. FLEMING, PHD,
TEMPORARY VOTING
MEMBER
B. GAIL MACIK, MD, TEMPORARY
VOTING MEMBER
IRMA O. SZYMANSKI, MD,
TEMPORARY VOTING
MEMBER
DONALD W.
TABLE OF CONTENTS
TOPIC
II: Lev Pharmaceuticals Inc.
Clinical
Trial for the Use of Plasma-
derived
C1 Esterase Inhibitor (Cinryze)
for
Prophylaxis of Hereditary Angioedema
Attacks..................................... 8
A.
Introduction...................... 8
B.
Lev Pharmaceuticals Presentation
i. Introduction................ 16
ii. Unmet need and patho-
physiology.................. 21
iii. Clinical Program........... 40
iv.
Clinical Considerations
For Patient Care........... 59
C.
FDA Review of Clinical Data..... 132
D.
Statistical Issues
Open
Public Hearing....................... 158
Open
Committee Discussion................. 204
TOPIC
III: Review of the Research Programs in
the
Laboratory of Hepatitis and Related
Emerging
Agents
A.
Overview of CBER Research....... 239
B.
Overview of OBRR Research....... 253
C.
Overview of the Division of Emerging
and Transfusion Transmitted
Diseases........................ 263
D.
Overview of the Laboratory of
Hepatitis and Related Emerging
Agents.......................... 272
E.
Questions and Answers........... 289
Open
Public Hearing....................... 294
Adjourn
to Closed Discussion
P-R-O-C-E-E-D-I-N-G-S
8:31 a.m.
CHAIRMAN SIEGAL: Okay, here we go. Good morning.
I'm Fred Siegal, the Chair of BPAC at this moment. I would like to welcome all of you who were
not here yesterday to us today. We have
some new temporary voting members today, Dr. Thomas Atkins, Andrea Apter, whom
we mentioned yesterday, Tom Fleming who was here, Larry Borish who wasn't here
yesterday and the others have been introduced already. Perhaps we should go around and introduce
those of us who weren't here yesterday.
Introduce yourself.
DR. ATKINSON: I'm Prescott Atkinson. I'm a Pediatric Immunologist at the
DR. BORISH: Larry Borish, I'm a Professor of Medicine at
the University if
DR. APTER: Andrea Apter, Professor of Medicine, Allergy
and Immunology,
DR. BALLOW: Mark Ballow, Allergy and Immunology, SUNY
DR. CRYER: Gil Cryer,
DR. DI BISCEGLIE: Adrian DiBisceglie, a Hepatologist at
DR. FINNEGAN: Maureen Finnegan, Orthopedic Surgeon, UT
Southwestern
DR. GLYNN: Simone Glynn, NHLBI.
MS. BAKER: Judith Baker,
DR. ZIMRIN: Ann Zimrin, Hematology,
MS. TROXEL: Andrea Troxel from the Biostatistics at the
DR. RENTAS: Frank Rentas, Blood Services,
DR. McCOMAS: Katherine McComas, a Professor of
Communication at
DR. MANNO: Catherine Manno, a Pediatric Hematologist at
Children's Hospital in
DR. KULKARNI: Roshni Kulkarni, Professor of Pediatric
Hematology, Oncology,
DR. FLEMING: Thomas Fleming, Professor of Biostatistics,
University of
DR. SZYMANSKI: Irma Szymanski, Professor of Pathology, U
Mass, now working in
DR. MASCIK: Gail Mascik, Hematologist,
CHAIRMAN SIEGAL: I'd like to mention that unfortunately Lou
Katz, our non-voting member from industry had to leave and I know that there
are a number of members who have flights to catch and they have to leave a
little early but as long as you can stay, we hope that you can because we do
have to vote on the last part of this meeting.
So, let's proceed. I'm sorry, Mr. Jehn would like to make a
statement.
MR. JEHN: Yes, I just have a conflict of interest
statement for me today. This brief
announcement is in addition to the conflict of interest statement read at the
beginning of the meeting on May 1st and will be part of the public
record for the Blood Products Advisory Committee meeting on May 2nd,
2008. This announcement addresses
conflicts of interest for Topic II on the committee discussion, review and
recommendations on Lev Pharmaceutical Incorporated clinical trial for the use
of plasma derived C-1 esterase inhibitor, Cinryze for the prophylactics of
Hereditary Angioedema Attacks. Based on
the agenda and all financial interests reported by members and consultants
related to Topics II, conflict of interest waivers have been issued to Dr. Mark
Ballow in accordance with 18 US Code 208, Section 3, and 712 of the Food and
Drug and Cosmetic Act. Dr. Ballow's
waivers include a consulting arrangement with a firm that could be affected by
the today's discussion of Topic II. The
waivers allow Dr. Ballow to participate fully and vote on the committee
discussions
For Topic III, the committee will
hear an overview of the research programs in the laboratory of hepatitis and
related emerging agents to vision and emerging in transfusion transmitted
diseases. There is no conflict of
interest involved with this overview.
This conflict of interest statement will be available for review at the
registration table. We would like to
remind members and participants that if the discussions involve any other
products or firms not already on the agenda for which an FDA participant has a
personal or imputed financial interest, the participants need to exclude
themselves from such involvement and their exclusion will be noted for the
record. FDA
encourages all other participants to advise the committee of any financial
relationships that you may have with any firms, its products and if known, its
direct competitors. Thank you.
CHAIRMAN SIEGAL: Thank you, Don. So let's proceed to Topic II, Lev
Pharmaceuticals, Incorporated clinical trial for the use of plasma-derived C1
esterase inhibitor (Cinryze) for the prophylaxis of heredity angioedema
attacks. The introduction will be given
by Dr. Felice D'Agnillo of FDA. Dr.
D'Agnillo.
DR. D'AGNILLO: Okay, good morning, everyone. My name is Felice D'Agnillo. I'm a Product Reviewer for the Office of
Blood Research and Review at the FDA.
The topic of discussion today is the original license application
sponsored by Lev Pharmaceuticals for C1 esterase inhibitor derived from human
plasma. This is indicated for use in
individuals with hereditary angioedema.
This is a rare but very serious disease associated with a deficiency in
the functional levels of this inhibitor.
My role today is going to be to
provide a very brief introduction and to briefly describe the product. Dr. Golding, also from the FDA, who will be
speaking immediately following the sponsor, will describe the regulatory
chronology of this application and he'll give an overview of the clinical
studies that were performed and then discuss issues related to efficacy,
safety, and immunogenicity.
So I'd like to start off by just
saying a few brief words on the protein.
Again, C1 esterase inhibitor is a plasma protein. It is a member of a family of proteins called
Serpins and this is short for serine protease inhibitor. The plasma concentration is in the range 180
micrograms per ml. It's molecular weight
is 105 kD based on SDS-Page analysis.
It's a heavily glycosylated protein and like Serpins in general, it
contains in its structure a reactive site loop shown here which plays a very
important role in the inhibitory function of this molecule. And the way this works is that serine
proteases cleave this loop at this amino acid residue and the protease remains
attached to the inhibitor and subsequent to a confirmational change in the
inhibitor, the active site of the protease is distorted and it loses its
function.
Now, unlike most Serpins that tend
to regulate one serine protease, C1 inhibitor is able to regulate a number of
important serine proteases in the plasma.
These include, among others, C1s, the pointer is going down a little
bit, C1s and C1r. That in conjunction
with C1q form a C1 complex which play -- which regulates the classical
compliment pathway. C1 inhibitor also
regulates Kallikrein, Factor 12 and 11, that play roles in the coagulation and
Kinin generation pathways and C1 also inhibits Plasmin and tissue Plasminigen
activator which play roles in the fibrinolytis.
Now before I move onto the next slide, I'd like to make one more point
and that's that the inhibition of the disregulations of the Kinin pathway is
very important in that it leads to uncontrolled production of bradikinin levels
and bradikinin is a vasodilator and it's believed that the levels of
bradikinin, the uncontrolled levels of bradikinin play an important role in the
etiology of the disease which I'll describe in my next slide.
Hereditary angiodema is an autosomal
dominant disease. It has a low incidence
and it's estimated that there are about 10,000 individuals in the
The attacks can last from a period
of hours to days and as I mentioned, this disease is caused by a deficiency in
functional levels of C1 inhibitor. Now,
there are two types of the disease. The
most prevalent form of the disease, Type 1, is associated with a decrease in
the production of the inhibitor. Type 2
is associated with normal or elevated levels of production but the protein is
mutated and dysfunctional. And this is
further illustrated in the next slide where this table shows some laboratory
markers used to classify HAE. In Type 1,
as I just mentioned, the production of C1 inhibitor is decreased and we're
going to need a -- the production of C1 inhibitor is decreased and this leads
to decreased levels of functional C1. In
Type 2, production can be normal or elevated but the protein is
dysfunctional. So this leads to
decreased functional levels of the inhibitor in the plasma.
Now in both these cases, this is
typically associated with a reduction in compliment four levels in the plasma,
but C3 and C1 levels are typically normal.
Now, another angioedema listed on this table is estrogen dependent
inherited angioedema. This used to be
called Type 3 HAE but this is very distinct from HAE in that there is no
deficiency of the C1 inhibitor.
As far as some of the approaches to
manage HAE, avoidance of known triggers, such as estrogens and ACE inhibitors
is important. Some therapeutic
interventions include anti-fibrinolytic agents to control the fibrinolytis. Attenuated androgens have been used to
increase the production of C1 inhibitor and fresh frozen plasma replacement is
also an approach -- it is also an option but the risk/benefit associated with
this therapy is sometimes questioned and finally, C1 inhibitor replacement
therapy has been used in Europe for many years, but in the US this therapy has
only been available under IND.
And this brings me to the C1
inhibitor product that we're going to be discussing here today. It's a produce sponsored by Lev
Pharmaceuticals with the trade name Cinryze, and this is a lyophilized
preparation of the protein derived from human plasma and it's manufactured
under contract to the Sanquin Blood Supply Foundation in the
It's manufactured from US licensed
source plasma and the manufacturing process contains two dedicated independent
viral reduction steps that include heat treatment at 60 degrees for 10 hours
and nanofiltration. And a third polyethylene
glycol precipitation step has also been shown to remove viruses. And this is illustrated in the next table.
This table shows log reduction
factors in various virus reduction -- virus spiking studies using enveloped and
non-enveloped viruses and without getting into -- we've analyzed the data and
without getting into all the details, we feel that these results show that the
steps provide very effective viral clearance.
Now, I'm going to end my very brief talk on that note but before having
the -- but before listening to the more detailed presentations that are to
follow, I'd like to present the questions that we would like the committee to
consider today.
And Dr. Golding will also be
repeating these questions at the end of his talk. Question 1, is the safety and efficacy
evidence sufficient for approval of Cinryze for prophylactic treatment of
HAE? Question 2, if the answer to
question 1 is yes, should post-marketing studies be performed to further
evaluate the following, the optimal dose for prophylaxis in males and females,
immunogenicity, and long-term safety?
Thank you.
CHAIRMAN SIEGAL: Okay, thank you Dr. D'Agnillo. We're now going to hear from Lev
Pharmaceuticals. I'd ask the presenters
to keep in mind that you have not longer than an hour to present your
case. Thank you.
MR. BABLAK: Good morning.
My name is Jason Bablak, and I'm Vice President of Regulatory Affairs
and Product Development at Lev Pharmaceuticals.
We are excited to be here today to Cinryze, human C1 inhibitor for the
treatment of hereditary angioedema. HAE
is a chronic debilitating and potentially life-threatening disease that has a
profound impact on the lives of patients and their families for which there is
no adequate treatment option available in the
After this introduction, Dr. Michael
Frank from
Dr. Paula Busse, from
Cinryze is a highly purified C1
inhibitor. Cinryze is manufactured by
the Sanquin Blood Supply Foundation, formerly the Central Laboratory of the
Dutch Red Cross. Sanquin has a 36-year
history of producing successive generations of C1 inhibitor products, including
the currently marketed product called Cetor, a highly purified pasturized C1
inhibitor which has been available in the
The manufacturing of Cinryze is an
enhancement to the Cetor manufacturing process.
Cinryze is produced from pooled
Cinryze manufacturing includes
multiple steps to insure the safety and quality of the product. Cinryze is derived from
The virus removing capacity for
Cinryze manufacturing has been validated and provides reduction of envelope
viruses ranging from greater than 16.7 to greater than 19.1 logs. And for non-envelope viruses ranging from
greater than 8.7 to greater than 10.5 logs.
A study of the nanofiltration step demonstrated that it achieves the
complete removal of spiked prion protein with a reduction factor of greater
than 4.25 logs as measured by Western Blot.
Two pivotal Phase 3 studies assess
the safety and efficacy of Cinryze. The
first study was for the treatment of acute HAE attacks and the second was for
prophylactic treatment to prevent HAE attacks.
Both studies met their pre-specified primary end points and drew upon
the same population of HAE subjects initially enrolled into the program.
The clinical program also included a
pharmacokinetic study in these subjects who were not experiencing an
attack. We are also providing continued
access to Cinryze for HAE patients through ongoing open label studies for both
acute and prophylactic treatment in which we are collecting additional safety
and efficacy information. One hundred
and eighty HAE patients have participated in our studies with over 6,000 doses
administered. More than 12 subjects have
each received over 100 doses extending well beyond one year on continuous
treatment with Cinryze prophylaxis.
The clinical development program
demonstrated that Cinryze if efficacious with no reported safety concerns and
an adverse event profile similar to placebo.
The results for both trials were statistically significant, clinically
meaningful and consistent with the experience in
DR. FRANK: Thank you.
Good morning. It's a pleasure to be here today. I was invited to come by Lev because of an
interest in hereditary angioedema and particularly the treatment of hereditary
angioedema that goes back more than 35 years.
What I've been asked to do is discuss the clinical disease, the
pathophysiology, current treatment as it exists in the
As you heard from Dr. D'Agnillo,
hereditary angioedema is an orphan disease.
We don't know the actual incidents, but we think it's one in 10,000 to
150,000 people. It has been estimated
that 6,000 to 10,000 people in the
Now, a company in Europe just a few
years ago did a survey of the same kind of information and in
I'm going to briefly discuss the
clinical manifestations which include extremity attacks, abdominal attacks
facial laryngeal and genitourinary attacks.
This is the kind of attack that effects the extremities. It's in many studies the most frequent
attack. On the left is a swollen hand and on the right is a normal hand of the
same patient at the same time. As you
can see, this attack can be functionally disabling. If it effects that hands, it may impede the
use of a keyboard, a phone. If it
effects the feet, it can impede walking or driving. It can effect the joints and there can be
immobility and dysfunction and discomfort of the joints. But it rarely results in
hospitalization. It can interfere with
work and school. It's really not the
reason we're here today.
The second very common attack in
some series the most common is the abdominal attack and this is the reason that
we're in part here today. This GI series
shows the spiculation or thumb printing of the bowel due to edema of the wall
of the bowel which is extraordinarily painful.
This can lead to debilitating symptoms, very severe pain, occasionally
intestinal obstruction, nausea, vomiting and dehydration. These patients literally climb the wall with
pain.
It usually leads to an emergency
room visit. It frequently leads to
hospitalization and because these patients' pain is so severe, they frequently
get operated on even though they don't need an operation at that time, so they
have unneeded surgery.
The facial attacks can be
temporarily disfiguring as shown in this patient of mine. The picture on the left was taken when the
patient was free of an attack and the picture on the right was a Polaroid taken
by her husband. It was one of a series
and in fact, it wasn't the most serious of the series. This lady was just sitting at home in an armchair
while her husband was watching here face get more and more disfigured. In fact, she should have been in an emergency
room.
Here is a series of pictures that
were taken not by me but quite extraordinary, showing a patient before an
attack, as the facial attack proceeds, even more severe facial attack and
ultimately leading to intubation in this patient. In fact, this underscores some of our
problem. And that is we do not have good
therapy to end an attack in this
country. So facial attacks can lead to
extreme swelling, temporary disfigurement. Subjects of course, tend not to
leave their home and the risk of local extension to the larynx is what we're
talking about at the present time.
Here is a pair of radiographs. The radiograph on the right is a nine-year
old girl who was not having an attack of hereditary angioedema at this time and
you can see the normal cervical curve and the open airway. The picture on the left is the same girl
during an attack of hereditary angioedema and you can see both the change in
the curvature of the spine and the occlusion of the airway in this young girl.
So the laryngeal attacks can be
life-threatening. When we did this first
clinical study, as I talked about earlier, we asked people, "How many
members of your family who had hereditary angioedema died of the disease by
choking to death"? And the answer
was 30 percent. That was a long time
ago, and 30 percent is not the figure now, but there are still people who die,
both in
Now, the urogenital attacks also
occur and should be mentioned. The
typical triggers are sexual intercourse or local trauma. You can get swollen genitalia. You can even have painful urination or be
unable to urinate because of swelling in the region of the urethra. So the impact on patients' lives of this
disease is really quite extraordinary.
It's a life-altering disease. It
interferes with work, school and their social life.
Attacks typically last two to five
days but they can last up to nine days.
They can move from place to place, a hand, a foot, et cetera. It's been estimated that patients, some
patients lose up to 100 days of school or work a year. There are about 15,000 emergency room visits
annually in the United States it's been estimated and it is frequently
misdiagnosed. This leads to unnecessary
surgery and the treatment, as we have now, as we'll talk about in a minute, is
really ineffective. We have ever-present
risk and there is a major psychological impact and that's worth a few more
words.
These patients have anxiety,
depression and feelings of isolation.
Many of them have seen members of their family choke to death of a
disease that they have that can't be adequately treated. The abdominal pain is so severe that these
patients learn to go into the emergency room and get narcotics and a very
frequent problem with this patient group is narcotic addiction which is very
difficult to deal with.
Now, the diagnosis is
straightforward if you have a typical clinical diagnosis. In fact, the first
attacks usually occur in childhood and often the disease is missed in
childhood. It usually gets much worse at
the time of puberty, both in males and females.
The clinical findings we've discussed and Dr. D'Agnillo discussed some
of the laboratory findings. The C1
inhibitor is functionally low. The C1
itself is normal because the inhibitor is now present, but C1 is present. C4 and C2 are low typically and C3, the most
common laboratory compliment protein that's studied is always normal in these
patients.
There is no correlation between C1
inhibitor levels in disease burden and I'll show you that in a second. As I've mentioned, the family history is not
reliable because of the new mutations and so we usually are helped by a family
history but it doesn't make the diagnosis.
The C1 inhibitor level and severity
of attacks is interesting. In our
original studies, we divided patients into patients that we considered having
very serious disease and patients having very mild disease. The normal range is shown in green and the
red dots are the patient who have a protein but it does not have normal
function.
As you can see, there's no
correlation between the seriousness of attacks and the level of C1 inhibitor
and this, I think, is a reflection of the fact that we do not understand every
aspect of the pathophysiology of this disease at the present time and we can
talk about that later if there's any interest.
As Dr. D'Agnillo mentioned, C1
inhibitor is a Serpin, serine protease inhibitor and inhibits many different
systems in the blood. It inhibits the
compliment system, multiple proteins is shown in yellow. It inhibits the contact activation systems
factors 12A and 12F. It inhibits the
clotting system, the Kinin system, and the Fibrinolytic system inhibiting both plasma and tissue
Plasminigen activator. We believe it's
the Kallikrein system that's critical in the development of attacks of swelling
in hereditary angioedema as I'll show on the next slide. Now, here is a complicated slide showing some
of the aspects of the Kinin generating and Factor 12 system and I'm not going
to go through it in detail.
The first thing I'm going to mention
though is that all of the yellow x's are places where C1 inhibitor can
function. And so you see it functions in
many places in this complex system of biochemical steps. Let's turn our attention to the dotted
box. As you can see in this box, we have
prekallikrein, which gets activated to kallikrein. Kallikrein is an enzyme capable of cleaving
high molecular kininogen and releasing Bradikinin. It is that step that we think is critical in
the development of hereditary angioedema. The generation of Bradikinin is not
inhibited. Now, as you also heard, C1
inhibitor is a suicide inhibitor. It's a
single chain molecule that presents a bate sequence shown as a white triangle
in this slide. The bate sequence is
cleaved by the enzyme which is show as a Pac Man in this slide that I
drew. And when this happens, the yellow
triangle, a highly reactive group within the molecule, becomes available, binds
to the enzymatic site and destroys the enzyme.
So the C1 inhibitor is used up during this process and the product of
one normal gene and one abnormal gene is not sufficient to keep you from having
attacks.
Well, triggers are highly variable
in this disease. Usually patients don't
know what brings on an attack except about a third of patients know that
physical trauma will bring on attack and that may be mechanical pressure or
repetitive motion. A seamstress who uses
a pair of scissors repeatedly will find that her hand swells up or someone who
uses a power lawn mower will find that their hands swell up. Similarly, infection can bring on an
attack. Strep throat can bring on an
attack in the throat.
Emotional stress is another thing
that's very interesting and that we don't understand. But emotional stress can have a major impact
in the frequency of attacks. Hormonal
influences are also important. We were
the first to describe estrogens worsening the severity of the disease and
occasionally you can have a woman who you just take off birth control pills and
their disease becomes much better. Most
of the referred patients are women probably reflecting this importance of
estrogens in making the clinical symptoms of the disease worse.
So what are the current
therapies? We haven't got time to go
into this in great detail given the one hour, but I'd like to say a word about
prophylaxis and a word about acute treatment.
I was the one that introduced impeded androgens for prophylaxis. We published a double-blind study on the use
of danazol and we showed that it's efficacious in prophylaxis. I put down that it has limited utility here
because I want to talk about that in detail.
It is useless in acute settings.
First of all, it takes at least two
days before it starts to have a biological effect. And it's only -- danazol and the other
impeded androgens are only available orally.
What I mean by that is that if you have a patient with an abdominal
attack, and their bowel is swollen, you really can't give them an oral medication
and expect it to have an effect. It's
contra-indicated in both pregnancy and children, and pregnancy because there
can be masculinization of the fetus, in children because it can be premature
closure of the epiphysis. And finally,
in some people it's ineffective. Some
people simply don't respond to androgens.
The side effects of androgens, I think, are probably well-known to this
group. It causes weight gain. It causes lipid abnormalities regularly and
that includes elevated LDL, decreased HDL. It can have psychological effects, feelings of
aggression, changes in libido, both in men and in women. In women, it can cause virilization in some women, certainly menstrual
irregularities. Since it was developed,
danazol was developed as a contraceptive.
It can cause muscle toxicity. Hepatocellular abnormalities including
transaminase elevations are frequent but occasionally patients will develop
adenoma and even carcinoma has been described and these patients are taking
these drugs for decades. All hereditary angioedema patients are at
risk for acute attacks and prophylactic treatment is not completed
preventative. I had a patient who was
not mine, who came into the Duke Emergency Room about a year ago on 600
milligrams of danazol a day and proceeded to be unable to intubated and had to
have an emergency tracheotomy. So
triggers vary over time, breakthrough attacks occur and I believe that there's
no adequate acute treatment approved in the
So what do we do for acute attacks? Well, for abdominal attacks, we give
narcotics and we've talked about that.
For laryngeal attacks we use supportive therapy. We use epinephrine which has limited efficacy
in this disease. We use intubation or
tracheotomy if it's necessary.
Fresh frozen plasma has been
mentioned and I'd like to say another word about it. It has been reported to be effective in many
case reports. I would say that 90
percent of people get better with fresh frozen plasma, but if you think about
it, you're giving C1 inhibitor and at the same time you're giving high
molecular weight kininogen, the substrate of kallikrein which will lead to more
greater kinin production. I and I think
everyone who have seen many people treated, have seen people get worse on fresh
frozen plasma and I personally believe it's contra-indicated.
Antifibrinolytics have been
used. EACA we were the first to do a
double blind study with EACA and I don't want to talk about it in detail except
to say that, yes, it works and yes, the toxicity profile is even worse in the
androgens. We use antihistamines and
steroids. They're commonly used. There really isn't any evidence of efficacy
but the antihistamines do have sedating properties. What about C1 inhibitor?
Obviously, it's the protein that's
low and so it's disease specific treatment.
It's widely used in
We published our first studies with
C1 inhibitor in the treatment of hereditary angioedema in 1980 in the New
England Journal of Medicine. That
was 28 years ago. And we reported at
that time, that it was effective in the treatment of the disease but this was
not a double blind study. In 1996, we
published a double blind study with the last Fred Rosen, using an
immuno-product, a product that's no longer available. We published the prophylactic side of the
study and Fred Rose actually did the acute side of the study and I'm going to
talk about the prophylaxis.
We brought in a group of six
patients into the hospital who had severe hereditary angioedema and had failed
all therapy. We treated them every three
days as you can see by the red triangles on this slide. The C1 inhibitor concentration rose rapidly
as shown in yellow and then fell rapidly reflecting its about two-day
half-life. It does not have a very short
half-life in the circulation. It does
not have a very long half-life in the circulation.
Placebo, as you can see in blue, had
no effect. If we follow the level of C4
as we did in these patients, what we found was that the C4 gradually came up
into the normal range and stayed there and the effect of placebo, again was
negative. It didn't have any
effect. These patients who were very
severely ill, having about five attacks per month, responded to the C1
inhibitor and got better. They didn't
respond completely. They still had about
-- occasional attack but at least 60 percent of their attack frequency was
decreased.
Frankly, when I published this data,
I thought that C1 inhibitor would become available for use in this country but
in fact, that was 12 years ago and it's still not available. We did not find antibody in our patient
population. So in conclusion, we think
that there's an unmet need, at least I do.
European patients have had access to
C1 inhibitor for decades. There are many
papers, mostly uncontrolled on the -- on saying that C1 inhibitor is effective and
no papers that say it's not effective.
It works in acute therapy as I've said.
It works in prophylaxis. It has
demonstrated safety and efficacy and there has been 36 years of experience with
this drug. Thank you.
DR. KALFUS: Good morning.
I'm Dr. Ira Kalfus, Vice President of Medical Affairs at Lev. I have worked extensively in the development
of Cinryze and I'm pleased to be here with you today. The pivotal studies demonstrated the safety
and efficacy of Cinryze in the treatment of hereditary angioedema in the
Numerous studies have demonstrated
the activity of 1,000 units of C1 inhibitor for treatment of acute
attacks. In
Based on the documented experience
with Cetor, the Cinryze dose was 1,000 units in both pivotal trials. For long-term prophylaxis the dosing
frequency is twice weekly reflecting the roughly two-day half-life of C1
inhibitor. A randomized parallel group
open label pharmakinetic study of Cinryze in asymptomatic HAE patients confirm
the expected half-life. Subjects receive
either a single dose of 1,000 units or 1,000 units followed by a second
injection 60 minutes later. The mean
half-life of Cinryze was 56.5 hours for a single does and 62.2 hours for the
double dose. The intravenous
administration of Cinryze demonstrated a temporary increase in plasma levels of
C1 inhibitor within one hour of administration.
Traditional Pharmakinetic
methodologies are difficult through the variable levels of endogenous C1
inhibitor as well as the variable utilization of both endogenous and exogenous
C1 inhibitor. The clinical benefit of
Cinryze is demonstrated in two pivotal trials.
Based on the European Cetor data, and consultations with FDA, we conducted
two pivotal multi-center Phase 3 studies, both of which included and open label
rescue option. The acute treatment trial
was a randomized placebo controlled double-blinded study designed to evaluate
the efficacy and safety of Cinryze as a therapeutic agent for treating acute
attacks of angioedema. The prophylactic
treatment trial was a randomized placebo controlled double-blinded cross-over
study designed to evaluate the efficacy and safety of Cinryze as prophylactic
treatment to reduce the incidence, severity and duration of HAE attacks.
To enter the Phase 3 program,
subjects needed to be at least six years old and have a documented history of
HAE based on evidence of a low C4 level plus either a low C1 inhibitor
antigenic or C1 inhibitor functional level.
Subjects could also be enrolled with a documented HAE causing mutation,
HAE causing C1 inhibitor mutation, excuse me.
The same pool of enrolled subjects
was the source of subjects for both the randomized acute and
prophylactic trials.
Exclusion criteria included B-cell
malignancy, presence of an anti-C1 inhibitor antibody, history of allergic
reaction to C1 inhibitor or other blood product. Narcotic addiction, participation in any
other investigational drug study within the past 30 days, participation in a C1
inhibitor trial or having received blood or blood product in the past 90 days,
pregnancy, lactation, for any clinically significant medical condition such as
renal failure that in the opinion of the investigator would interfere with the
subject's ability to participate in the study.
After pre-qualification, to confirm
the diagnosis of HAE, subjects presenting to a clinical site within four hours
of the onset of an acute HAE attack were evaluated for potential
randomization. Subjects who were
experiencing a laryngeal attack received immediate open-label Cinryze and
remained eligible for randomization for a subsequent attack.
Subjects with an attack limited to
their extremities, were treated with standard medical and did not receive
Cinryze. These subjects also remained
eligible for randomization of a subsequent attack. Subjects presenting with either moderate or
severe attacks that involved the GI system, face or genital urinary system were
randomized to be treated in a double-blinded fashion with either 1,000 units of
Cinryze or an identical volume of normal saline placebo.
A second injection of the same study
drug could be given in 60 minutes if the attack had not started to resolve or
was getting worse. Subjects were evaluated
for four hours following the initial injection of the study drug. Open label Cinryze could be given as rescue
therapy if the subject had not reported onset of relief by four hours or if the
subject had airway compromise at any time.
Subjects were eligible for a second
dose of open label rescue medication if they had not responded to the initial
rescue dose within one hour. The primary
end point of the acute treatment trial, the median time to unequivocal onset of
relief, was positive with a P value of 0.026.
After randomization into the acute trial, subjects were eligible to
enter the prophylactic trial if they had a prior history of at least two HAE
attacks per month. This was to insure
that the trial would have a sufficient number of events for analysis.
In addition, subjects were required
to have had no change in the androgen or EACA dosing within 30 days of trial
entry. Once enrolled in the prophylactic
trial, no changes in the dose of androgens or EACA were permitted. All subjects were enrolled and randomized
into the prophylactic treatment trial prior to completion and unblinding of the
acute treatment trial. The prophylactic
trial was a randomized double-blind placebo controlled cross-over, multi-center
study. Subjects received two periods of
12 weeks of treatment for a total of 24 weeks.
During the first period, half the subjects received placebo, while the
other half received Cinryze in a blinded fashion. At the end of the first 12-week period, the
subjects crossed over such that those who had been receiving placebo received
Cinryze and vice versa. There was a
treatment-free interval of two to 11 days between the last dose of blinded
study medication in the first period and the first dose in the second period.
Subjects were eligible for open
label rescue for any acute attack. The
subjects who enrolled in the trial were reflective of the presenting HAE
population. The mean age was 38 with a
range of nine to 73 years. The majority
of subjects were female and white. There
were no notable differences between the treatment sequence periods in terms of
demographic characteristics. The results
from the controlled prophylactic study demonstrated a statistically significant
and clinically meaningful reductions in disease burden. The protocol specified enrollment was 24
subjects with a goal of 20 being evaluable in the efficacy set. Twenty-four subjects were enrolled and
treated with randomized study medication.
Two of the 24 subjects were excluded from the efficacy set because they
failed to complete the first period of the study and did not cross over to
receive at least one treatment in the second period of the study. The remaining 22 subjects crossed over and
were treated with both Cinryze and placebo and are therefore, included in th
efficacy set. Two of the 22 subjects
included in the efficacy set withdrew prior to completion of the second period.
The remaining 20 subjects completed
the entire 24 weeks of the study. The
protocol defined primary end point of the prophylactic study was the normalized
number of attacks of angioedema per day during each treatment period using
subjects as their own controls. The
number of attacks consisted of all angioedema that occurred during treatment,
irrespective of whether the subject received Cinryze -- or the label Cinryze or
not. An
angioedema was defined as the period between the development and
resolution of symptoms of
angioedema. Attacks involving a progressing to multiple
sites were considered to be single attacks.
Analysis of the data demonstrated a statistically significant and
clinically meaningful difference between the Cinryze and placebo periods.
Subjects treated with placebo
experienced a mean of 12.7 attacks over the 12-week treatment period compared
to a mean of 6.3 attacks for those subjects treated with Cinryze. This demonstrated a 51 percent reduction in
the total number of attacks with a P value of less than 0.0001 without regard
to the severity, duration or location of each individual attack.
The interpretation of a cross-over
design is clearest when there are no period or sequence effects. The results show no evidence of these effects
in this trial. A per patient analysis
demonstrated the consistency of the effect.
Because each subject was his or her own control it is helpful to look at
the attack frequency during the Cinryze blinded treatment period and compare it
to the attack frequency during the placebo treatment on a per patient
basis. Twenty of the 22 subjects showed
improvement, though one of the 20 had only a minimal reduction in attack
frequency. The secondary end points
consistently support the conclusions of the primary analysis.
All secondary end points were
statistically significant. The P values
demonstrate that there was a significant difference in the severity of attacks,
the mean number of open label injections administered for acute attacks, the
duration of attacks and the total number of days of swelling. Each of the end points demonstrated a
clinically meaningful benefit. Represented
is the median of the percent difference in placebo minus Cinryze. There is a consistent benefit from treatment
with Cinryze.
The primary end point was the
reduction in the number of attacks and the effect favored Cinryze. Severity of attacks was reduced by 26
percent. The number of open label
infusions of Cinryze was reduced by 97 percent.
The duration of attacks was reduced by 21 percent and the number of days
of swelling was reduced by 75 percent.
The 95 percent confidence interval
of these changes demonstrate the robustness of the benefit of Cinryze. In addition to the efficacy demonstrated in
the protocol defined analysis, looking at median percent differences by
treatment period, the positive effect of Cinryze treatment is also apparent for
the majority of subjects when the data is analyzed on a subject by subject
basis.
For the primary end point of the
number of HAE attacks, 91 percent of the subjects showed positive results on
the Cinryze period. For the secondary
end point of attack severity, 85 percent of subjects showed improvement. Ninety-five percent of subjects experienced a
reduction in the number of Cinryze open label rescue treatments. The percent of subjects experienced a
reduction in the duration of attacks with 77 percent and 95 percent of subjects
had a decrease in their total days of swelling.
And event chart allows us to look at the time course of events and treatment by individual subject.
For example, here is subject number
51001. The clinical course is represented
along each line with placebo treatment period on the upper line and the Cinryze
treatment on the lower line. The magenta
bars represent days and severity of swelling.
The yellow bars represent open label treatments with Cinryze and the
gray dots indicate scheduled blinded treatments.
Duration of individual attacks are
represented by contiguous magenta bars.
The height of the magenta bars reflect the severity of swelling and the
length of yellow bars represent the number of open label doses administered. Looking at the results of every subject
individually reveals the benefit of Cinryze on a per patient basis. On the left are individual subject
identification numbers. The
preponderance of color on the placebo side of the graph reflects the extent of
swelling and the need for open label treatment.
By contrast, the Cinryze size of the graph has less color reflecting the
benefits seen in the majority of subjects.
Cinryze was successful in the
prophylactic treatment of hereditary angioedema. The study met its primary end point and every
secondary end point with reductions in disease burden that were statistically
significant and clinically meaningful.
Cinryze treatment reduced the frequency of attacks, the severity of
attacks, the number of open label treatments required, the duration of attacks
and perhaps most importantly, the total number of days with swelling. These effects were consistent in the
prospectively defined protocol analysis by treatment group and were confirmed
by graphical analyses of individual subject data. The safety of Cinryze has been demonstrated
in the US Phase 3 pivotal studies which showed the safety profile of Cinryze to
be similar to that of placebo. The
safety is further supported by the ongoing open label studies and years of safe
use in
No drug interactions or
contraindications have been identified with Cinryze or with C1 inhibitor
products in general. Cinryze was
administered to 96 unique subjects in the placebo controlled and PK studies. This includes the acute treatment study, the
prophylactic treatment study and a 27-subject PK study. In total, these subjects received 1413, 1,000
unit doses of Cinryze. Overall, more
than 6,000 injections of Cinryze have been given in the
During the acute study, the most
common adverse events were mild. Six
subjects had treatment emergent adverse events in the Cinryze arm and seven
subjects experienced treatment emergent adverse events in the placebo arm of
the acute treatment study. The most
common treatment emergent adverse event reported was sinusitis which occurred
in two subjects both on the Cinryze arm.
There were also two reports each of nausea and decreased blood pressure
which were evenly split between arms.
Twelve subjects who did not randomize to Cinryze or placebo received
open label treatment with Cinryze. None
of these open label treatment subjects had treatment emergent adverse
events. There were no reports of serious
adverse events during the acute treatment study.
In the prophylactic treatment trial,
because all subjects received open label Cinryze while in the placebo period,
safety data is presented as an overall analysis reflecting contributions
throughout both periods of treatment.
This approach conservatively regards all subjects as receiving Cinryze
throughout the trial.
Twenty-one of 24 subjects in the
safety population had one or more adverse event reported in approximately seven
months of treatment and observation. The
most common adverse events were upper respiratory infection and sinusitis
reported by seven subjects. There were
five reports of rash and four subjects reported headache. There were four reports of serious adverse
events requiring hospitalization while on treatment during the prophylactic
phase and one additional SAE requiring hospitalization was reported prior to
dosing with study medication. All the
SAEs were attributed to HAE itself or some other unrelated medical condition
and resolved without discontinuation of treatment.
There were no deaths during the
study. There were no withdrawals from
either period of the study due to adverse events. There were no significant changes in
clinical, laboratory or hematology findings.
Viral surveillance studies demonstrated no seroconversion for parvovirus,
Hepatitis B, Hepatitis C or HIV.
There were a significant number of
unexpected positive C1 inhibitor antibody results at screening and during
treatment which raise questions regarding the validity of the assay. Confirmatory tests showed that only two
screening tests were positive and these patients were excluded from the
trial. No patients had positive
confirmatory tests during treatment. To
further support these findings, we are currently in the process of testing all
subjects in the open label studies at Sanquin Clinical Reference Laboratory and
will provide these results to FDA.
The overall safety profile with
Cinryze in double blind and open studies has been consistently favorable. No Cinryze related SAEs have been
recorded. The type and severity of other
adverse events have been similar between Cinryze and placebo. Adverse events throughout the studies have
been mild. The safety of Cinryze is
consistent with the reported safety of Cetor in
The safety profile of Cinryze is
favorable. There are few treatment
emergent adverse events reported from all studies and those reported on placebo
were of the same type and level of severity as on Cinryze. Five SAEs were reported in the prophylactic
study and another 28 SAEs have been reported in the ongoing open label
studies. All have been determined to be
unrelated to Cinryze. The history of
Cetor use in
DR. BUSSE: Good morning.
My name is Paula Busse and I'm an Assistant Professor in the Division of
Clinical Immunology at
HAE can present unpredictably. There is variability in the type of the
attack, severity of the attack, timing of the attack and pattern and frequency
of attacks. One example of this
variability is the occurrence of a first laryngeal attack. It can occur at any point in a person's life
who has HAE. A German retrospective
study looked at six fatal laryngeal attacks in patients with HAE. Five of these attacks were the first
laryngeal attacks that the patients had ever experienced. This also included a nine-year old boy for
whom it was his first HAE attack ever of his life.
The sixth patient had experienced
over 100 prior laryngeal attacks. This
demonstrates the importance of educating patients and their families about the
unpredictability of HAE and the ever-present risk of a laryngeal attack even in
a person who has never experienced a laryngeal attack or any HAE attack previously.
While HAE is hereditary, genetics
alone do not determine the course of the disease. A good example of this is a case report on
twins -- monozygous twins, both of whom had HAE. These identical twin sisters were in fact,
genetically indistinguishable but their disease was phenotypically
different. Each twin had different
triggers of attack, duration of edema and sensitivity to fluctuation of sexual
hormones. The authors concluded that
beyond genetics multiple factors can influence the manifestations of HAE. Those of us who treat HAE further recognize
that similar clinical manifestations can have different impacts on the
patients' lives. This makes it essential
to understand how the disease effects each patient's life and to treat each
patient differently.
The goal of HAE therapy is to allow
each patient to live a normal life as possible.
We need to individualize each patient's medication regiment. The disease is variable and its effects on
patients' lives also vary. Similarly, a
patient's response to therapy can vary.
Therefore, therapy will vary from one patient to the next. It will also vary over time for any given
patient. For many patients, prophylactic
therapy is an important option at some time point in the course of their
disease. In addition to reducing the
physical manifestations of this disease, prophylactic therapy can provide peace
of mind for patients and help them lead more normal lives. Several studies have demonstrated that
neither the severity of the disease nor the response to therapy is correlated
with any biochemical marker or laboratory value.
Two patients may have the exact same
levels of the C1 inhibitor but may have completely different burdens or
responses to treatment. While decreased
functional C1 inhibitor and decreased C4 levels are important for making the
diagnosis of HAE, we do not follow these levels during treatment. The actual treatment of HAE focuses upon the
management of clinical symptoms and their impact on patients' lives. The current treatment approach recognizes the
need for individualizing care. It relies
upon a discussion between the patient and the physician. The treating physician can generally not
decide a priori which patients will need prophylactic therapy. When we discuss this decision with our
patients, there are some well-defined considerations that we must keep in mind.
Those patients most likely to
benefit from prophylactic therapy include those with frequent attacks, rapidly
progressive attacks, and those with a history of a laryngeal attack. Patients who also live in remote areas
without access to emergency rooms or hospitals and those patients who also have
had a history of multiple hospitalizations, ICU's days or intubations are strong
candidates for prophylactic therapy. The
dependency upon narcotics is also another important consideration. Perhaps, most importantly, there are patients
whose diminished quality of life makes them strong candidates for
prophylaxis. These patients, many of
whom cannot otherwise maintain gainful employment or complete school have the
greatest need. I have completed
disability paperwork on one of my patients because she could no longer sit in
an office because of her frequent abdominal attacks. This was in spite of androgen therapy, the only
current therapy that we have for prophylaxis in the
Because of their contra-indications
and side effects, androgens are not appropriate for all patients. Patients who should not receive androgens
include children, patients with heart disease, and patients who cannot tolerate
the side effects. Most women have
difficulty taking androgens due to the side effects which include weight gain,
unwanted hair growth, and menstrual abnormalities. It is also contra-indicated in
pregnancy. While androgens can be
effective, they may not completely prevent attacks. Patients are usually dosed to the highest
dose to gain control of their symptoms.
Then patients are adjusted to the lowest effective dose based upon the
frequency of attacks and the patient's ability to tolerate the side effects of
these medications.
Patients end up on a wide range of
doses because there is substantial variation and response to androgens. We have a patient who had regularly had
attacks several times a week. We prescribed
and she received high doses of two different androgens. However, neither helped control her
attacks. The availability of Cinryze
will expand the potential for prophylaxis.
Prophylactic treatment with Cinryze
is an important and much needed option for any patient who is a candidate for
prophylaxis. In addition, Cinryze will
also help patients for whom androgens are ineffective, intolerable, or simply
inappropriate. Treatment with Cinryze
makes sense. Cinryze therapy is a
rational approach to treating HAE because it is a disease specific replacement
therapy. The Cinryze dose of two times
per week has demonstrated activity in 90 percent of the patients. In clinical practice we will need to dose
patients based upon response. As with
androgens, we will start with the dose that is effective for the majority of
patients. With Cinryze, we see that most
patients responded to two times per week dosing. Based upon the individual response, there may
be some patients who benefit from a dose frequency modification. All 22 patients from the controlled
prophylactic study continue to take C1 inhibitor including my prophylaxis
patients. Fourteen of the 22 subjects
entered the open label prophylaxis extension study. The eight other patients are importing or
self-importing Cetor through a program with the HAE Association. Thirteen of the 14 Cinryze patients have
remained on the twice weekly dosing, the 14th patient receiving
dosing three times per week. My two
patients have remained on the twice weekly dosing. Both of these prophylactic patients had
considerably fewer attacks and days of swelling. Neither patient needed any open label rescue
treatment while on the Cinryze arm. Witnessing the benefits of Cinryze is
compelling.
One of my patients, 06018, has a
markedly different profile while on the Cinryze treatment arm. Her days of swelling were reduced from 59 to
2 and the number of rescue treatments were reduced from seven to zero. My other patient has done very well and feels
much better. Patient 06001 saw her days
of swelling reduced from 17 to zero and the number of rescue treatments reduced
from five to zero. Furthermore, she is
currently off androgens and doing very well.
While my patients recognize that C1
inhibitor represents the standard of care for HAE, they know it is not a
cure. Even a fully compliant patient may
have a new or amplified trigger such as emotional stress or physical illness or
trauma which cannot be predicted but can cause a breakthrough attack. The goal is to enable patients to live as
normal a life as possible by reducing and preventing attacks. Cinryze significantly reduced the number of
these events. Cinryze works. It has a clearly positive risk benefit ratio
and meets an important unmet medical need.
It is safe and effective. We have
strong evidence from our Phase 3 trial as well as supportive evidence from its
use in
Cinryze should be approved and
available for use in the
CHAIRMAN SIEGAL: Thank you for that discussion. Is there anything that you'd like to add? You have a couple of minutes.
MR. BABLAK: No, we'd be happy to answer any questions
from the committee at this time.
CHAIRMAN SIEGAL: Okay, then, this is open for discussion.
DR. APTER: I have a quick question. Why was 1,000 units chosen instead of a dose
suggested by weight as most of the protein replacement therapies are?
MR. BABLAK: The 1,000 unit dose was selected based on the
European experience with Cetor and the half-life of approximately two days of
the drug. I'm going to ask Dr. Kalfus to
come up and explain in a little more detail.
DR. KALFUS: As Jason mentioned, the half-life also was
consistent with the stabilization of C4 levels demonstrating biological
activity of C1 inhibitor. Slide up. When we looked at actual weight and response
to weight during the study, we saw that in the scattergram, there actually is
no correlation to response to therapy to the weight of the subjects.
DR. APTER: How were HAE episodes identified to go
-- to have the required number to go on
prophylactic treatment and also how was laryngeal edema diagnosed in the acute
trial?
DR. KALFUS: The number -- to obtain the number to the
attacks on the prospective trial, that was base on historical record of the
patients.
DR. APTER: So not physical exam.
DR. KALFUS: It was not, no, that was based on patient
history. And the identification of the
evidence of laryngeal tap was basically, I'm not sure, for the treatment it was
-- all the treatments for laryngeal
attacks were provided by physicians who were evaluating subjects who had
presented with complaints of laryngeal attacks and were treated by physicians
for laryngeal attacks.
DR. APTER: So you don't have records of soft tissue
laterals of the neck or --
DR. KALFUS: No, if the clinical circumstance dictated for
whatever time that there was additional testing but there was no required
radiographic studies. It was a clinical
decision. The subjects were treated
clinically and were given Cinryze as rescue therapy. It was not part of the acute trial itself.
DR. ZIMRIN: Why were patients with B-cell malignancies
excluded? I'm here.
DR. KALFUS: Sorry.
Patients with B-cell malignancies were excluded because B-cell
malignancy and other lymphoproliferative disorders are common for the cause for
required angioedema. The exclusion in
the criteria of B-Cell was to exclude those subjects who happened to have
acquired angioedema who could present very, very similarly to hereditary
angioedema but their treatment is different.
They both require C1 inhibitor.
Acquired patients require significantly higher levels of C1 inhibitor.
DR. ZIMRIN: Also, was there any pattern in terms of when
the attacks occurred? If you look at
twice weekly dose, did it occur on day 7?
It didn't look like it from the two patients that I could see in detail.
DR. KALFUS: I'm happy to look at it again. There was no pattern that we noticed on the
-- across the board as far as when subjects were having their attacks or not.
CHAIRMAN SIEGAL: Dr. Kulkarni?
DR. KULKARNI: Two questions. What was the volume of the -- you know, the
medication and did these patients require central venous access devices for the
prophylaxis?
DR. KALFUS: The medication is 10 ccs of 100 units per cc
and administered intravenously. These
subjects did not require central venous access.
It was administered either through a butterfly or through an IV.
DR. MANNO: I'm interested in the inhibitory antibody
development. Can you tell us a little
bit about how you assay for inhibitory antibodies and what the prevalence is in
patients who haven't received the plasma derived concentrate?
DR. KALFUS: I'm going to have Dr. Zuraw to come up to
discuss the antibodies. Dr. Zuraw was
the principal investigator for the study as well as being an antibody
specialist.
DR. ZURAW: Hi, my name is Bruce
Zuraw. I'm a Professor of Medicine at
the
In my experience, acquired C1
inhibitor deficiency is usually associated with anti-C1 inhibitor
antibodies. I've looked at about 50 of
my own hereditary angioedema patients and a number of other samples sent to me from
around the country and I don't believe that patients with hereditary angioedema
have any auto antibodies against C1 inhibitor.
I don't think that really does occur.
DR. MANNO: Even after treatment with replacement
therapy.
DR. ZURAW: Well, we had an opportunity in this study to
look at that and so my lab did look at a
number of these patients after therapy and I certainly saw no evidence of
antibodies developing, nor in general if you talk to European investigators,
who have been treating with C1 inhibitor for quite a long time, there's no
relationship between the administration of C1 inhibitor replacement therapy and
auto antibodies developing. Remember
that this is a disease that's autosomal dominant and the patients all have C1
inhibitor in their plasma.
DR. SZYMANSKI: I was very impressed with the results that
you presented. And it's a very long
missing drug finally coming to the
MR. BABLAK: I'll try an introductory answer to that and
then I'll ask Dr. Frank to come up and talk a little bit about the variability
but certainly within HAE patients there is a wide variability in terms of the
manifestation of the disease. We noticed
that some patients, obviously, did not have any attacks while on the Cinryze
arm, and other patients, while they had minor attacks, didn't have attacks that
required open label Cinryze. There were
other patients who did require open label treatment even on the two times a
week dosing. I'd ask Dr. Frank to come
up and explain a little bit about the variability.
DR. FRANK: Yes, I can't speak to the Cinryze situation
but I can speak to variability. This is
a highly variable disease in which we don't understand all of the parameters
that cause attacks. So for example,
someone can have this abnormality in their cord blood and never have an attack
until their 70. It's actually
well-described. When we developed
Danazol for the treatment of this disease, we figured that we would find a dose
that was useful in most patients and that would be the end of it.
And in fact, that's not exactly what
happened. What happened is we found that
many patients responded to 600 milligrams a day. That was a high dose. Some patients responded to 800 milligrams a
day. We then started to lower the dose
to see what would be the sort of the cutoff point and we found that there
wasn't any cutoff point. We found
patients that would respond to 50 milligrams once a week which is I would have
thought a homeopathic dose.
What happens is that the other
factors that we talked about including emotional state, including, I'm sure,
things that we have no knowledge of, make an enormous difference in the way
that patients respond. When we did our
prophylactic study, the one that I told you about, we actually used a higher
dose of C1 inhibitor.
The patients were very sick and we
got about a 60 percent response rate, but even with a higher dose, we didn't
completely turn off attacks.
DR. FLEMING: I had a couple questions and the overall
efficacy for the measure that you used certainly appears to be
established. Dr. Frank, though provided
some very important insights that were consistent with issues that I have been
thinking about as I have been reviewing this.
He showed us a number of graphs and the graphs included episodes or
attacks that involve hands and facial attacks and then he focused very much on
the abdominal attacks and laryngeal attacks referring to the sequelae
there. ER, is it hospitalization,
life-threatening and he said this is why
we're here today. So could you show us the
results by treatment arm for the events, the attacks that in fact specifically
involved ER visits, hospitalizations or were viewed as life-threatening?
MR. BABLAK: The primary end point was looking at total
attacks.
DR. FLEMING: I understand.
MR. BABLAK: Not broken down.
DR. FLEMING: So what I'm trying to get at is his point
that I very much endorse, why we're here today.
In particular, are these more serious?
Can you show us by arm, the numbers of attacks that were attacks
characterized as involving ER visits, hospitalizations or were
life-threatening?
MR. BABLAK: We don't have the data broken down in that
type of an analysis.
DR. FLEMING: Well, let me go on then. If you could get that for us, that would be
very helpful. The second issue is, when
you look at the scale in the FDA advisory or briefing document on pages 21 and
22, the scale of mild, moderate and severe appears to be very non-linear. Your primary end point is treating it as
linear, it's scaled 1, 2, 3 and it's looking at average which views it as
linear but mild is events or attacks that didn't interfere with daily living,
moderate somewhat interfered and severe significantly interfered.
My sense is, looking at all the
graphs in CC 12, 14, 16, 17 to 20, 22, 23, and 24 shown to us by Dr. Frank my
understanding is these were severe scenarios that you were showing us for those
specific symptoms. When you look at
patients by severity, for example, Patient 53002, that patient had two attacks
on treatment, nine attacks on control, but nearly all of the nine attacks on
control were mild. The two attacks --
excuse me, nearly all the attacks that occurred on the control arm were
mild. The two attacks that occurred on
treatment were severe.
So the impression, when you look at
the scale as you're presenting it for that patient is you've reduced from nine
attacks to two but in the control, those nine were essentially mild. The two on treatment were both severe. So could you show us the results by treatment
arm, if you look at severe attacks? So
basically take all the severe attacks and show us how treatment is playing out in terms of reducing the rate of what Dr.
Frank said are the kinds of events that we're here today about?
MR. BABLAK: I'm going to ask Dr. Kalfus to come up and
respond to that question.
DR. KALFUS: You brought up -- I'm going to start with
Subject 53002 that you brought up. Can I
have the event plot? This subject
actually had two attacks, slide up, please, during the Cinryze treatment arm
that actually were of more significant severity than the attacks that she had
during the placebo period. What was of
note is we actually looked into this.
There were only -- there were a couple of patients that we actually have
been speaking, when we source data like this and what we found out is if you
looked at these attacks from around day 18 to 20, they're on their Cinryze arm,
this is actually a high school junior or senior who was having exams and
preparing for prom at that particular time.
So while we can't really speak to
everything that's going on, because we don't understand everything about this
disease, we do know that the physiological triggers and the emotional triggers
are such that patient symptoms can manifest differently based upon what's going
on. And we believe that this is a
possibility that's what happened to this particular patient during that particular
time during her treatment period.
If we bring up the event plot or the
event chart for all the subjects, you will see that while we haven't broken
them down by severity, you can look at the severity of attacks by the slide up
please, I'm sorry. The severity of
attacks is demonstrated by the height of the magenta slides and just looking at
the height of the magenta slides, we'll be able to determine what we did to the
severity of attacks from the placebo treatment arm to the Cinryze treatment arm.
DR. FLEMING: If you could provide that, if some time
today, you could actually provide an analysis that shows the reduction in the
rate if there is one, in severe attacks, that would be very informative.
DR. BALLOW: Just kind of a follow-up if you'd actually
put that slide back up, the one you just -- there's two patients actually on
the treatment arm were worse and I wonder whether there's anything to learn
from those two patients. Were they using
any medication, you know, during the trial which may have adversely effected
their clinical response to the drug or is there any understanding why those two
patients did worse on the treatment arm?
DR. DI BISCEGLIE: And if I can add to Dr. Ballow's question, I
was going to ask about the graph that you showed of the number of attacks per
person, and there are -- I think it's maybe three in whom the number of attacks
increase. Maybe the same that he's
referring to.
DR. KALFUS: Different questions and I'll answer them
sequentially. Slide up, please. This is Subject 16005. This is one of the two subjects who had an
increase of attack. She actually had one
increase, one more attack during the treatment period than she did during the
placebo treatment period.
Slide up; however, if you look at
the secondary end points, we see that despite that fact that she had one more
attack, she actually had clinically meaningful benefit in some of the other
parameters that we were looking at.
Slide up, please.
This is subject 17002, the other
subject who had a worsening and actually was clearly and outlier in the
study. This particular subject, slide
up, had almost double the number of acute attacks, had increased days of
swelling, and attacks of shorter duration and had increase in severity. And as we mentioned, there's significant
variability of the disease and we don't understand everything about the
disease.
We do know that this particular
subject had significant stressors during her time on the Cinryze period. She actually lost her job. She had a significant loss of income. Her finances, her business was -- she lost
her business. She had to close her attorney practice and she also entered
menopause. So there were significant
triggers that was going on during this particular patient.
This subject actually continues in
the open label extension trial, is on 1,000 units twice a week and because
she's such an outlier, we actually have spoken to her investigator because
there was a question as to whether he thought that the subject was actually
benefitting from the treatment and he said, absolutely the subject is doing
extremely well. Her life situation has
changed.
She's actually requiring less than
half the dose of treatment that she required while on the placebo arm and has
had half the number of attacks than she's had on placebo arm. So clearly, this subject actually had a
change in her triggers and had a change in her response to therapy.
Can I have the slide up,
please. This is, I believe, the slide
you were referring to. And it's actually
quite interesting. We looked at this
slide and we knew the data. We know --
imagine you're looking at the subject near number 6. Slide up. We knew the subject actually had a
1.2 percent differential in the normalized number. That's because he had six
attacks and it just wasn't quite a 12-week period. So we drew a line, just to make sure that it
was a straight line and this -- you
know, this was not an increase. And what
we discovered, slide up, was that this is actually an optical illusion. This is the Zollner effect and if you take
parallel lines and you intersect them with diagonals, you will actually give
the impression that the lines are not parallel.
I don't want to get into the
mathematics of this. There's a reference
at the bottom. I clearly cannot explain
it.
DR. APTER: But these attacks are self-report, correct?
DR. KALFUS: Yes, these attacks are self-report.
DR. BALLOW: So and this individual -- because these
individuals were also used for acute therapy as well, correct?
DR. KALFUS: All the subjects in the prophylactic
treatment trial were -- had gone through the acute treatment.
DR. BALLOW: Yes, so how did she respond during the acute
phase of her attack with Cinryze?
DR. KALFUS: The -- when the subjects
were entered into and randomized as the prophylactic treatment trial, the
results -- the Part A of the acute treatment trial had not yet been completed
or unblinded.
DR. BALLOW: No, no, but I thought that was an open
part. In other words, on the
prophylactic part of the study, if they had an attack I thought that they were
administered Cinryze as an open --
DR. KALFUS: We actually are in the midst of compiling the
data across the board for how subjects have been responding to acute
label. We have not submitted that
data to FDA for review. If we look at some of the other charts, you
can see just on responses, days of swelling.
Dr. Frank would like to say something.
DR. FRANK: Obviously, I don't have the Lev data but we
actually in the trial that I talked about, broke out the attacks by type;
abdominal, extremity, laryngeal, et cetera, and all were benefitted by C1
inhibitor.
CHAIRMAN SIEGAL: I have a couple of questions. First of all, can you tell us a little bit
more about the case of lymphadenopathy.
Did that play out as anything that we can understand?
DR. KALFUS: It was actually, it was more of a -- it
wasn't really lymphadenopathy. It was
more of an infection that -- it was just an infected node. Somebody had a thyro-glossal duct and it was
not related to anything hematologic whatsoever and it's listed as an SAE
primarily because she required hospitalization to have that drained and in the
course of having that drained, she actually wound up having a port placed.
CHAIRMAN SIEGAL: The other question is, has there been any
experience with subcutaneous administration of this product?
DR. KALFUS: There has not been any subcutaneous
administration of Cinryze.
CHAIRMAN SIEGAL: Is that something that might be feasible?
DR. KALFUS: It's something that might be feasible. It's
nothing that we have actually made any plans for right now.
DR. BALLOW: Can I follow up on that because I was going
to ask a related question. These
patients are going to be using this at home, I assume, correct?
DR. KALFUS: Currently, the application is for use with a
healthcare provider and a home healthcare provider clearly would be --
DR. BALLOW: But eventually, they'll self-infuse, I
assume. What happens if it
infiltrates? Does it damage any of the
tissues? Did you have any feedback on
that occurrence?
DR. KALFUS: We have anecdotal references from one or two
patients that have had some infiltration and I guess by extension, we have some
anecdotal reference on subcutaneous administration via infiltrated IV. The product seemed to work and there were no
secondary adverse events from that.
DR. GLYNN: I had a couple of questions, one related to
in terms of the experience and I guess he's from
DR. KALFUS: I would like to call up Dr. Marshall Levi,
who is from the
DR. LEVI: Good morning, I'm Marshall Levi. I'm Professor of Medicine University of
Amsterdam. We have quite some experience
with long-term prophylaxis in patients.
A couple of patients are using the product for more than seven or eight
years now on a very regular basis and we haven't seen any adverse events. We're checking our patients regularly for
viral serology and also for any formation of antibodies. We didn't see any one of them.
DR. GLYNN: How about clotting?
DR. LEVI: How about?
DR. GLYNN: Clotting or phlebitis?
DR. LEVI: Well, we haven't seen any complication in our
patients.
DR. GLYNN: So I had another question
also on long-term. In terms of how often
you change the dose. I mean, we heard
about the androgen, but I haven't heard about this particular treatment, how
often we need to change the dose, either you know, going lower or higher, more
often, less often? And again, that's I
would guess would come from the European experience.
MR. BABLAK: We also have the open label studies that are
ongoing with prophylaxis. Some patients
who have been on for longer than two years.
Typically, patients are started on a dose. We've only had one patient go from the two
times per week to three times per week in that period.
DR. GLYNN: And has anyone tried to give it less often?
MR. BABLAK: We actually have some patients in the open
label study who are on once a week as well.
DR. GLYNN: And the dose?
MR. BABLAK: It's 1,000 units. Always 1,000 units given starting out twice a
week and then adjusted and Dr. Busse could come and talk to that more in terms
of clinical practice.
DR. BUSSE: Unfortunately, treating HAE is very difficult
especially prophylactically and acute because we don't really have anything but
that's a different hearing. But anyway,
prophylactically we start with a dose in the trial, a dose of 1,000 units two
times a week seem to work for most patients.
Unfortunately, with HAE, unlike
asthma where we have guidelines, not to say that asthma is not difficult to
treat but we don't have guidelines for HAE to, you know, tell us how we should
treat these patients. We have some
simple -- we have some things actually that can suggest how we should change
the dose.
The first and most important is the
patient. The patient knows their -- his
or her disease better than anyone else and they can tell us how the disease is
effecting their life, if they're missing school, missing work. Also we know for prophylactic -- well, for
the dosing, you know, if they're having more breakthrough attacks, we know that
we should potentially increase the frequency to three times a week as per two,
but I would start with two times per week and then really work with the patient
to see, you know, see how effective this dosing regiment is.
DR. KULKARNI: Is there a rule for adjunct therapy with
antifibrinolytics in the European thing
that showed any kind of efficacy or --
MR. BABLAK: In the European experience you're saying?
DR. KULKARNI: Right, I mean or use of antifibrinolytics and
Cinryze?
DR. FRANK: I think I'm probably the person with most
experience with the antifibrinolytics.
The dose that we use in patients with hereditary angioedema that's
effective is about eight grams a day.
That's not a very strong dose in terms of antifibrinolysis. Exactly how it works, we don't know. For example if you do pharmacokinetics, 97
percent of the drug is out in six hours but the drug doesn't work fro two or
three days. The toxicity profile is
really quite severe. You don't see any
early toxicity but in two or three months, people will start to have muscle
aches and pains and they'll start to have tremendous feelings of fatigue. So we don't see anything in terms of clotting
problems but we do see that.
We use it in children and the reason
is we don't have another -- we don't have another agent to use in children
because we don't want to use androgens.
Now, I've never used the antifibrinolytics with C1 inhibitor because
we've never had C1 inhibitor available.
But I have used it with androgens and I've seen no augmentation of the
effect of either the androgen or the antifibrinolytic when they're used
together.
DR. KULKARNI: I just have one more question was. Is there any pheno-type, geno-type -- you
said the levels don't really tell you much but is there a pheno-type, geno-type
correlation and from --
DR. FRANK: We have not detected any and so that there
obviously is something going on and remember, what we're looking at is the
generation of Bradikinin. There's a
metabolism of Bradikinin and there may be more than one protein involved in
that metabolism. We know that we can't
give adults ace inhibitors. Ace does --
is responsible for the -- one of the proteins responsible for the degradation
of Bradikinin. Ace inhibitors make the
disease much worse, as do estrogens.
We do not even understand why
estrogens make the disease so much worse, so there's still things to learn.
DR. ATKINSON: Both Dr. Frank and Dr. Busse have mentioned
that this treatment of children is problematic.
Is there -- is the company -- is
there an age range that you're applying for the use of this product and if it's
going to be used in young children, what will your recommendations be or what
will your suggestions be as far as dosing?
MR. BABLAK: We -- in our study we included children down
to the age of six. The youngest child
who was in the study was a nine-year old and the dosing was the same for all
patients across the board of 1,000 units twice a week.
DR. ATKINSON: So the application will not have a lower age
range or what does that --
MR. BABLAK: For the prophylaxis study, we're still under negotiations in terms of the label with the FDA. In our open label studies we have the age down to one-year old. We are currently not treating any one-year olds on prophylaxis and as Dr. Frank referred