UNITED STATES OF AMERICA

P-R-O-C-E-E-D-I-N-G-S

8:31 a.m.

CHAIRMAN SIEGAL: Okay, here we go. Good morning. I'm Fred Siegal, the Chair of BPAC at this moment. I would like to welcome all of you who were not here yesterday to us today. We have some new temporary voting members today, Dr. Thomas Atkins, Andrea Apter, whom we mentioned yesterday, Tom Fleming who was here, Larry Borish who wasn't here yesterday and the others have been introduced already. Perhaps we should go around and introduce those of us who weren't here yesterday. Introduce yourself.

DR. ATKINSON: I'm Prescott Atkinson. I'm a Pediatric Immunologist at the University of Alabama at Birmingham.

DR. BORISH: Larry Borish, I'm a Professor of Medicine at the University if Virginia, Charlottesville.

DR. APTER: Andrea Apter, Professor of Medicine, Allergy and Immunology, University of Pennsylvania.

DR. BALLOW: Mark Ballow, Allergy and Immunology, SUNY Buffalo.

DR. CRYER: Gil Cryer, UCLA Medical Center, Department of Surgery.

DR. DI BISCEGLIE: Adrian DiBisceglie, a Hepatologist at St. Louis University.

DR. FINNEGAN: Maureen Finnegan, Orthopedic Surgeon, UT Southwestern Parkland Hospital.

DR. GLYNN: Simone Glynn, NHLBI.

MS. BAKER: Judith Baker, Federal Hemophilia Treatment Center's Region 9 based at UCLA.

DR. ZIMRIN: Ann Zimrin, Hematology, Oncology University of Maryland.

MS. TROXEL: Andrea Troxel from the Biostatistics at the University of Pennsylvania.

DR. RENTAS: Frank Rentas, Blood Services, Walter Reed Army Medical Center.

DR. McCOMAS: Katherine McComas, a Professor of Communication at Cornell University.

DR. MANNO: Catherine Manno, a Pediatric Hematologist at Children's Hospital in Philadelphia.

DR. KULKARNI: Roshni Kulkarni, Professor of Pediatric Hematology, Oncology, Michigan State University and Director of Division of Blood Disorders, CDC.

DR. FLEMING: Thomas Fleming, Professor of Biostatistics, University of Washington.

DR. SZYMANSKI: Irma Szymanski, Professor of Pathology, U Mass, now working in Boston University, Boston, Mass.

DR. MASCIK: Gail Mascik, Hematologist, University of Virginia.

CHAIRMAN SIEGAL: I'd like to mention that unfortunately Lou Katz, our non-voting member from industry had to leave and I know that there are a number of members who have flights to catch and they have to leave a little early but as long as you can stay, we hope that you can because we do have to vote on the last part of this meeting.

So, let's proceed. I'm sorry, Mr. Jehn would like to make a statement.

MR. JEHN: Yes, I just have a conflict of interest statement for me today. This brief announcement is in addition to the conflict of interest statement read at the beginning of the meeting on May 1^st and will be part of the public record for the Blood Products Advisory Committee meeting on May 2^nd, 2008. This announcement addresses conflicts of interest for Topic II on the committee discussion, review and recommendations on Lev Pharmaceutical Incorporated clinical trial for the use of plasma derived C-1 esterase inhibitor, Cinryze for the prophylactics of Hereditary Angioedema Attacks. Based on the agenda and all financial interests reported by members and consultants related to Topics II, conflict of interest waivers have been issued to Dr. Mark Ballow in accordance with 18 US Code 208, Section 3, and 712 of the Food and Drug and Cosmetic Act. Dr. Ballow's waivers include a consulting arrangement with a firm that could be affected by the today's discussion of Topic II. The waivers allow Dr. Ballow to participate fully and vote on the committee discussions

For Topic III, the committee will hear an overview of the research programs in the laboratory of hepatitis and related emerging agents to vision and emerging in transfusion transmitted diseases. There is no conflict of interest involved with this overview. This conflict of interest statement will be available for review at the registration table. We would like to remind members and participants that if the discussions involve any other products or firms not already on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement and their exclusion will be noted for the record. FDA encourages all other participants to advise the committee of any financial relationships that you may have with any firms, its products and if known, its direct competitors. Thank you.

CHAIRMAN SIEGAL: Thank you, Don. So let's proceed to Topic II, Lev Pharmaceuticals, Incorporated clinical trial for the use of plasma-derived C1 esterase inhibitor (Cinryze) for the prophylaxis of heredity angioedema attacks. The introduction will be given by Dr. Felice D'Agnillo of FDA. Dr. D'Agnillo.

DR. D'AGNILLO: Okay, good morning, everyone. My name is Felice D'Agnillo. I'm a Product Reviewer for the Office of Blood Research and Review at the FDA. The topic of discussion today is the original license application sponsored by Lev Pharmaceuticals for C1 esterase inhibitor derived from human plasma. This is indicated for use in individuals with hereditary angioedema. This is a rare but very serious disease associated with a deficiency in the functional levels of this inhibitor.

My role today is going to be to provide a very brief introduction and to briefly describe the product. Dr. Golding, also from the FDA, who will be speaking immediately following the sponsor, will describe the regulatory chronology of this application and he'll give an overview of the clinical studies that were performed and then discuss issues related to efficacy, safety, and immunogenicity.

So I'd like to start off by just saying a few brief words on the protein. Again, C1 esterase inhibitor is a plasma protein. It is a member of a family of proteins called Serpins and this is short for serine protease inhibitor. The plasma concentration is in the range 180 micrograms per ml. It's molecular weight is 105 kD based on SDS-Page analysis. It's a heavily glycosylated protein and like Serpins in general, it contains in its structure a reactive site loop shown here which plays a very important role in the inhibitory function of this molecule. And the way this works is that serine proteases cleave this loop at this amino acid residue and the protease remains attached to the inhibitor and subsequent to a confirmational change in the inhibitor, the active site of the protease is distorted and it loses its function.

Now, unlike most Serpins that tend to regulate one serine protease, C1 inhibitor is able to regulate a number of important serine proteases in the plasma. These include, among others, C1s, the pointer is going down a little bit, C1s and C1r. That in conjunction with C1q form a C1 complex which play -- which regulates the classical compliment pathway. C1 inhibitor also regulates Kallikrein, Factor 12 and 11, that play roles in the coagulation and Kinin generation pathways and C1 also inhibits Plasmin and tissue Plasminigen activator which play roles in the fibrinolytis. Now before I move onto the next slide, I'd like to make one more point and that's that the inhibition of the disregulations of the Kinin pathway is very important in that it leads to uncontrolled production of bradikinin levels and bradikinin is a vasodilator and it's believed that the levels of bradikinin, the uncontrolled levels of bradikinin play an important role in the etiology of the disease which I'll describe in my next slide.

Hereditary angiodema is an autosomal dominant disease. It has a low incidence and it's estimated that there are about 10,000 individuals in the US with the disease. It's characterized by severe debilitating attacks. These attacks can be brought upon spontaneously or triggered by stress, trauma, injury or surgery. And these attacks are characterized by swelling in the face, airway, extremities and in the digestive tract. In the case of airway swelling, this can lead to obstruction of the airway and these -- under these conditions, this can be life-threatening.

The attacks can last from a period of hours to days and as I mentioned, this disease is caused by a deficiency in functional levels of C1 inhibitor. Now, there are two types of the disease. The most prevalent form of the disease, Type 1, is associated with a decrease in the production of the inhibitor. Type 2 is associated with normal or elevated levels of production but the protein is mutated and dysfunctional. And this is further illustrated in the next slide where this table shows some laboratory markers used to classify HAE. In Type 1, as I just mentioned, the production of C1 inhibitor is decreased and we're going to need a -- the production of C1 inhibitor is decreased and this leads to decreased levels of functional C1. In Type 2, production can be normal or elevated but the protein is dysfunctional. So this leads to decreased functional levels of the inhibitor in the plasma.

Now in both these cases, this is typically associated with a reduction in compliment four levels in the plasma, but C3 and C1 levels are typically normal. Now, another angioedema listed on this table is estrogen dependent inherited angioedema. This used to be called Type 3 HAE but this is very distinct from HAE in that there is no deficiency of the C1 inhibitor.

As far as some of the approaches to manage HAE, avoidance of known triggers, such as estrogens and ACE inhibitors is important. Some therapeutic interventions include anti-fibrinolytic agents to control the fibrinolytis. Attenuated androgens have been used to increase the production of C1 inhibitor and fresh frozen plasma replacement is also an approach -- it is also an option but the risk/benefit associated with this therapy is sometimes questioned and finally, C1 inhibitor replacement therapy has been used in Europe for many years, but in the US this therapy has only been available under IND.

And this brings me to the C1 inhibitor product that we're going to be discussing here today. It's a produce sponsored by Lev Pharmaceuticals with the trade name Cinryze, and this is a lyophilized preparation of the protein derived from human plasma and it's manufactured under contract to the Sanquin Blood Supply Foundation in the Netherlands. And I just want to say a few words on the product.

It's manufactured from US licensed source plasma and the manufacturing process contains two dedicated independent viral reduction steps that include heat treatment at 60 degrees for 10 hours and nanofiltration. And a third polyethylene glycol precipitation step has also been shown to remove viruses. And this is illustrated in the next table.

This table shows log reduction factors in various virus reduction -- virus spiking studies using enveloped and non-enveloped viruses and without getting into -- we've analyzed the data and without getting into all the details, we feel that these results show that the steps provide very effective viral clearance. Now, I'm going to end my very brief talk on that note but before having the -- but before listening to the more detailed presentations that are to follow, I'd like to present the questions that we would like the committee to consider today.

And Dr. Golding will also be repeating these questions at the end of his talk. Question 1, is the safety and efficacy evidence sufficient for approval of Cinryze for prophylactic treatment of HAE? Question 2, if the answer to question 1 is yes, should post-marketing studies be performed to further evaluate the following, the optimal dose for prophylaxis in males and females, immunogenicity, and long-term safety?

Thank you.

CHAIRMAN SIEGAL: Okay, thank you Dr. D'Agnillo. We're now going to hear from Lev Pharmaceuticals. I'd ask the presenters to keep in mind that you have not longer than an hour to present your case. Thank you.

MR. BABLAK: Good morning. My name is Jason Bablak, and I'm Vice President of Regulatory Affairs and Product Development at Lev Pharmaceuticals. We are excited to be here today to Cinryze, human C1 inhibitor for the treatment of hereditary angioedema. HAE is a chronic debilitating and potentially life-threatening disease that has a profound impact on the lives of patients and their families for which there is no adequate treatment option available in the United States. Today we are going to focus on the prophylactic treatment of hereditary angioedema with Cinryze.

After this introduction, Dr. Michael Frank from Duke University will present the pathophysiology of HAE and the clinical need for C1 inhibitor in the United States. Dr. Ira Kalfus from Lev will present the clinical program that demonstrated the safety and efficacy of Cinryze in the prophylaxis of HAE.

Dr. Paula Busse, from Mt. Sinai Medical Center will describe how Cinryze will fit into clinical practice and individualization of care for HAE. After the presentation, I will return to help address any questions from the committee.

Cinryze is a highly purified C1 inhibitor. Cinryze is manufactured by the Sanquin Blood Supply Foundation, formerly the Central Laboratory of the Dutch Red Cross. Sanquin has a 36-year history of producing successive generations of C1 inhibitor products, including the currently marketed product called Cetor, a highly purified pasturized C1 inhibitor which has been available in the Netherlands for 11 years.

The manufacturing of Cinryze is an enhancement to the Cetor manufacturing process. Cinryze is produced from pooled US source plasma by ion exchange chromatography and PEG precipitation. The purified C1 inhibitor is then pasturized, nano filtered and lyophilized. Before final Cinryze product is released, two separate quality assurance reviews of critical manufacturing parameters are completed and documented to insure adherence to good manufacturing practices.

Cinryze manufacturing includes multiple steps to insure the safety and quality of the product. Cinryze is derived from US source plasma collected in QPP certified centers which meet FDA standards and additional industry safety standards. Our manufacturing incorporates two dedicated viral and activation reduction steps, pasteurization and nanofiltration. The PEG precipitation step has also been validated as adding a significant contribution to the viral safety of Cinryze.

The virus removing capacity for Cinryze manufacturing has been validated and provides reduction of envelope viruses ranging from greater than 16.7 to greater than 19.1 logs. And for non-envelope viruses ranging from greater than 8.7 to greater than 10.5 logs. A study of the nanofiltration step demonstrated that it achieves the complete removal of spiked prion protein with a reduction factor of greater than 4.25 logs as measured by Western Blot.

Two pivotal Phase 3 studies assess the safety and efficacy of Cinryze. The first study was for the treatment of acute HAE attacks and the second was for prophylactic treatment to prevent HAE attacks. Both studies met their pre-specified primary end points and drew upon the same population of HAE subjects initially enrolled into the program.

The clinical program also included a pharmacokinetic study in these subjects who were not experiencing an attack. We are also providing continued access to Cinryze for HAE patients through ongoing open label studies for both acute and prophylactic treatment in which we are collecting additional safety and efficacy information. One hundred and eighty HAE patients have participated in our studies with over 6,000 doses administered. More than 12 subjects have each received over 100 doses extending well beyond one year on continuous treatment with Cinryze prophylaxis.

The clinical development program demonstrated that Cinryze if efficacious with no reported safety concerns and an adverse event profile similar to placebo. The results for both trials were statistically significant, clinically meaningful and consistent with the experience in Europe where C1 inhibitor is used for both acute treatment and prophylaxis. We are honored today to have Dr. Michael Frank from Duke University discuss the pathophysiology and unmet need in the treatment of HAE. Dr. Frank has pioneered research on HAE in the United States and is recognized internationally as a leader in the field. He was Clinical Director at the National Institute of Allergy and Infectious Diseases and he then served as Chairman of Pediatrics at Duke University for 14 years. Dr. Frank also served as an investigator in the Cinryze trials.

DR. FRANK: Thank you. Good morning. It's a pleasure to be here today. I was invited to come by Lev because of an interest in hereditary angioedema and particularly the treatment of hereditary angioedema that goes back more than 35 years. What I've been asked to do is discuss the clinical disease, the pathophysiology, current treatment as it exists in the United States and my experience with C1 inhibitor. We published a first paper on the use of C1 inhibitor in 1980.

As you heard from Dr. D'Agnillo, hereditary angioedema is an orphan disease. We don't know the actual incidents, but we think it's one in 10,000 to 150,000 people. It has been estimated that 6,000 to 10,000 people in the United States have hereditary angioedema but we think that less than half have been properly diagnosed. When we did the first clinical description of the disease in the 1970s we asked patients how long it was from the time they started having attacks to the time an appropriate diagnosis was made and at that time the time was 21 years.

Now, a company in Europe just a few years ago did a survey of the same kind of information and in Europe at the present time it was about nine years. So a lot of patients go for a long time without diagnosis. This is an autosomal dominant disease meaning that people have one normal gene and one abnormal gene allele. Therefore, 50 percent of the offspring would be expected to have the disease. Like many autosomal dominant diseases, new mutations are fairly common and 25 percent of the cases are estimated to be new mutations.

I'm going to briefly discuss the clinical manifestations which include extremity attacks, abdominal attacks facial laryngeal and genitourinary attacks. This is the kind of attack that effects the extremities. It's in many studies the most frequent attack. On the left is a swollen hand and on the right is a normal hand of the same patient at the same time. As you can see, this attack can be functionally disabling. If it effects that hands, it may impede the use of a keyboard, a phone. If it effects the feet, it can impede walking or driving. It can effect the joints and there can be immobility and dysfunction and discomfort of the joints. But it rarely results in hospitalization. It can interfere with work and school. It's really not the reason we're here today.

The second very common attack in some series the most common is the abdominal attack and this is the reason that we're in part here today. This GI series shows the spiculation or thumb printing of the bowel due to edema of the wall of the bowel which is extraordinarily painful. This can lead to debilitating symptoms, very severe pain, occasionally intestinal obstruction, nausea, vomiting and dehydration. These patients literally climb the wall with pain.

It usually leads to an emergency room visit. It frequently leads to hospitalization and because these patients' pain is so severe, they frequently get operated on even though they don't need an operation at that time, so they have unneeded surgery.

The facial attacks can be temporarily disfiguring as shown in this patient of mine. The picture on the left was taken when the patient was free of an attack and the picture on the right was a Polaroid taken by her husband. It was one of a series and in fact, it wasn't the most serious of the series. This lady was just sitting at home in an armchair while her husband was watching here face get more and more disfigured. In fact, she should have been in an emergency room.

Here is a series of pictures that were taken not by me but quite extraordinary, showing a patient before an attack, as the facial attack proceeds, even more severe facial attack and ultimately leading to intubation in this patient. In fact, this underscores some of our problem. And that is we do not have good therapy to end an attack in this country. So facial attacks can lead to extreme swelling, temporary disfigurement. Subjects of course, tend not to leave their home and the risk of local extension to the larynx is what we're talking about at the present time.

Here is a pair of radiographs. The radiograph on the right is a nine-year old girl who was not having an attack of hereditary angioedema at this time and you can see the normal cervical curve and the open airway. The picture on the left is the same girl during an attack of hereditary angioedema and you can see both the change in the curvature of the spine and the occlusion of the airway in this young girl.

So the laryngeal attacks can be life-threatening. When we did this first clinical study, as I talked about earlier, we asked people, "How many members of your family who had hereditary angioedema died of the disease by choking to death"? And the answer was 30 percent. That was a long time ago, and 30 percent is not the figure now, but there are still people who die, both in Europe and in this country over the last year or so. These always require an emergency room stay or hospitalization. They frequently require intubation and most patients suffer at least one laryngeal attack.

Now, the urogenital attacks also occur and should be mentioned. The typical triggers are sexual intercourse or local trauma. You can get swollen genitalia. You can even have painful urination or be unable to urinate because of swelling in the region of the urethra. So the impact on patients' lives of this disease is really quite extraordinary. It's a life-altering disease. It interferes with work, school and their social life.

Attacks typically last two to five days but they can last up to nine days. They can move from place to place, a hand, a foot, et cetera. It's been estimated that patients, some patients lose up to 100 days of school or work a year. There are about 15,000 emergency room visits annually in the United States it's been estimated and it is frequently misdiagnosed. This leads to unnecessary surgery and the treatment, as we have now, as we'll talk about in a minute, is really ineffective. We have ever-present risk and there is a major psychological impact and that's worth a few more words.

These patients have anxiety, depression and feelings of isolation. Many of them have seen members of their family choke to death of a disease that they have that can't be adequately treated. The abdominal pain is so severe that these patients learn to go into the emergency room and get narcotics and a very frequent problem with this patient group is narcotic addiction which is very difficult to deal with.

Now, the diagnosis is straightforward if you have a typical clinical diagnosis. In fact, the first attacks usually occur in childhood and often the disease is missed in childhood. It usually gets much worse at the time of puberty, both in males and females. The clinical findings we've discussed and Dr. D'Agnillo discussed some of the laboratory findings. The C1 inhibitor is functionally low. The C1 itself is normal because the inhibitor is now present, but C1 is present. C4 and C2 are low typically and C3, the most common laboratory compliment protein that's studied is always normal in these patients.

There is no correlation between C1 inhibitor levels in disease burden and I'll show you that in a second. As I've mentioned, the family history is not reliable because of the new mutations and so we usually are helped by a family history but it doesn't make the diagnosis.

The C1 inhibitor level and severity of attacks is interesting. In our original studies, we divided patients into patients that we considered having very serious disease and patients having very mild disease. The normal range is shown in green and the red dots are the patient who have a protein but it does not have normal function.

As you can see, there's no correlation between the seriousness of attacks and the level of C1 inhibitor and this, I think, is a reflection of the fact that we do not understand every aspect of the pathophysiology of this disease at the present time and we can talk about that later if there's any interest.

As Dr. D'Agnillo mentioned, C1 inhibitor is a Serpin, serine protease inhibitor and inhibits many different systems in the blood. It inhibits the compliment system, multiple proteins is shown in yellow. It inhibits the contact activation systems factors 12A and 12F. It inhibits the clotting system, the Kinin system, and the Fibrinolytic system inhibiting both plasma and tissue Plasminigen activator. We believe it's the Kallikrein system that's critical in the development of attacks of swelling in hereditary angioedema as I'll show on the next slide. Now, here is a complicated slide showing some of the aspects of the Kinin generating and Factor 12 system and I'm not going to go through it in detail.

The first thing I'm going to mention though is that all of the yellow x's are places where C1 inhibitor can function. And so you see it functions in many places in this complex system of biochemical steps. Let's turn our attention to the dotted box. As you can see in this box, we have prekallikrein, which gets activated to kallikrein. Kallikrein is an enzyme capable of cleaving high molecular kininogen and releasing Bradikinin. It is that step that we think is critical in the development of hereditary angioedema. The generation of Bradikinin is not inhibited. Now, as you also heard, C1 inhibitor is a suicide inhibitor. It's a single chain molecule that presents a bate sequence shown as a white triangle in this slide. The bate sequence is cleaved by the enzyme which is show as a Pac Man in this slide that I drew. And when this happens, the yellow triangle, a highly reactive group within the molecule, becomes available, binds to the enzymatic site and destroys the enzyme. So the C1 inhibitor is used up during this process and the product of one normal gene and one abnormal gene is not sufficient to keep you from having attacks.

Well, triggers are highly variable in this disease. Usually patients don't know what brings on an attack except about a third of patients know that physical trauma will bring on attack and that may be mechanical pressure or repetitive motion. A seamstress who uses a pair of scissors repeatedly will find that her hand swells up or someone who uses a power lawn mower will find that their hands swell up. Similarly, infection can bring on an attack. Strep throat can bring on an attack in the throat.

Emotional stress is another thing that's very interesting and that we don't understand. But emotional stress can have a major impact in the frequency of attacks. Hormonal influences are also important. We were the first to describe estrogens worsening the severity of the disease and occasionally you can have a woman who you just take off birth control pills and their disease becomes much better. Most of the referred patients are women probably reflecting this importance of estrogens in making the clinical symptoms of the disease worse.

So what are the current therapies? We haven't got time to go into this in great detail given the one hour, but I'd like to say a word about prophylaxis and a word about acute treatment. I was the one that introduced impeded androgens for prophylaxis. We published a double-blind study on the use of danazol and we showed that it's efficacious in prophylaxis. I put down that it has limited utility here because I want to talk about that in detail. It is useless in acute settings.

First of all, it takes at least two days before it starts to have a biological effect. And it's only -- danazol and the other impeded androgens are only available orally. What I mean by that is that if you have a patient with an abdominal attack, and their bowel is swollen, you really can't give them an oral medication and expect it to have an effect. It's contra-indicated in both pregnancy and children, and pregnancy because there can be masculinization of the fetus, in children because it can be premature closure of the epiphysis. And finally, in some people it's ineffective. Some people simply don't respond to androgens. The side effects of androgens, I think, are probably well-known to this group. It causes weight gain. It causes lipid abnormalities regularly and that includes elevated LDL, decreased HDL. It can have psychological effects, feelings of aggression, changes in libido, both in men and in women. In women, it can cause virilization in some women, certainly menstrual irregularities. Since it was developed, danazol was developed as a contraceptive.

It can cause muscle toxicity. Hepatocellular abnormalities including transaminase elevations are frequent but occasionally patients will develop adenoma and even carcinoma has been described and these patients are taking these drugs for decades. All hereditary angioedema patients are at risk for acute attacks and prophylactic treatment is not completed preventative. I had a patient who was not mine, who came into the Duke Emergency Room about a year ago on 600 milligrams of danazol a day and proceeded to be unable to intubated and had to have an emergency tracheotomy. So triggers vary over time, breakthrough attacks occur and I believe that there's no adequate acute treatment approved in the United States.

So what do we do for acute attacks? Well, for abdominal attacks, we give narcotics and we've talked about that. For laryngeal attacks we use supportive therapy. We use epinephrine which has limited efficacy in this disease. We use intubation or tracheotomy if it's necessary.

Fresh frozen plasma has been mentioned and I'd like to say another word about it. It has been reported to be effective in many case reports. I would say that 90 percent of people get better with fresh frozen plasma, but if you think about it, you're giving C1 inhibitor and at the same time you're giving high molecular weight kininogen, the substrate of kallikrein which will lead to more greater kinin production. I and I think everyone who have seen many people treated, have seen people get worse on fresh frozen plasma and I personally believe it's contra-indicated.

Antifibrinolytics have been used. EACA we were the first to do a double blind study with EACA and I don't want to talk about it in detail except to say that, yes, it works and yes, the toxicity profile is even worse in the androgens. We use antihistamines and steroids. They're commonly used. There really isn't any evidence of efficacy but the antihistamines do have sedating properties. What about C1 inhibitor?

Obviously, it's the protein that's low and so it's disease specific treatment. It's widely used in Europe and has demonstrated efficacy both in acute attacks, prophylactic attacks, as prophylaxis, et cetera. I'll show you a bit more about that. It's the physiologic protein. All patients are heterozygotes and therefore, they have some normal C1 inhibitor in their circulation. Allergy and immunogenicity are unlikely and in the studies that we did, we did not see allergy or immunogenicity. The prophylactic treatment does improve homeostasis.

We published our first studies with C1 inhibitor in the treatment of hereditary angioedema in 1980 in the New England Journal of Medicine. That was 28 years ago. And we reported at that time, that it was effective in the treatment of the disease but this was not a double blind study. In 1996, we published a double blind study with the last Fred Rosen, using an immuno-product, a product that's no longer available. We published the prophylactic side of the study and Fred Rose actually did the acute side of the study and I'm going to talk about the prophylaxis.

We brought in a group of six patients into the hospital who had severe hereditary angioedema and had failed all therapy. We treated them every three days as you can see by the red triangles on this slide. The C1 inhibitor concentration rose rapidly as shown in yellow and then fell rapidly reflecting its about two-day half-life. It does not have a very short half-life in the circulation. It does not have a very long half-life in the circulation.

Placebo, as you can see in blue, had no effect. If we follow the level of C4 as we did in these patients, what we found was that the C4 gradually came up into the normal range and stayed there and the effect of placebo, again was negative. It didn't have any effect. These patients who were very severely ill, having about five attacks per month, responded to the C1 inhibitor and got better. They didn't respond completely. They still had about -- occasional attack but at least 60 percent of their attack frequency was decreased.

Frankly, when I published this data, I thought that C1 inhibitor would become available for use in this country but in fact, that was 12 years ago and it's still not available. We did not find antibody in our patient population. So in conclusion, we think that there's an unmet need, at least I do.

European patients have had access to C1 inhibitor for decades. There are many papers, mostly uncontrolled on the -- on saying that C1 inhibitor is effective and no papers that say it's not effective. It works in acute therapy as I've said. It works in prophylaxis. It has demonstrated safety and efficacy and there has been 36 years of experience with this drug. Thank you.

DR. KALFUS: Good morning. I'm Dr. Ira Kalfus, Vice President of Medical Affairs at Lev. I have worked extensively in the development of Cinryze and I'm pleased to be here with you today. The pivotal studies demonstrated the safety and efficacy of Cinryze in the treatment of hereditary angioedema in the United States. A standard dose of 1,000 units was used in these studies. One unit of Cinryze corresponds to the mean quantity of C1 inhibitor present in 1 cc of normal plasma.

Numerous studies have demonstrated the activity of 1,000 units of C1 inhibitor for treatment of acute attacks. In Europe the recommended dose of Cetor for acute attacks of hereditary angioedema is 1,000 units. Similarly the dose for short-term prophylaxis is 1,000 units. <