to,
typically the disease presents itself in children but doesn't become serious
until puberty where we'd start to see patients on prophylaxis.
DR. SZYMANSKI: I'm going back to a case where the frequency
of attacks increased during the, you know, C inhibitor and your response was
that he had added stressors during that time.
And my question is, if you would have increased the dose of medication,
do you think it would have decreased the attacks? Would that have been effective?
DR. KALFUS: I'm not going to speculate about that. Perhaps Dr. Frank would come up and talk
about what potentially could happen with the larger dose.
DR. FRANK: The doses that are being given in this kind
of study and the dose that we gave never brought the C1 inhibitor back to a
normal level. It's hard to do that because there's -- would require so much
product. My feeling is that the higher
you get the better off you are, but I think you would continue to have attacks
and I think there are things going on that we simply don't understand.
DR. MASCIK: During -- and maybe I just missed this, but
during the trial were there a dose of Danozol held constant?
DR. FRANK: Subjects who -- before they entered into the
trial were able to either stop their dose or maintain their dose. There was a 30-day washout period for either
reducing or stopping the dose and then it was maintained throughout the trial
at the same level.
DR. MASCIK: And in your open-arm study, has -- have most
patients been able to come off their Danozol, have they stayed on? Is there any trend being able to get off that
medication?
DR. FRANK: We haven't specifically collected that data
but just in talking to some of the patients and the physicians, they have come
off their Danozol dose.
DR. APTER: Do you have a record of experience of the
patients who were on Danozol during the study and those that weren't?
DR. FRANK: Yes, I'm going to ask Dr. Kalfus to come up
and go over that data.
DR. KALFUS: Slide up, please. This demonstrates the first three subjects
where the subjects actually were on Danozol during their course of treatment
and the next set of seven subject were subjects who actually had discontinued
their Danozol prior to being randomized into the study. The response rate basically and their
clinical situation, both prior or on placebo and on Cinryze are remarkably
similar.
DR. APTER: And the group below that's not labeled, I'm
sorry?
DR. KALFUS: These were subjects that were not on
androgens. These were all the other
subjects. This is all 22 subjects. The first three of those subjects who had
discontinued androgens who -- I'm sorry, who had continued their androgen, the
next group of those who had discontinued prior to randomization and then the
balance of the studies.
DR. DI BISCEGLIE: Is it likely that this agent would be
effective in acquired angioedema for example, as occurs with lupus and the
follow-up question to that is, if so, is it likely that there would be
off-label use occurring once -- with this agent being approved?
MR. BABLAK: Subjects who suffer from acquired angioedema
suffer from a similar disease. They have
C1 inhibitor deficiency. Dr. Levi actually
is the person who in the room probably has most significant experience with C1
inhibitor and acquired. I'd like to ask
Dr. Levi to come up to reference that.
DR. LEVI: Yes, in some severe cases of required
angioedema, you can use the C1 inhibitor concentrate, although our experience
is that you have to use it at a higher dose and more frequently, in some patients
very frequently. We have a couple of
patients that use that for many years actually.
Those were patients who had idiopathic acquired angioedema although some
of them only after years had the diagnosis of indolent lymphoma. And they have all been treated with C1
inhibitor concentrate quite successfully.
DR. BORISH: Going back to the genotype, phenotype
question, a simple question, I think
maybe Dr. Zuraw knows the answer, whether or not the mutated gene
produces a product big enough to be detected immunologically I assume a
truncated protein gets secreted. Does
that protein act as a dominant negative fashion?
DR. ZURAW: I guess the best answer to that question is
most of the protein that gets secreted is the dysfunctional protein with the mutation
right around the active site and the reactive mobile loop. It turns out that both the truncated mutant
proteins as well as missense mutant proteins largely get trapped in the
endoplasmic reticulum through quality control system and very little to none of
it seems to be able to exit the cell.
DR. BORISH: And does it interfere with the ability of the
normal protein to exit the cell. I don't
know, I'm just --
DR. ZURAW: That's actually a question that I'm actively
involved in. I believe there is actually
a gain of toxic function and we're pursuing that and I think it's a different
direction to treat this disease. But I
think it's really just simply interfering with the ability of the protein to
get out of the cell. We've never seen
any functional interference if we mix mutant and wild type protein on the
activity of the wild type protein.
DR. BORISH: Thank you, and my one other question was,
just a clarification. I just want to
make sure I heard this correctly. The
reporting of swelling and episodes in this study, this was all patient
subjective recording, filling in diaries and to what extent, if any, is that
different from Dr. Frank's study 12 years ago in the New England Journal? Was there objective measures that they these
really were HAE episodes in both of those studies?
MR. BABLAK: You're correct in that in our study it was
all patient reported through a daily diary that was filled out by the subject
and I'll ask Dr. Frank to explain the collection.
DR. BORISH: And just as a -- I mean, I see a lot of these
patients and as Dr. Frank said, these patients do get anxiety, they do get --
despite your efforts to exclude narcotic addiction, I think a number of my
patients probably are and I might not label them that way.
DR. FRANK: This is an interesting point and that is that
these patients learn their disease as I'm sure you know, very, very, very
well. They know when they're having an
attack of hereditary angioedema. They
can't tell how bad it's going to be when it starts but they know -- they can
put it in a reference of how bad attacks have been in the past. When I'm treating a throat attack, I almost
always find it easier to find out if I'm being successful by asking the patient
rather than by either examining the patient or doing x-rays.
DR. BORISH: My point being that when we're all focused on
17002 and somebody who's going through a really bad phase of his or her life,
might be more likely to, for lack of a better word, exaggerate the presence and
severity of some of these episodes and subject -- in the absence of objective
measures of was this a real HAE episode.
DR. FRANK: Yes, but the problem is, of course, this is
done as a double-blind study. So the
patient may be doing that but they don't know whether they're getting drug or
placebo.
DR. BORISH: No, I understand, but I think your point that
this disease can be very variable for reasons we don't understand is cogent
here.
CHAIRMAN SIEGAL: Dr. Fleming will have a word.
DR. FLEMING: Just on that related point. It's a key point.
It's a subjective end point. Blinding is
integral to the integrity of this. How
can we be assured? How do you assure
yourselves as well as us that the integrity of the blind is maintained
particularly since each patient experiences both sides?
MR. BABLAK: The study was blinded. There was an unblinded pharmacist at the
study site who maintained all the study drug, mixed the study drug and provided
it to both the --
DR. FLEMING: Time is short. I'm not so worried about that level. I'm more concerned about there's nothing that
the patient experiences that could, in some way, unblind them? Obviously, if there was any kind of
difference in the safety profile or other aspects of the intervention versus
placebo as the patient would witness it.
Of course, as the patient is beginning to experience both sides, if they
were first on the active and then were on placebo and started to feel more
events, that might actually give them a sense that they are now in the second
half on placebo and could that, in fact, lead them to amplifying how they're
reporting what they're seeing.
A downside to a patient as their own
control is it does in fact, challenge the integrity of the blind. How do you assess that?
MR. BABLAK: I'm going to ask Dr. Blumenstein to come up
and explain a little bit about that.
DR. BLUMENSTEIN: Could I have the slide showing the -- my name
is Brent Blumenstein. I'm a consultant
to Lev. I would like the slide that
shows the test of a period in sequence.
DR.
FLEMING: I saw that Brent. I understand there's no sequence and no
period effect, and that is reassuring.
That's not really getting at my issue as to whether or not -- well, it
could partially get at it, I guess your point is. If the integrity of the blind is compromised
in those patients who start on active and then go to control.
DR. BLUMENSTEIN: We can only piece that together. That was one piece. Slide up, please. Here's another indication. This is a Kaplan-Meier of time to first attack
and it breaks it down by whether the patient got Cinryze first or second and
placebo first versus second. And as you
can see, the Kaplan-Meier plots for the treatment period are roughly the same
in both cases and beyond that, I don't have any other thing to offer you.
CHAIRMAN SIEGAL: I think time is a little bit late and we're
going to have plenty of opportunity to discuss this further in the appropriate
period but I think since it's already
10:20, of Dr. Golding and Dr. Zaslavsky have no objection, I'd like to take a
break at this time and then come back and hear from the FDA and then we'll have
plenty of time for discussion.
DR. FLEMING: If we're breaking, it would be great if the
sponsor could use that time to be able to report to us differences by arm in
the number of events that were ER visits, hospitalizations or life-threatening.
CHAIRMAN SIEGAL: That's fine.
Let's be back in 10 minutes, half past roughly.
(A brief recess was taken.)
CHAIRMAN SIEGAL: So I have the approval of Dr. Golding and Dr.
Zaslavsky to complete the questions that
the Committee had before we proceed to the FDA analysis. I know there are a few burning questions and
we might as well start with Dr. Apter.
But why don't we give people a chance to reassemble.
All right. Why don't we start.
DR. APTER: My burning question is what were the C4
levels at baseline at the start of the study and how did they change over the
course of the study with treatment or placebo?
MR. BABLAK: Sorry.
Could you ask the question again?
DR. APTER: What were the C4 levels of the patients at
baseline and the range and how did they change individually with therapy?
MR. BABLAK: We did not actually measure C4 levels during
the study.
DR. APTER: Why?
MR. BABLAK: The C4 levels were not measured during the
study.
DR. APTER: Why?
MR. BABLAK: I'm sorry.
Why? I thought you said --
There's no correlation between C4 level and clinical response. So we did measure C1 inhibitor levels during
the course of the study, but C4 levels were not reported.
DR. APTER: So you were giving C1 inhibitor.
MR. BABLAK: We were giving C1 inhibitor. We measured C1 inhibitor at various points
throughout study, but C4 levels were not monitored.
There is also a question about
blinding from Dr. Fleming and we had an additional response to your question
which was that in the acute studies patients were asked after they got the
injection to monitor injection site pain and any kind of reaction and there was
no difference between drug and placebo there.
So there was in terms of the injection itself when given it didn't feel
any different one way versus the other.
DR. McCOMAS: I had a question about you excluded pregnant
women from the study.
MR. BABLAK: That's correct.
DR. McCOMAS: So this will not be recommended for pregnant
women or women who are lactating.
MR. BABLAK: We actually have treated pregnant women
outside of the blinded study. The main
reason for exclusion was we didn't want to have women on placebo experience
attacks. We have, I think, five during
the course of the open label study.
We've have five women at different times on prophylactic therapy with
Cinryze and we are working with the FDA in terms of the labeling of how to
include that.
MS. BAKER: Did you take any standardized quality of life
measures? You had mentioned depression
and anxiety being significant disease burdens.
MR. BABLAK: We did take the SF-36. That data has not been analyzed at this
point. It has not been submitted to the
FDA.
MS. BAKER: Is there a plan to analyze and submit that
data to the FDA?
MR. BABLAK: Yes, there is.
DR. RENTAS: Have you had any cases on overdose and, if
you have, how have the patients dealt with that?
MR. BABLAK: Sure.
I'm going to ask Dr. Kalfus to come up and talk about the dosing.
DR. KALFUS: We had no cases of overdosing. The maximum dose that any individual subject
received at any point during the study was 9,000 units during a seven-day
period or 4,000 units in five-hour period.
DR. FINNEGAN: While you have not shown any safety problems,
I think everybody in the room knows that eventually when you have enough
numbers, something is going to show up.
Can you guesstimate what caused the URIs and/or the sinusitis which
seemed to be the two biggest problems, the sinusitis in particular in both
groups?
DR. KALFUS: What we have to remember when we look at this
data is that these subjects were seen over a seven-month period. If they received no open label treatments on
either the placebo or Cinryze arm, they were seen 24 times in a six to seven
month period. Some subjects were seen
actually closer to 40, actually, 60 times.
It was twice a week for 12 weeks in each arm. So subjects were actually seen 60 or 70 times
during this period in an allergy practice and quite often subjects actually
will have a URI or sinusitis during the course of treatment.
It's important that when you look at
the sinusitis reports these are not sinusitises that are documented by CAT scan
or by ENT evaluation. These are reports that were generated by the clinician
when they were seeing the patient for either their emergency open-label rescue
therapy or for their regularly scheduled injections. So we actually don't think that there is any
higher incidence of URI or sinusitis with these subjects.
DR. FINNEGAN: And you don't think there's anything in the
function of the inhibitor that might, in fact, cause the sinusitis.
DR. KALFUS: It has not been reported ever in its use in
DR. KUEHNERT: Just on a follow-up on the overdose
questions, maybe it's somewhere in this package, but what sort of symptoms or
findings would you expect with an overdose?
Has that ever been reported in the literature?
DR. KALFUS: It hasn't been reported in the literature and
I'd like to have Dr. Zuraw come up and speak to some of the use of C1 inhibitor
in general.
DR. ZURAW: I think there have been two ways to get at
that type of information that you asked about.
The first is C1 inhibitor, the Cetor product in particular, has been
given in very high dose to humans in the context of acute myocardial infarction
because there's reason to believe it may be cardio-protection and in that case
patients were loaded with 100 units per kilo and then given two units per kilo
per hour for the next 48 hours and that's the equivalent of 14 Cinryze doses in
two days and they looked -- one of their parameters was safety outcomes and
there were no adverse effects whatsoever.
And then moving away from a human
model, there have been transgenic mice developed expressing the human C1
inhibitor transgene at very high copy level, six to seven copies, with very
high levels in the plasma and so followed over a long period of time in most
years and the finding was there was no phenotypes so that the transgenic mouse
model didn't turn out to be useful.
CHAIRMAN SIEGAL: Dr. Kulkarni.
DR. KULKARNI: I was just curious to know after
administration of this do the levels of C4 go up or did it change or did it do
anything to it and what is the significance of that?
MR. BABLAK: In the pharmacokinetic study we did, we did
show that the administration of Cinryze in addition to raising the levels of C1
inhibitor there was a level of -- a rising level, can I have a slide up please,
of C4 level over time. So depending on
which dose, the single dose or the single dose followed by a double dose, shows
that after 12 to 24 hours there was a rise in the C4 levels that was maintained
for about three days.
DR. APTER: So why didn't you do it during the study?
MR. BABLAK: The bloodwork during the study was taken
every four weeks and we weren't looking at doing a PK study during the study
which would have required the patients to come in on a much more frequent time
period than they were already coming in and had a lot more blood draws and so
we were looking at -- We'd already shown that C4 levels could be raised by
administering the C1 inhibitor and we were looking at the clinical outcome
which was the number of attacks.
CHAIRMAN SIEGAL: Mark.
DR. BALLOW: Question.
What's the osmolarity of this preparation? It's a lyopholized preparation, right?
MR. BABLAK: This is a lyopholized product.
DR. BALLOW: Reconstituted with?
MR. BABLAK: It's reconstituted with water for injection.
DR. BALLOW: And so what's the osmolarity?
MR. BABLAK: Dr. Koenderman from Sanguin can come up and
answer that. I don't have that
particular number.
DR. KOENDERMAN: My name is Aki Koenderman from Sanguin in the
DR. BALLOW: So it's iso-osmolar.
DR. KOENDERMAN: Yes, it is.
DR. BALLOW: Okay.
You know, the product reminds me of some of the IVIG products that
contain sucrose and that were lyopholized that caused unexpected renal
compromise and thromboembolic events.
Now the volume here is only 10 cc.
So it's much lower, but one wonders when it's used out in the general
population who may have other underlying risk factors that tend to get excluded
in these sorts of trials that, you know, the use of two times a week or even
three times a week might present an issue as was seen with some of the older
lyopholized sucrose-containing IVIG products.
MR. BABLAK: That would be possible, but given that these
are very low volumes we wouldn't expect that.
DR. ZIMRIN: I mean, isn't the IVIG more typically like a
liter or like 100 times that?
MR. BABLAK: This is a dose of 10 ml.
CHAIRMAN SIEGAL: Dr. Fleming, do you have any questions?
DR. FLEMING: There are a number of issues I wanted to
raise on safety. I just think it might
be more efficient to allow the FDA to go first in case they want to address
some of them and then come back to them.
CHAIRMAN SIEGAL: Well, are there any other burning questions
from the Committee at this time and, if there are not, then we will proceed to
Dr. Golding.
MR. BABLAK: There was -- I'm sorry. There was the question from Dr. Fleming about
the analysis and while we're not able to run that particular analysis I would
like to ask the Dr. Frank to respond to your question as it was raised.
DR. FRANK: Yes.
It was pointed out that perhaps I was unclear when I said the reason
we're here. At the start of an attack,
the patient cannot tell whether they're going to have a life-threatening attack
or mild attack of heredity angioedema.
So the true is that we are trying to end all attacks of heredity
angioedema.
The way this study was designed all
patients who are on placebo or drug who felt that the disease was getting very
severe received rescue medication which would be expected to end the
attack. So the idea of how often they
wound up in the emergency room is really
not easily analyzed since most of the patients were saved that visit.
DR. FLEMING: You showed us a series of fairly compelling
illustrations of the sequelae.
DR. FRANK: Yes.
DR. FLEMING: My understanding is those were severe.
DR. FRANK: Yes.
DR. FLEMING: And you emphasized in particular in the
settings of the abdomen attacks and the laryngeal attacks how important the
sequelae can be.
DR. FRANK: Yes.
DR. FLEMING: As it relates to ER visits, hospitalizations,
life-threatening episodes. Just a simple
question. How many of the attacks that
occurred in this trial had, in fact, or were associated with ER visits,
hospitalizations or life-threatening episodes?
DR. KALFUS: None of the subjects who actually presented
with laryngeal attacks were failed therapy, failed treatment, with C1
inhibitor. The only subjects who were
hospitalized during the course of the study, slide up please, were those
serious adverse events. Every other
subject who was treated actually did not require hospitalization and, in fact,
some of these adverse events were not related at all to Cinryze treatment. They were related actually to the inability
of a subject to obtain Cinryze because they may have been traveling or they
presented to an emergency room which did not have Cinryze.
DR. FLEMING: It's always difficult to sort out what is, in
fact, truly disease-related and treatment-related which is the importance of
randomized controlled trials. So what you're
saying is at most the number of the attacks that were in fact linked to or had
ER visits, hospitalizations or life-threatening would be four and you
potentially lessen that because some of these may not have been related to
attacks.
DR. FRANK: No, I'm saying that these were the most --
These were the number of patients who were hospitalized. There were some clinic sites or physician
sites which actually were directly related to hospital settings where treatment
was given in emergency room. These
subjects were actually instructed not to go to the emergency room, to go their
physician's office first unless they felt it was life-threatening and there was
no other choice. Their first options --
DR. FLEMING: So just a simple answer, were there events in
the attacks? In all the attacks, that
we've been analyzing, were any of those attacks involving ER visits,
hospitalizations or viewed as life-threatening?
DR. KALFUS: Yes, we were, but we didn't break down that
data because an emergency room visit for a treatment where the site was the
emergency room is not really an emergency room visit. It's going to your site to be treated just
the same as if you were going to a clinician's office that was across the
street from the hospital. The study
wasn't designed to capture hospitalization, emergency room or treatment. The study was designed to just capture the
total number of attacks.
DR. FLEMING: Well, then there are two other related
questions. One is these four events
occurred. I realize it's difficult here
to assess safety because everybody is being treated. But do these events occur during the period
when the person was on the control or on the active?
DR. KALFUS: All these events we can go through them
individually.
DR. FLEMING: You don't have to. Just the global answer.
DR. KALFUS: No, these -- Slide up please. The first event is post prophylactic
treatment period. The second, the
lymphadenopathy, was post prophylactic and the
HAE attack was while on placebo.
The third was on placebo and the last one was prior attacks or
randomization into the prophylactic treatment period.
DR. FLEMING: So three of these people were on active or
had been on active when the events occurred.
DR. KALFUS: Had or had already completed being on active
treatment.
DR. FLEMING: And the last question is you've coded all the
events as severity one, two, three. I've
already mentioned this is not a linear scale.
So it really would be of interest to analyze your data based on reducing
the rate of events that are severe. Have
you been able to produce that?
DR. KALFUS: I'd like to ask Dr. Blumenstein to come up
for a moment.
DR. BLUMENSTEIN: We are not able to deliver to you that
analysis at this time in a validated way.
It would be very complicated.
Could I have the diary please?
Slide up. I think it's useful for
you to see the actual instrument used to collect the data from the patients and
to recognize that we have really no validation of the quantification of the
risk as mild, moderate or severe and the primary endpoint is based on
distinguishing between the no column all the way to the left versus anything in
the other columns. So we don't really
feel that severe is necessarily something that's really quite distinct from that.
DR. FLEMING: I understand perhaps. But if one could take that one step further
and say there's lack of adjudication of all of these events, we're willing to
let that go. I'm willing to let that go.
I've been impressed by Dr. Frank's
presentation and his photographs, etc., that there is a diversity of severity
that's real and this is at least making attempt to capture it. So giving credence to this, it would be
relevant to understand what do the data show when you look at severe events. I won't keep pressing it. It sounds like you don't have that on your
fingertips.
DR. BLUMENSTEIN: Well, it would be very difficult to program
that and deliver it to you in a validated way in this short time.
DR. FLEMING: Okay.
I might have thought it would have already been done given Dr. Franks's
recognition of the severe events, but we can go on.
MR. BABLAK: I'd just like to add one more thing to that. During each phase of the study, patients were
asked to go in and get open label treatment.
So the idea was to prevent the attacks from getting to be severe. So that also complicates the analysis of --
DR. FLEMING: Understood.
But your case that you're trying to make here is that there's benefit
and benefit to risk for prophylaxis beyond treatment. You're going to make the case at a different
advisory committee about treatment, although you have presumed in your design
of the trial that treatment is effective and so the assessment here is
prophylaxis against treatment alone and now we're trying to understand. That's what the study design is. So let's look at what the relative merits are
within that design.
CHAIRMAN SIEGAL: Are there any other questions?
Then let's hear from Dr. Basil
Golding at FDA about the FDA's position.
Dr. Boris Zaslavsky has consented to let Dr. Golding present all the
data.
C. FDA REVIEW OF
CLINICAL DATA
DR. GOLDING: Good morning, everyone. We are talking about C1 Cinryze inhibitor,
the product produced by LEV Pharmaceuticals.
Just very briefly, the regulatory
chronology, the company was signed off on drug destination for the treatment of
angioedema. They were also given fast
track destination on
In terms of clinical studies, the
Applicant conducted two studies, two Phase 3 randomized, double blinded
studies. The treatment study they called
Part A of HAE attacks and this was in 71 subjects with -- angioedema and the
prophylaxis study they called Part B and this was for prevention of HAE attacks
and that study has you have heard had 22 patients. They also performed a randomized parallel
group, open label pharmacokinetics study.
In the treatment study, the Part A,
this study is still under FDA review and will not be discussed before this
advisory committee. The Part B or
prophylaxis study we think has demonstrated safety and efficacy for the
prophylaxis indication and is the subject for today's discussion.
So the prophylaxis study objectives
and endpoints, the objective was to investigate the efficacy and safety of
Cinryze as a prophylactic treatment to prevent HAE attacks. The primary endpoint, the number of attacks
of HAE during active and placebo treatment phases of 12 weeks duration
normalize for the number of days the subject participated in this phase using
each subject as his or her control.
The secondary efficacy endpoints
were the number of subjects dropping out during each treatment period, the
average severity of attacks, the average duration of attacks, the number of
open label C1 inhibitor infusions, the change from baseline in C1 inhibitor
antigenic and functional labels.
So brief synopsis of the study
procedures for the prophylaxis study, subjects who had completed treatment of
acute attacks and who had demonstrated a high frequency of HAE attacks equal to
or more than two per month were enrolled into the prophylaxis study. Twenty-four were enrolled and two dropped out
leaving 22 patients.
Subjects were randomized to 12 weeks
prophylaxis with either 1,000 units of C1 inhibitor or placebo. They were infused twice weekly at the study
site. This was followed by a crossover
to 12 weeks prophylaxis with the other study agent.
HAE attacks of any severity were
recorded. Subjects in either arm could
receive open label C1 inhibitor 1,000 units during acute attacks while on the
prophylaxis part of the study.
Safety monitoring for the
prophylaxis study, adverse event information was collected at each visit. In addition, they had diary cards and weekly
telephone calls to collect information on HAE attacks and adverse events and
viral safety was monitored at a three month follow-up visit after the final
prophylaxis treatment.
The pharmacokinetic studies which
were interpreted at CBER by Dr. Camahmood, I won't go through it in
detail. But the point is that they do
both single dose and double dose and you actually saw graphs of these data in
the LEV presentation and the values are corrected for baseline. What I think I would focus on is the
relatively long half-life of this product and the clearance start, the
relatively long clearance start.
So the PK of Cinryze in subjects
with HAE indicates that the drug has a long half-life and slow clearance and
the long half-life indicates or at least suggests that a dose schedule of two
administrations per week is reasonable and would likely result in C1 INH levels
greater than 40 percent of normal which are generally regarded as levels
sufficient to avoid attacks.
The demographics for the study,
there were 22 subjects. The age, the
median age, was 38.5 years, the range nine to 73 years. There was obviously a gender imbalance. There were two males and 20 females and,
ethnicity, there were 21 Caucasians and one African American.
So if you then look at the results of
the prophylaxis study Cinryze has the stable where this is just descriptive
statistics where they look the mean number of attacks in the treatment arm and
the mean number of attacks in the placebo arm and you can see there are about
half the number of attacks on average in the treatment arm and these are other
just descriptive statistics without being subjected to a statistical test. These descriptive attack frequency data were
obtained by pulling data during active or placebo treatment phases.
The primary endpoint was to actually
do an analysis looking at each patient as his or her control. The analysis performed was ANOVA. The treatment was shown to be effective at a
highly significant P value and is not confounded by sequence and period
effects. So the treatment effect has
this P value and the sequence and period effects are not significant. FDA has verified these calculations showing a
highly significant treatment effect.
We took the data and presenting it
now as a histogram showing the number of subjects on the Y axis and the
reduction of frequency of attacks on the X axis. So, for example, patients who had a reduction
of frequency between 91 percent to 100 percent, these are all ten percent bins. But at the top end here, the patients who had
the best response and falling into this bin, there were four patients in that
bin. There were four patients in the bin
to the left of that. But then you see
there are some patients that had a relatively poorer response and there were
actually two patients that had more attacks on the treatment arm than in the
placebo arm. And there were some
patients who obviously had a very mild effect in terms of the treatment
response. In other words, there's not a
uniform response to this product during the prophylaxis treatment.
And then summarizing the slide,
treatment with Cinryze resulted in varying reduction in HAE attack
frequency. So of 45 percent of patients,
ten out of 22, had a reduced attack frequency of greater than 75 percent. Thirty-two percent, seven out of 22, had
intermediate reductions in attack frequency.
That's in 25 to 75 percent range of reduction. Eighteen percent of patients, four out of 22, had modest reductions, one to
25 percent reduction in attack frequency.
And two individuals, nine percent, had more attacks with Cinryze than
with placebo.
FDA also independently evaluated
some of the secondary endpoints. The
more critical ones we think we are presenting here. We looked at attack severity as a secondary
endpoint and agree with the sponsor that this is highly significant. We also looked at the duration of attacks and
agree that this is highly significant.
So FDA found both severity and duration of attacks to be reduced at a
statistically significant level comparing Cinryze to placebo.
What are the conclusions in terms of
efficacy? The prophylaxis arm met its
primary and secondary endpoints for efficacy. Patients, however, did not
respond uniformly suggesting that dosing may not be optimal for some patients
and Phase 2 dosing studies might have helped find a more uniformly effective
dose.
In terms of the gender imbalance,
there were 20 females and two males. The
uneven gender distribution in this study for an autosomal dominant disease may
be due to estrogen predisposing females the more frequent attacks and female
advertence prevent the therapy with attenuated androgens and possibly this
relates to more females being enrolled in this study.
The FDA efficacy overall conclusion
is that Cinryze has been demonstrated to be effective for prevention of HAE
attacks when used for prophylaxis in persons with heredity angioedema.
Let's look at safety and
particularly safety during the prophylaxis trials. But during the prophylaxis trial, the
patients were monitored much more closely.
We did in our issue summary summarize safety in the acute treatment
trial and for the Cetol product that was available in
So the adverse events that we saw,
there were 81 total events in 20 patients on Cinryze and about half the number
of or less than half the number of total events in 13 patients on the
placebo. Why this discrepancy? Well, there was open label use of C1
inhibitor for acute attacks which increased the number of total infusions from
Cinryze to placebo, so 1190 infusions of Cinryze versus 526 infusions of
placebo. So if you correct the events
per infusion, you end up with identical fractions. So we don't think that this is a cause for
concern and we think that the number of events was similar on placebo and on
Cinryze when you correct for the number of infusions.
As already mentioned, there were
four serious adverse events attributed to HAE attacks and not related to study
medication. One actually of these was
pointed out to be a lymphadenopathy.
There were not deaths and there were no signs of hypersensitivity type
drug reactions.
So the safety conclusions that the
FDA made is that the adverse events appear to be related to intercurrent
illnesses and the underlying disease rather than being due to treatment with
Cinryze. Cinryze appears to have
acceptable safety profile for prophylaxis of HAE attacks when administered
according to the proposed label dose schedule.
Since prophylaxis involves repeated and long-term treatment, post
marketing safety monitoring may be required.
Immunogenecity, I'd just like to say
as a general point for any protein therapeutic based on recent history, for
example, with erythropoietin, I think a very strong argument can be made for
all protein therapeutics having to have both pre marketing and post marketing
studies for immunogenecity.
Immunogenecity was evaluated in Part A and in Part B and there were some
issues with the laboratory results.
In the first laboratory that was used,
a large number, unanticipated number, of subjects, 93 out of 329, were deemed
as being antibody positive, 28 percent, on screening or preinfusion. Retesting some of these samples gave
inconsistent results. So the some that
were positive then became negative and visa versa.
So what the sponsor did is took a
sample from these subjects. One hundred
and nineteen samples were then sent to a second laboratory and retested in the
second laboratory and when you compare the testing in the first laboratory and
the second laboratory you find a very big discrepancy. In the first laboratory nearly half of these
samples were positive. In the second
laboratory, very few were positive.
The sponsor then sent some samples,
another subset, a much smaller subset of 11 samples, to a third laboratory and
again if you compare this to the testing in the first laboratory, there's a
major discrepancy. You see nearly half
of them are positive in the first laboratory and none of them were positive in
the second laboratory.
So this is an ongoing discussion
between us and the company which has not yet been resolved. But there were some issues here that do need
further clarification and that the FDA will work with the company to resolve those
particular issues.
Our conclusions regarding
immunogenecity are as follows. The
results from the first laboratory were not confirmed in two other labs. Since these are binding assays, not
functional assays, it is not known whether these purative antibodies have
neutralizing activity. There was no
evidence from the trial that the purative antibody that was correlated with
adverse events or treatment effects of Cinryze and we think this is
important. However, we think that most
post marketing studies may be needed to resolve this issue.
So I'm just doing to again mention
the questions to the Committee. I know
that afterwards there's going to be discussion before you answer these
questions, but the first question is is the safety and efficacy evidence
sufficient for approval of Cinryze for prophylactic treatment of HAE and the
second question, if the answer to question one is yes, is should post marketing
studies be performed to further evaluate the following: the optimal dose for
prophylaxis in males and females; immunogenecity; and long-term safety.
Thank you for your attention.
CHAIRMAN SIEGAL: Thank you very much, Dr. Golding.
Are there any questions for Dr.
Golding from the Committee? Dr. Fleming.
DR. FLEMING: Could we go back to your slide where you
talked about the active arm essentially getting twice as many doses as the
control which does, in fact, reflect the fact that since everybody is getting
treatment intervention and the number of doses that are given, average number
of doses, rescue so to speak, a treatment, are 15.4 against 4.7 that you end up
with not a contrast of 1190 versus zero but 1190 versus 526? So when it comes to a safety assessment and
you're trying to determine whether or not the product is safe a design like
this is potentially, well, is going to underestimate what the safety risk is
because the control arm is getting a lot of doses.
Your analyses seem to be saying that
there were twice as many doses in the active than the control. There were twice as many events. Therefore, we have safety.
Let me just use a more extreme
example. Suppose in an MS setting, Arm A
had twice as much Tysabri as Arm B. Arm
A has four cases of PML. Arm B has two cases of PML. Hence, Tysabri is safe. Nonsense.
Tysabri is causing the PML. No
PML would be occurring in the absence of Tysabri in an MS patient.
So the fact that we have twice as
many events occurring in the arm that has twice as much dose doesn't mean the
agent is safe. What it means is you're
probably -- In fact, one approach would be to say if all events that were, in
fact, occurring are treatment related and not dose related, not disease
related, if everything is treatment not disease related, then what you're
seeing is a dose response.
But I'm not willing to conclude that
every adverse event that occurs here is due to treatment. Some of it, in fact, is due to disease. But this analysis doesn't give me a
reassurance that the agent is safe. How
is it that you're concluding that that this is what this is saying?
DR. GOLDING: Well, when you look at the actual adverse
events and that's part of your handout in the issue summary and you look at the
type of events that occur.
DR. FLEMING: Yes.
DR. GOLDING: So as already alluded to by the sponsors,
most of the events are upper respiratory type of events, sinusitis and other
types of events, it seemed to our reviewers and myself to be really
intercurrent illnesses.
Now if you have someone presenting
to a doctor and on a very frequent basis and they are common intercurrent
illnesses that these people have, then it's likely that the more they come to the doctor's office the
more often they're going to say I have an earache or I have a sore throat or I
have a sinusitis. We then -- We weren't
able to pick out particular types of clusters of adverse events that in our
minds could be related to the actual treatment or different in nature to what
was happening in the placebo group.
DR. FLEMING: So if, in fact, what you have are events that
are truly disease related, then when you give more doses you shouldn't get more
events.
DR. GOLDING: Well, I didn't say they were all
diseases. I said intercurrent
illness. So a lot of them, most of them,
are intercurrent illness, not HAE related, but intercurrent illness, you know,
mild infections.
DR. FLEMING: So what this is telling me is that you have
twice as many events even though the placebo arm is getting half the doses that
the intervention arm is getting. So
we're underestimating what the actual true treatment related number of events
would be.
DR. ZIMRIN: Can I get in here? I follow patients. Maybe you don't. But when you see patients, they come in and
they tell you about things that are happening to them. They tell you about their colds. They tell you about falling down the stairs. They tell you about things and if these are
recorded as adverse events, you will see them.
So I think you might be making a
little bit too much of these numbers.
Looking at the type of adverse events that we were seeing --
DR. FLEMING: How does that differ? What you're saying is in any trial when we're
assessing safety, we're getting that evidence from patients. We're making too much of safety data?
DR. ZIMRIN: Well, you have to look at the adverse events.
DR. FLEMING: Understood and I --
DR. ZIMRIN: I just think PML is something different than
a cold and I think --
DR. FLEMING: Understood and that's why I used an extreme
example just to make the point that when you have twice as many events for
twice as many doses it doesn't mean the treatment is not inducing the events. But my next question was getting at
no data has been given to us on how these break out as moderate to severe
events. Are all of these mild events in
which case it is much less of a concern?
DR. GOLDING: Well, you were told by the previous speaker
and myself that there were four --
DR. FLEMING: Four SAEs.
DR. GOLDING: Four SAEs.
DR. FLEMING: But that's separate. I'm asking moderate to severe. So all of these CRF-based AEs are going to be
coded as mild, moderate, severe. So are
these 117 events that we're seeing, are they all mild? How many of them would be coded moderate or
severe that might be of more clinical concern?
DR. GOLDING: Well, you know, I'm just talking from memory,
but most of these events were relatively mild.
The types of events as I said were mainly intercurrent. The only ones that were bordering on moderate
were ones that were related to the underlying disease. So patients who had swelling during, say, the
placebo phase and then came in for treatment, they would be scored as having
swelling and because they were getting the drug that would be scored as being a
moderate or an event occurring during treatment with the Cinryze. So even during the placebo arm, you were
scored as having drug related effect related to the Cinryze if you received
open label treatment.
DR. FLEMING: I'm not even looking at how we attribute
relatedness. I'm just looking for a very
traditional CRF-based characterization of events as mild, moderate, severe. Has anybody tabulated these according to
severity, i.e., numbers of events that are moderate or severe?
DR. FINNEGAN: Slide 68 in their presentation has the list.
DR. FLEMING: In the?
DR. FINNEGAN: In the sponsor's presentation.
DR. FLEMING: Right, and that's listing the total number of
adverse events by body system or by type and then there are SAEs. But in between those two categorizations
there would be moderate to severe adverse events.
DR. CRYER: Moderate to severe back pain?
DR. FLEMING: Yes.
Every event here that you would have would traditionally be coded as
mild, moderate, severe and so to really get at my colleague's point that while
there may be excess events, these may not be events for which there is
substantial clinical relevance. If
they're coded as mild, that's true.
So the question is how many of these
events and how do they break out by treatment arm that are moderate and severe,
which is a separate issue from totality of AEs and just these four SAEs.
CHAIRMAN SIEGAL: Do you have a response?
DR. KALFUS: Slide up please. These are the nine treatment emergent events
that occurred in five subjects with the prophylactic treatment trial that were
listed as definitely, possibly or probably --
DR. FLEMING: I'm sorry.
I'm not looking for relatedness.
I'm looking for severity. So
traditionally in any trial, you're going to characterize CRF-based events
according to relatedness and according to mild, moderate, severe.
DR. GOLDING: I must say.
I don't think that's traditional.
I don't think that's uniform. It
might be done independently in a particular study. Serious SAEs of course fall into another
category. But as somebody who makes my
living doing clinical trials, these things are not routinely graded by severity.
DR. FLEMING: Well, I've monitored 200 trials on data
monitoring committees across all disease areas and we always code two sources
of events, the regulatory-based SAE reporting system and you've given us that
and the CRF-based coding system for adverse events and every trial I've ever
monitored would code them as mild, moderate, severe. And the issue is exactly as my colleague is
saying. If the events are mild, they have
much less clinical relevance.
DR. FINNEGAN: Can the sponsor tell us how many patients
listed on 68 had to be hospitalized for their adverse event?
DR. KALFUS: Can I have core slide 68?
Slide up please. Slide up please.
Actually, looking at these, the only
possible ones that were hospitalized were the two for HAE. I don't recall whether those two subjects
actually were hospitalized with HAE. But
I would imagine that they might have been hospitalized for them to be listed as
HAE. But again, this is data that was
filled out by a physician. As said
earlier, patients are being seen by clinicians.
I would like to go back to SA 12
before, the slide that we had up a moment ago.
In our study, the analysis that we did, we actually looked at those
adverse events that were definitely, possibly or probably related and we grouped
them and then listed them, if you look at the slide, mild, mild, moderate,
moderate, mild, mild, severe, moderate, moderate. These are the only ones that were mild,
moderate and severe and they were listed because they were definitely,
possibly, or probably related to the study drug.
DR. ATKINS: There is an Appendix 3 that lists all the
SAEs and all 81 of them in our briefing document and just looking over the
distribution from placebo to treatment I don't -- there may be something in the
total number of infections and infestations.
There could be a trend. But it
doesn't seem that there's any statistically -- I mean, that there doesn't seem
to be an imbalance between the two groups as far as one could look at.
DR. FLEMING: There are -- And I hear your point and there
are a number of subcategories where nervous system infections, GI, etc., that
show up in excess and this is what's accounting for the fact there were twice
as many. This may not be a problem if
these are all mild. But it would be traditionally
recorded as to whether they're moderate or severe.
CHAIRMAN SIEGAL: All right.
If there are no more pressing questions, perhaps we should move to the
open public hearing. Dr. Szymanski.
DR. SZYMANSKI: In your table, these dose effects, you have
two limbs injuries. I hope that these
people didn't lose their limbs or anything that severe.
DR. KALFUS: These were limb injuries. For instance, one person hit his thumb with a
hammer. These were not life threatening. These were just life living injuries.
CHAIRMAN SIEGAL: Anybody else?
DR. DI BISCEGLIE: I would like to ask the sponsor. They had showed data in the preclinical work
about NAT testing of the product for various viral agents, but I did not see
Hepatitis B alluded to and we were also told that there was no seroconversion
but not told what actual tests were done for HCV, HVV and HIV.
DR. KALFUS: In the preclinical work on the product in
terms of the viral safety, could I have the back-up slide for -- There's a
variety of, slide up, model viruses and actual viruses that are used. So for Hepatitis B, the model virus is
pseudo-Rabies virus.
DR. DI BISCEGLIE: Well, I would say that donated blood is
routinely -- Every pint of donated blood is tested by NAT for Hepatitis B. We don't need a model. You just test for it.
DR. KALFUS: All the units before they go into pooling are
tested for Hepatitis B, Hepatitis C.
DR. DI BISCEGLIE: By what assay?
DR. KALFUS: The Hepatitis B is tested with the surface
antigen assay.
DR. DI BISCEGLIE: Donated blood is routinely tested by
NAT. Surface antigen testing is not
sufficiently sensitive. That's why we
use NAT.
DR. GLYNN: I'm sorry.
Not for Hep B. For Hep B it's the
HBS antigen and the anti-core.
DR. DI BISCEGLIE: My mistake then.
DR. EPSTEIN: We have licensed NAT tests for Hepatitis B
but we have not at this point recommended their routine use as donor streams,
the reason being that the added sensitivity compared to the more sensitive
HBsAG assays has not warranted that intervention as a public health
measure. This field may evolve because
the tests that are practical to use are mini-pool tests and really there isn't
a significant public health advantage unless the system can tolerate individual
sample testing by HBV NAT and maybe that lies in the future.
But at the present time, neither --
or making transfusable components nor source plasma is routinely screened by
HBV NAT. There is a small number of
centers that participate in the HBV NAT trials who have continued to use them,
but it's not routine.
DR. GLYNN: I just wanted to know if we could look again
at the slide that was presented before in terms of the possibly related and if
someone could go over that again.
DR. KALFUS: Slide up please.
So when it says days last Cinryze
that's because it was reported on the same day of the subject's office
visit. So these were subjects who
actually presented to a physician's site either for a open label treatment for
an acute attack or for the regularly scheduled prophylactic injection during
the treatment study and when asked by the physician how are you doing or if
something is going on if there was a reaction this is what it is.
So the first one had some pruritus
and a rash and the physician thought that this was definitely related to study
drug and they were both mild. The next
one is some lightheadedness which he viewed as moderate. We know this resolved shortly after the
injection and was possibly related. It's
been reported in the European literature and it's common knowledge that what
really happens when this drug is administered, we did it at 10 cc per minute in
our, I'm sorry, 10 cc, one cc per minute and 10 cc over ten minutes and what is
known is that if the diluent is not at room temperature and it's cold or if
it's given excessively fast, then there are subjects who have reported feeling
a sense of lightheadedness or a sense of feeling a little flushed when getting
an intravenous administration that's cold.
If anyone of you have actually received an IV injection, you're very
sensitive to the temperature of the IV that is actually being given whether
it's an infusion or slow push.
The next one was a fever. The subject had some fever on the day of the
administration. This was judged as
possibly related. This was judged as
moderate because it was a fever as opposed something that was less severe and
more mild. These were subjects that were
all receiving Cinryze.
The next set of adverse events were
subjects that were actually receiving placebo on the day of their event. The evidence of C1 inhibitor antibodies
actually we discussed. These subjects
actually upon repeat testing did not have presence of C1 inhibitor antibodies. The reason it's listed is because these
bloods were drawn on that regular rescheduled visit for that patient. That patient was due to have antibodies drawn
for that day and it was just the lab value that came back. Of course, we have repeated many of these tests. This is one of the tests that repeatedly is
negative.
The last one is a subject who had
some chest discomfort and a cough. This
was a patient who had bronchitis and upper respiratory infection. It was coded by the clinician as definitely. I'm not sure if this subject actually had a
reaction to Cinryze. It was clear that
the patient did have a cough and bronchitis and on a different admission had
some erythema which was also put as moderate and was possibly related.
CHAIRMAN SIEGAL: Just a point of clarification, these patients
all were continued on the trial and rechallenged?
DR. KALFUS: Every subject continued on trial. There were no subjects who actually withdrew
from the trial for any sort of adverse event during the course of treatment.
CHAIRMAN SIEGAL: Thank you.
DR. APTER: There were only three patients really though
because two of the patients are in both groups.
Right? Aren't the ID numbers the
same?
DR. KALFUS: The ID numbers are the same. That's correct.
CHAIRMAN SIEGAL: Are there any other questions?
MS. TROXEL: To follow up on that, could you tell us about
those two patients who didn't make it into this analysis of 22 subjects? What were they initially randomized to and
what were the reasons for their withdrawal?
DR. KALFUS: Certainly.
One of the subjects was a subject who was randomized to placebo. The other one of the subjects was a subject
who was randomized to Cinryze. Slide up
please.
This subject was randomized to
placebo. You want to know about the subjects who withdrew in Part 2 or
the subjects who withdrew from the first treatment period?
MS. TROXEL: Yes, the two subjects who weren't included in
the overall analysis that were initially randomized. So I guess withdrew in the first period.
DR. KALFUS: Slide down please. There were two subjects who withdrew prior to
crossover. Slide up. This subject withdrew -- slide up. This subject withdrew while on the placebo
arm. The reason this subject withdrew
was because it became very difficult for the subject to actually go to the
clinician office. The subject lived at a
greater than two hour drive to the clinician office, had a very young child,
was a young mother and just could not make the appointments.
Do we have the slide for 17001? All right.
Slide up. Slide up. This subject withdrew while on the Cinryze
arm. Basically this subject had
tremendous difficulties in actually making appointments. There are large gaps. There were major protocol deviations. There were seven to nine to ten day periods
where the subject was not showing up for their regularly scheduled injection.
Can I have the slide that shows all
four withdrawals please? Slide up.
These are all four withdrawals
demonstrated where they were during the course of their treatment. The two subjects who withdrew in the second
period, one subject withdrew because it became impossible for her due to
personal reasons to continue coming to the clinician office and that was a
subject who was on the Cinryze arm on the Cinryze period.
And the subject who was being
treated with placebo withdrew because of severe intercurrent illnesses. An elderly patient with multiple medical
problems who found it quite difficult to go to the clinician office for placebo
treatment and then continue her follow-up medical care.
Slide down.
DR. FLEMING: Just quickly since you're showing cases. Can you show the two cases for the males
since you have only two males just to give us a sense of what benefit looked
like in those two? Which ones were the
males?
DR. KALFUS: Certainly.
We had two subjects who were males in the study. Slide up please. Slide up.
Similar to the format we used
earlier, the males are the subjects that are in the first two lines. One subject had a response that had
absolutely no further attacks. Another
subject actually had a diminishing of attacks but did not do as well. Can I have the bar graph for 52001? Slide up.
This particular subject had one more
attack, but still showed improvement during the course of treatment with this
particular -- while on the Cinryze arm.
She had attacks of fewer severity, less days of swelling and a fewer
number of attacks with just one aspect of a mild increase of duration.
CHAIRMAN SIEGAL: Okay.
Are there any other questions?
One last question.
DR. DI BISCEGLIE: Sorry.
But we're going to have to discuss the second question, the issues
related to the question of dosing. So
I've heard discrepancies between what Dr. Golding said that the dosing was such
to get about 40 percent of the effective level and I've heard the sponsors say
that there is no known effective level, that there's not a really good
correlation between the serum level achieved with the therapeutic agent and the
benefit. So I'm a little puzzled by that
still.
CHAIRMAN SIEGAL: Perhaps we will have time after the open
public hearing for more discussion, of course, and I'd like to defer that at
this time if you don't mind.
OPEN PUBLIC HEARING
CHAIRMAN SIEGAL: All right.
So I have to read a statement before the open public hearing. The announcement of particular matters that
are product specific. Both the Food and
Drug Administration (FDA) and the public believe in a transparent process for
information gathering and decision making.
To ensure such transparency at the open public hearing session of the
Advisory Committee meeting, FDA believes that it is important to understand the
context of an individual's presentation.
For this reason, FDA encourages you,
the open public hearing speaker, at the beginning of your written or oral
statement to advise the Committee of any financial relationship that you may
have with the sponsor, its product or and, if known, its direct
competitors. For example, this financial
information may include the sponsor's payment of your travel, lodging or other
expenses in connection with your attendance at the meeting. Likewise, FDA encourages you at the beginning
of your statement to advise the Committee if you do not have any such financial
relationships. If you choose not to
address this issue of financial relationships at the beginning of your
statement, it will not preclude you from speaking.
MR. JEHN: Yes, Mr. Chair. At this time, we have seven speakers who
requested to speak for the HAE community and one from Nord. I'd like to limit to five minutes each. So let's go ahead and start with Anthony
Castaldo.
MR. CASTALDO: Good morning.
My name is Anthony Castaldo and I'm the President of the United States Hereditary Angioedema
Association and also the President of Hereditary Angioedema International. By day, I'm the Assistant Inspector General
at the Board of Governors of the Federal Reserve System here in
Even though the Federal Reserve is
an independent entity, we comply with the rules set forth by the Office of
Government Ethics. Therefore, let me acknowledge
that statutes covering the ethical conduct of government employees preclude me
from representing a third party at this governmental gathering today. As a result, to ensure strict statutory
compliance, let me say for the record that notwithstanding the fact that I'm
the President of the U.S. HAE Association and we have identified 4500 HAE
patients who we represent in addition to 1100 doctors who treat these patients,
let me state for the record to ensure strict statutory compliance that I appear
before you today only representing myself and my family members who have severe
HAE.
I thank you for providing HAE
patients with an opportunity to discuss the critical need for a safe and
effective non-steroidal HAE therapy. I
do not have any financial ties to LEV Pharma and I am not a shareholder.
Perhaps the best characterization of
how HAE affects patients appeared in the 1996 New England Journal of
Medicine article and I quote "Patients with a deficiency of C1
inhibitor are not just an interesting model for study. They are critically ill and many have
ancestors who died suddenly from suffocation.
Patients live in constant dread of life-threatening laryngeal
obstruction."
It is both ironic and sad that the
very same volume of the New England Journal of Medicine published 12
long years ago also contained a paper referred to today authored by Dr. Frank
that summarized the results of a double blind, placebo controlled crossover
study that demonstrated safety and statistically significant efficacy of a C1
inhibitor concentrate product for both prophylaxis and the acute indication.
Ladies and gentlemen, hereditary
angioedema represents a catastrophic unmet medical need in the
Moreover, the utility of these
agents is limited because they are not well tolerated by women, are directly
linked to increased serum lipid levels and their use is contraindicated in
children, many of whom tragically are severely affected and suffer frequent
severe attacks. Is it not paradoxical
that 350 lb. NFL linemen are suspended and counseled on the extreme danger,
toxicity and undesirable long-term side effects posed by relatively short
courses of the same drugs that our patient community is forced to use on a
chronic basis?
We are delighted that the Committee
will be considered the prophylaxis indication today. To be sure, prophylaxis will serve to finally
ameliorate HAE's dreadful morbidity.
Nevertheless, prophylaxis will only address a portion of the problem
faced by HAE patients. As noted earlier,
the scientific literature provides ample evidence that patients can have
breakthrough, life-threatening attacks or excruciating abdomen or laryngeal
attacks no matter what therapy they are using.
HAE is indeed a very unpredictable
disease. Moreover, why should a patient
who only has one attack a month or less be forced to take androgens every day
when documented experience from hundreds of patients in Germany, Denmark and
the Netherlands demonstrate that less severely effected patients prefer to
manage their HAE by working with their physicians to set up an on-demand C1
inhibitor program for acute attacks and I think Dr. Marshall Levi from the
Netherlands actually has published data on that very fact.
You have before you today a
preponderance of evidence demonstrating that the LEV Pharma C2 inhibitor
product is both safe and effective. We
hope that the Committee recognizes that everyone in beleaguered patient
community deserves the opportunity for access to a non-steroidal alternative
that provides relief from this catastrophic unmet medical need.
Thank you.
MR. JEHN: Sally Urbanic is next.
MS. URBANIC: Thank you.
Good morning. My name is Sally
Urbanic and I live in
I do not have any financial ties to
LEV Pharma. I am not a shareholder. And the HAE Association paid for my travel
here today.
I'm going to take a slightly
different approach during my time here with you this morning. Let me start by asking each of you to step
out of your role as medical professionals and from the next couple of minutes
think of me as your sister or your daughter.
I cordially ask you to spend a few moments living a life of a severely
affected HAE patient.
Imagine waking up one morning and as
you get out of bed, you realize your feet are so swollen that even a short walk
to the shower is going to be painful.
When you stand up, your feet feel like they are ready to explode from
supporting your body weight. But soon
you have no choice rather to get up and get moving because a sharp pain in your
stomach signals a sickening and urgent need to throw up. The fluids which cause the swelling leaked
out of your circulatory system and your blood pressure is very low. The lightheaded, faint feeling you're
experiencing makes you wonder if you can even make it to the bathroom before
passing out.
You want to ignore the dangers of
not seeking medical help for what you know is going to be a miserable
attack. You want to just stay home and
tough it out, but then the next wave of excruciating pain hits and your spouse
intervenes and convinces you to make yet another trip to the emergency room for
fluids and pain medicine. You are so
weak you can barely muster the strength to call in sick at work, but you have
to and when you do you can sense your boss's frustration in the tone of his
voice because this is the second time you've called out in the last week and a
half.
On the way to the hospital, you
start thinking of how you're going to handle the emergency room staff's
not-so-subtle questions that all but directly accuse you of being a drug
seeker. You are so weak and sick at this
point, but you know the endless questions are coming.
Before you even arrive at the
hospital, your swallowing becomes difficult and it feels like your throat is
swelling. You're somewhat content that
the car is just dark enough that your spouse besides you doesn't notice how
frightened you are of your throat closing.
When you finally arrive at the
emergency room, you say a silent prayer that the next 72 hours will not be
filled with the fear of a doctor having to cut a hole into your windpipe
because your throat has swollen shut.
Ladies and gentlemen, this
represents my life before becoming part of the HAE Association program with the
C1 inhibitor. I am the poster child for
demonstrating the true impact of access to C1 inhibitor therapy. The C1 inhibitor product has totally
transformed me and my family. This
amazing medicine has allowed me to once again pursue my career and to be a wife
and a mom.
Thirty years of safe and effective
use in Europe and two successful
Thank you.
MR. JEHN: Darla Williamson.
MS. WILLIAMSON: My name is Darla Williamson. I do not have any financial ties to LEV
Pharma. I'm not a shareholder. I do work for the HAE Association.
I'm one of the hundreds of thousands
of HAE patients for whom 17 alpha alkylated androgens are not effective. During 23 long years of androgen therapy, I
suffered through countless emergency room visits or attacks that not only
involved excruciating abdominal pain but also involved my airway and required
more than a dozen laryngeal intubations and emergency tracheotomy.
I was disabled for the majority of
my adult life, but access to C1 inhibitor through LEV Pharma's open label
program has allowed me to finish my college degree. I've held a job now for well over a
year. I'm a living, breathing example of
why HAE patients in the
A tragedy that almost took my life
last February illustrates this point.
After receiving open label C1 inhibitor therapy for a number of months I
felt joy for the first time in well over a dozen years. I decided I was well enough to take a weekend
trip. I had what only can be described
as an ideal getaway until HAE fully asserted itself.
While on the way to catch a return
flight home, I realized I was experiencing a laryngeal attack and it was coming
on rapidly. My boyfriend noticed that I
was having trouble swallowing. So he
flagged down a police officer who called for ambulance. At the emergency room despite my objections,
the doctors treated me with medicines that HAE patients know do not work,
epinephrine and benadryl. They also tried
fresh-frozen plasma to no avail.
The advance of the swelling attack
and the baffled look on the faces of the ER staff made me fear for my life and
I prepared myself to die again. I told
my boyfriend tell my son that I loved him, that I was proud of him, that I was
sorry, to make the phone calls to my mom, to my sister. As I lay helpless with my airway tightening,
I remember coughing and then nothing else.
I spent the next seven days
intubated, sedated. My lungs had
collapsed. I lost the use of my legs
from being bedridden. I could barely
manage to sit up until day 11 when I managed to take three steps forward before
hyperventilating and fainting. I woke up
hearing doctors trying to decide whether or not to intubate again and telling
me I should consider a permanent tracheotomy.
After 19 days in the hospital and an
$80,000 bill, I was sent home with antibiotics to treat hospital-acquired
pneumonia and endured weeks of rebuilding leg muscles so I could walk
again. The tragedy is that this entire
situation could have been avoided by two vials of C1 inhibitor concentrate.
So as you deliberate approving the
LEV Pharma product today, I kindly ask you to consider patients like me who
need this therapy for both preventing and treating acute HAE attacks. Thank you.
MR. JEHN: Janet Long.
MS. LONG: Good morning.
My name is Janet Long. I do not
have any financial ties to LEV Pharma. I
am not a shareholder and the HAE Association paid for my travel here today.
I would like to provide the Committee
and FDA staff with a perspective of a typical HAE patient who endured countless
years of suffering before getting a proper diagnosis. Unfortunately, I do not live close enough to
participate at a LEV Pharma clinical trial site. So I must rely on androgens to maintain the
semblance of normal life.
I would like to begin my remarks by
providing a specific case history that illustrates why HAE is a catastrophic,
unmet medical need in the
At age 21, I experienced an
abdominal episode that was so severe it caused internal bleeding which led to
an unnecessary exploratory laparotomy and days in the intensive care unit. Despite this catastrophic event, no one could
figure out what was wrong with me and the ensuing years brought nothing but
ceaseless agony including laryngeal attacks that came close to completely
closing my airway. I saw scores of
doctors who either admitted to being totally baffled or offered diagnostic theories
that at least to me never seemed to make much sense.
Over the years, I continued to
suffer and I felt helpless, hopeless, caught in the grips of a mysterious
illness that no one including me understood.
I got tired of showing up at the emergency room only to be sent home
after being told that nothing could be done and that I would have to learn to
live with my condition.
In light of these distressing
experiences, I chose to endure the excruciating pain and discomfort associated
with abdominal attacks at home where at least I was in familiar
surroundings. In retrospect, I realize
that might not have been the best medical idea, but at the time I felt trapped
and again hopeless and I resigned myself to an unknown fate.
I remember vividly one particularly
devastating attack that had me curled up in agony. The pain and the nausea and the vomiting had
become so unbearable I was convinced I was going to die. I faced what I believed was the very real
possibility that my three beautiful
young daughters would be left motherless and through my tears, I told my
husband if I don't make it through the night please tell the girls that I loved
them.
Finally, after almost 40 years of
horrific suffering with a prospect of living getting bleaker as the attacks
continued unabated, a brilliant gastroenterologist unraveled my mystery and
came up with a diagnosis of hereditary angioedema. I have been on androgens ever since and daily
endure the unfortunate and embarrassing side effects one would expect for a
woman on long-term therapy with a potent male hormone.
Today you have before you two
separate double blind placebo controlled studies that provide statistically
significant evidence of something European doctors and patients have known for
over three decades. C1 inhibitor
concentrate has amassed a remarkable safety record and is the unequivocal gold
standard treatment of hereditary angioedema.
This Committee's recommendation for
approval and swift action by the FDA staff will prevent other mothers from the
fear of leaving their children behind and assure that no one else has to endure
40 years of lonely and horrifying pain.
The evidence is compelling. The
need is overwhelming and any further delay in helping this under-served patient
community would be tragic.
Thank you so much for allowing me to
address you today.
MR. JEHN: Beth Mercante.
DR. BARAKAT: Good morning.
My name is Dr. Amin Barakat. I'm
Clinical Professor of Pediatrics at
I'm here today to provide the
Committee and the FDA staff with the viewpoint of a physician who witnessed the
severity of HAE disease and who supervised a severely affected patient on open
label prophylaxis therapy with LEV Pharma's C1 inhibitor product. I personally witnessed how access to this
remarkable medication and its prudent use transformed a disabled young woman
into a healthy, vibrant and successful individual. This medication provided the most dramatic
outcome I have witnessed in my 35 years of pediatric practice.
I'm troubled that the Committee is
considering approval of C1 inhibitor for prophylaxis only especially since the
acute trial has also met its clinical endpoint.
I would like to discuss an incident that provides compelling evidence
that prophylaxis alone does not provide HAE patients with the full range of
therapy needed to treat this unpredictable life-threatening disease.
My patient was working on a college
project that required out of town travel.
Since this young lady often experiences dangerous laryngeal swelling we
worked things out to make sure she would be back in town for her regular
infusion. The return flight that would
have allowed her to keep her prophylaxis schedule was cancelled. The patient got on the next morning flight
but right before landing she began experiencing an acute attack.
Upon deplaning, she called my office
and said she was very sick and was on her way for treatment. I examined her as soon as she arrived and
noted severe abdominal pain, dehydration and hypotension. Fortunately our nurse had already prepare the
C1 esterase infusion but dehydration made it difficult to find a vein and it
took two of us to start the infusion.
It was very evident to me then that
any further deterioration in the patient's condition would warrant
hospitalization and I told the patient that I might have to send her to
hospital by ambulance. Despite being
severely ill, the young lady was adamant that she would get better quickly and
cited past use of imported C1 inhibitor that provided rapid and dramatic relief
from severe acute attacks. I continued
to monitor her vital signs and noted marked improvement after 15 minutes of treatment. I was astounded that 40 minutes post infusion
the young woman's vital signs were normal and she was demanding that we allow
her to leave so she could attend her late afternoon classes.
Without access to C1 esterase
inhibitor, the acute attack would have required hospitalization and this young
lady would have had to suffer for 48 to 72 hours. My patient's experience illustrates that the
HAE patient community would be ill-served by an approval that ignores the
important need and life-saving value of acute C1 inhibitor esterase therapy.
Thank you.
MR. JEHN: Dr. Amin Barakat.
DR. BARAKAT: I'm sorry.
That's me.
MR. JEHN: Okay. Beth Mercante.
MS. MERCANTE: Good morning.
My name is Beth Mercante and I'm here today thanks to travel provided by
the HAE Association and I have no financial ties whatsoever to LEV.
I'm here to provide the Committee
with some insights into the life-altering impact of the LEV Pharma C1 inhibitor
product. I have experiences
overwhelmingly positive results by participating in the LEV prophylaxis trial
for over two years. I'm actually one of
the people that have probably gotten over 200, well over 200, infusions and
have not had one, not one, adverse effect and I continue to do remarkably well
in the open label extension. Two
infusions per week at the clinic are a small inconvenience for being able to
have a virtually attack-free life.
Well, I'm not here today to focus on
me. I think the Committee should know
that before I gained access to LEV's C1 inhibitor I missed countless school,
work and child care days because HAE swelling left me either grossly
disfigured, doubled over with excruciating abdominal pain or wondering if the
throat attack underway would finally be the one to take my life. Instead I'm here because I have a
seven-year-old son, Julian, who has HAE and I am compelled to do whatever I can
to make sure that C1 inhibitor is approved so he does not have to experience
the pain and suffering that my family members and I have endured in our
lifetimes.
One morning when my son was 18 months
old I went to get him out of his crib and saw something that changed my world
forever. My precious child was beaming
at me with his usual loving grin but his eyes were almost swollen shut and his
lips were about five times their normal size.
I immediately knew he had inherited my genetic deficiency and had HAE.
Before Julian was accepted for open
label acute treatment with the Lev C1 inhibitor product, he experienced
horrific abdominal attacks that resulted in a level of suffering that was
really unbearable to witness. My family
represents both sides of the spectrum with regard to the therapy needed by HAE
patients. I'm doing beautifully on
prophylaxis and the access to acute therapy has radically reduced my son's HAE
related suffering.
One morning a few months ago Julian
was getting ready for school and I noticed that he was walking slowly and
gingerly. As an HAE patient, I
immediately knew what was going on and I said, "You look like your tummy
is really swollen. Do you want to stay
home from school?" He was like
"No, mommy. I don't want to miss
school. I think I'll be okay."
Coincidentally, I had a meeting at
the school that morning. So when it
ended I headed off to Julian's classroom to see how he was doing. As I walked down the corridor, I saw my son's
second grade class coming down the stairs.
So I went over to see if Julian was feeling better.
At first, my son was nowhere to be
seen. But a few moments later, there he
was shuffling along in obvious pain barely capable of walking down the
stairs. I scooped him up into my arms
and told him it was time to make him feel better. We headed off the LEV Clinical Trial Center
were the C1 inhibitor was waiting for us.
Twenty minutes post infusion, Julian was able to walk normally and within
40 minutes he was doing jumping jacks in the waiting room to show how much
better he was feeling. I had tears of
joy in my eyes as I thanked the compassionate doctors and nurses for all
they're doing to treat this debilitating and deadly disease.
Based on experience, I can look each
and every member of the Committee in the eye and tell you that the LEV C1
inhibitor product is remarkably safe.
Both prophylactic and acute therapy are vital and offer the prospect of
a normal life for me, my son and thousands of other patients just like us. Too many have suffered for far too long. Both prophylactic and acute therapies deserve
swift approval.
Thank you.
MR. JEHN: Tracy Conaway.
MS. CONAWAY: Good morning.
My name is Tracy Conaway. I feel
like my life has come full circle. I am
here today to share a spouse's perspective of HAE, the horrible, psychological
and physical burden this disease creates and my concerns for this story
repeating itself with my son.
Thank you very much for the
opportunity to tell my story. But first
it's important to note that I do not have any financial relationship with LEV
Pharma. The HAE Association has provided
for my transportation in today's meeting.
I married Norm Conaway 22 years
ago. He had a tragic history of HAE in
his family with one of his sisters dying from the disease in the early 1970s
when she was just 26 years old. She was
found at home with an EpiPen in her leg surrounded by her two infant children.
Despite what the disease had done to
his family and despite his very severe and very frequent attacks, my husband
never let HAE get the best of him. He
was a police officer for 24 years and was excited to be a subject in the first
clinical trial for HAE therapy many, many years ago.
Before he started receiving
experimental therapy in the early `90s, Norm took desperate measures to find
relief from this terrible disease, driven like so many other HAE patients
because C1 inhibitor is not available in the
I begged him to go to the hospital,
but men can be so stubborn. He was tired
of being the freak show whenever we showed up at the emergency room, forced to
deal with residents and nurses who had no idea what was happening or how to
treat him. A few hours after I nervously
fell asleep, he woke me up when he got out of bed and placed a small knife on
the night stand. I asked him why it was
there. He answered that I would have to
use the knife to open his airway if the swelling got much worse.
He had had two tracheotomies
before. So he knew the kind of relief
they could provide when there were no other options. Before I could say to him there was no way I
could ever do that, his eyes rolled back in his head and his breathing stopped.
Then in the next moment, his eyes
opened suddenly. He grabbed the knife
and stuck it through his neck into his throat.
I pulled him off the bed and began CPR.
There was blood everywhere. It
was difficult for me to get any air into his lungs because his throat was now
almost completely shut.
Miraculously, the paramedics arrived
and were able to get a small tube into his crude tracheotomy. Norm was transported to the hospital alive
where they cleared his airway, stitch up his wound, and he was given fresh,
frozen plasma. On its own, the swelling
went down and my husband walked out of ICU a few days later only to have his
job taken away because the department thought he couldn't have the disease and
be a police officer.
Our family was busy and productive
and we were relieved when we finally were able to enroll Norm in a C1 INH
clinical trial. Having open label
access to C1 inhibitor concentrate as both a prophylactic therapy and for acute
treatment was nothing short of a miracle for my husband.
I am here today telling you this
story because Norm couldn't be. He died
14 years later, just four years ago, at the age of 47 from what we are
convinced were complications related to decades of extremely high doses of
anabolic steroids. The steroid therapy
barely helped his HAE attacks but it remains the only treatment option
available to the thousands who would give anything for the promise of relief.
We always knew that having children was a risky proposition. So Norm and I waited a long time before our son, Jake, was born. Tested when he was just a few weeks old, Jake has HAE. The news was devastating for my husband and I. He had his first