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 Europe and we don't think there is.

            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 Netherlands and as Jason said it's a lyopholized product.  You have to dissolve it in water for injection and then it is normal physiology to administer.  It contains some amino acids, sodium citrate and sodium chloride.

            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.


            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 IND and priority review was granted under the BLA.  This takes into account the unmet need and the life-threatening situation.

            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 Europe.  But I'm going to just focus on safety in the prophylaxis trial.

            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.


            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 Washington, D.C.

            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 United States.  While 17 alpha alkylated anabolic steroids are useful for HA prophylaxis in certain adults, the scientific literature reveals that many patients continue to experience periodic acute abdominal and laryngeal attacks notwithstanding ongoing therapy.

            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 Jacksonville, Florida.  I also very much appreciate having the opportunity to address the community and the FDA staff.

            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 U.S. clinical trials provide overwhelming evidence that cannot be denied.  I urge the Committee to vote yes for approval and I ask the FDA staff to expedite licensing this incredibly safe and effective life-saving and life-giving medicine.

            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 United States desperately need C1 inhibitor but not only for preventing HAE attacks.  Life-saving acute therapy is every bit if not more important.  I truly hope the Committee understands that throat attacks and excruciating abdominal attacks can occur at any time even for patients on androgen or C1 inhibitor prophylaxis.

            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 United States.  I began having severe abdominal attacks at age seven and to this day I am haunted by the horrible look of helplessness on my mother's face.  When she could only offer me a hot water bottle and a couple of baby aspirins.  Treatments that she knew could do nothing to ease my suffering.

            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 Georgetown University Hospital.  I also practice pediatrics in Northern Virginia.  I have no financial ties to LEV Pharma or any other pharmaceutical company.

            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 United States.  Norm, then a police officer in Tacoma, Washington, came home late, quite late, from work one night and told me that his throat was swelling.  He assured me he would be fine and that the swelling would go down because it usually did.  As we settled into bed, he propped himself up with pillows to prevent his neck from bending and cutting off the little breathing space left in his airway.

            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