UNITED STATES FOOD AND DRUG ADMINISTRATION

P R O C E E D I N G S 8:05 AM

MR. JEHN: Okay, we are going to go ahead and get started here. Mr. Chairperson, members of the Committee, invited guests, consultants and public participants, I would like to invite you all to the 84th meeting of the Blood Products Advisory Committee.

I am Donald Jehn, the Executive Secretary for this meeting. The BPAC meeting is unusual in this case because it is a cross-center meeting. We have a CDER topic to discuss in the morning here and again, we welcome our CDER folks.

At this time I would like to introduce the individuals seated at the head tables for today's first session. On my right, going around the table we have Dr. Allen, our Chair. We have Dr. Davis on the Committee here and Dr. Kato is a temporary voting member. He is not present at the moment, Dr. Harvey Klein, Dr. Brittenham, Dr.Whittaker, Dr. Doppelt, our patient rep, Susan Winner, our consumer rep, Judith Baker, Marc Ghany, a temporary voting member, Dr. Quirolo, Dr. Liana Harvath, Dr.Schreiber and our industry rep, Dr. Maldonado and then FDA folks sitting at the table are again, Dr. Shashaty, Dr. Kathy Robie-Suh, Dr. George Jills, Dr. Karen Weiss and Dr. Richard Pazdur.

I have got a COI statement, rather lengthy that I need to read now and again, also, what we have linked by teleconference is Dr. Portman from Houston, Texas. He was sick earlier. So, he couldn't travel, but he has agreed to be on with us today via teleconference.

The Food and Drug Administration is convening today's meeting of the Blood Products Advisory Committee under the authority of the Federal Advisory Committee Act of 1972. With the exception of the industry rep, all members and consultants of the Committee are special government employees or regular federal employees from other agencies and are subject to federal conflict of interest laws and regulations.

The following information on the status of this Advisory Committee's compliance with federal ethics and conflict of interest laws including but not limited to 18 US Code, Section 208, 21 US Code, Section 355 and 4 is being provided to participants today in today's meeting and to the public. FDA has determined that members of the Advisory Committee and consultants of the Committee are in compliance with federal ethics and conflict of interest laws including but not limited to 18 US Code, Section 208 and 21 US Code, Section 355 and 4.

Under 18 US Code, Section 208 applicable to all government agencies and 21 US Code, Section 355 and 4 applicable to certain FDA committees Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for particular individual services outweighs his or her potential conflict of interest, Section 208 and when participation is necessary to afford essential expertise, Section 355.

Members and consultants of the Committee who are special government employees at today's meeting include special government employees appointed as temporary voting members. They have been screened for potential financial conflicts of interest of their own as well as those imputed to them including those of their employer, spouse or minor child related to the discussions of a new drug application, NDA 21-882, proposed trade name Exjade, deferasirox tablets for oral suspension, Novartis Pharmaceutical Corporation proposed for the indication of the treatment of chronic iron overload due to blood transfusions, transfusional hemosiderosis. Also, the Committee will discuss the research programs of the Laboratory of Hemostasis and the Laboratory of Plasma Derivatives, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research.

In closed session the Committee will discuss the report from the laboratory site visit of February 25, 2005.

These interests may include investments, consulting, expert witness testimony, contracts, grants, CRDAs, teaching, speaking, writing, patents and royalties and primary employment.

Today's agenda includes topic one, review, discussion and recommendations on the safety of Exjade, deferasirox tables for oral suspension for the treatment of chronic iron overload due to blood transfusions manufactured by Novartis Pharmaceuticals.

For topic two the Committee will review and discuss the research programs of the Laboratory of Hemostasis and Laboratory of Plasma Derivatives, Division of Hematology, Office of Blood Research and Review.

In accordance with 18 US Code, Section 208, B3 waivers have been granted to the following topic one participants. Please note that all interests are in firms that could potentially be affected by the Committee's discussions, Dr. Klein for ownership of stock in the sponsor currently valued between $5001 and $25,000, Dr. Portman who is participating via teleconference for consulting with the sponsor on unrelated matters for which he receives less than $10,001 for negotiation consulting with sponsor on unrelated matters and for serving as a site investigator for unrelated study supported by the sponsor where one patient was enrolled at less than $10,001. A copy of the written waivers statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A30 of the Parklawn Building.

This conflict of interest statement and all acknowledgement and consent to disclosure statements will be available for review at the Registration Table.

Dr. Samuel Maldonado is serving as the industry representative acting on behalf of all related industry and is employed by Johnson & Johnson. Industry representatives are not special government employees and do not vote.

Based on the agenda for topic two it has been determined that the Committee discussions present no actual appearance of conflict of interest for today's meetings.

We would like to remind members and consultants that if the discussions involve any other products and 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 the sponsor, its product or if known the direct competitors.

Thank you.

After reading that very lengthy COI statement I just wanted to before I turn it over to our Chair, Dr. Allen, I just want to make sure everybody has their cell phones either muted or off and again, welcome to the meeting.

DR. ALLEN: Thank you, Don. As Chairman, I would like to welcome you all to the discussions today. This is a very important consideration. We have got one topic that is going to take up most of the day and I would just like to remind each of the speakers, please adhere to your time limits that are given to you and that will be clocked over here.

Given the number of presentations and the lengthy deliberations that the Committee is being asked to undertake I would really like to ask everybody please to adhere to the time limits, to give the Committee members a chance to ask questions and to participate in the necessary discussion.

For our FDA colleagues over here the equipment is sort of blocking you over there. So, if you have a comment or want to be recognized please ask one of your colleagues down towards the left of your side to wave a flag or something because I might otherwise not be able to see you and recognize you.

Okay, we will begin our morning's presentations with an introduction from the FDA perspective by Dr. George Mills, Director of the Division of Medical Imaging and Hematology Products.

DR. MILLS: Good morning. Thank you. I would like to take this opportunity to thank the Blood Products Advisory Committee this morning as well as the attendants from the public today as we bring Exjade first oral iron chelator to our review and discussion this morning of the safety and efficacy elements.

We will have presentations and then following that we have a number of very interesting questions. We will address many of the safety and efficacy issues that you will be hearing about this morning.

Without further information or need, we will proceed from here.

Thank you, Mr. Chairman.

DR. ALLEN: We will move right into our sponsor presentations by Novartis Pharmaceutical Corporation, first an introduction by Dr. Narang, Vice President, Global Head Drug Regulatory Affairs, Oncology Business Unit, Novartis.

Welcome.

DR. NARANG: Thank you, Mr. Chairman. Good morning. Thank you, Mr. Secretary, Mr. Jehn and other distinguished members of the Advisory Committee.

My name is P. K, Narang and I am the Global Head for Drug Regulatory Affairs for Oncology at Novartis Pharmaceuticals.

It I my pleasure to be here today and have the opportunity to present our new and exciting oral iron chelator submitted under NDA 21-882.

Our agenda this morning is as follows: After my brief introduction Dr. Porter from University College of London will present the clinical complications of iron overload, current treatment options and the need for therapy.

He is an internationally recognized expert in the field of chelation therapy and hemoglobinopathies and has treated iron overload patients with beta-thalassemia, sickle cell disease and myelodysplastic syndrome. He was, also, an investigator in our trials. He will be followed by Dr. Peter Marks, Senior Director in Clinical Development at Novartis who will present the efficacy and safety data from our large clinical profile.

Then we will have Dr. Elliott Vichinsky from Children's Hospital in Oakland who will provide his perspective on the benefit/risk profile for ICL and its place in therapy of iron overload. He is a world renowned expert in the field of chelation therapy and is currently the Chairman of the Medical Advisory Board of Cooley's Anemia Foundation.

He was, also, an investigator in our clinical trial program.

Last but not least I will ask Dr. Marks who is presenting the safety and efficacy data for us to moderate the Q&A session after our sponsor's presentation.

Iron overload is recognized as a serious outcome in patients with anemias who routinely receive life-saving blood transfusions.

If patients do not receive adequate chelation therapy iron accumulates in various endocrine organs and the heart, eventually causing end organ failure, significant morbidity and early mortality.

Desferal is the only approved chelation therapy in the US. It is a parenteral product, also, from Novartis and has been on the market for over 40 years.

While Desferal is deemed safe and effective its dosing is very inconvenient and leads to poor compliance. Its administration requires 8-to-12-hour subcutaneous infusion using pumps daily for 5 to 7 days per week.

As you can imagine this must be difficult for young children, adolescents and their parents who often risk potential complications of iron overload rather than deal with the cumbersome dosing.

So, suffice it to say there exists a significant unmet medical need for a safe and effective chelator with a positive benefit/risk profile.

ICL670, the one we are discussing today represents a new class of tridentate iron chelator. Its generic name as was previously mentioned was deferasirox and the brand name is Exjade.

This compound is the result of 14 years of research from Novartis for an orally bioavailable yet safe and effective iron chelator. Its drug kinetics, half life estimates, etc., support once daily dosing for this product and the data we will present today will demonstrate that ICL670 is efficacious and has an acceptable safety profile both in adults and in children.

The proposed indication in the NDA is for the treatment of chronic iron overload due to blood transfusions in adults and pediatric patients 2 years of age or older.

As you must realize the chronic iron overload population for ICL use meets the regulatory definition of rare diseases. That means prevalence in the US is 200,000 patients or less.

Just to briefly give you a regulatory history for developing ICL Novartis conducted a very large global clinical program. Three years after we submitted the IND ICL use in transfusion iron overload as I mentioned, a rare disease setting, was granted an orphan designation and a fast track status a year later.

Fast track programs are designed to facilitate development and expedite the review of promising agents to treat serious and life-threatening conditions. Agents with this designation are deemed to exhibit a potential to address a significant unmet medical need.

Using the special protocol assessment provision prior to initiation of our clinical trials in 2003, Novartis sought the agency feedback on issues related to these trials being deemed adequate. That means we discussed issues related to design of studies, conduct of studies and aspects of analysis plans.

ICL670 NDA was accepted into a continuous marketing program in January of this year. We submitted the final data in May and in June we learned that the agency had granted ICL NDA a priority review.

With these regulatory provisions FDA has provided us with timely guidance and an ongoing recognition for ICL and its potential to meet a significant unmet medical need.

Novartis' development and registration strategy focused on beta-thalassemia as a model disease to document drug effectiveness. This was supported by the agency as mortality and morbidity due to iron overload are well-documented in this population.

It is worth noting that the studies in the ICL program are the largest prospective trials every conducted for an iron chelator especially considering the rare disease setting.

Based on the minutes of the formal meetings and the SPA feedback we had from the agency we also believe that the findings from beta-thalassemia were generalizable to other iron overload settings. In fact, FDA's intent is captured by the following feedback we received, that the conclusion of efficacy from ICL studies 107 and 108 that we will share with you today may be applicable to other conditions of transfusional iron overload and anemias including sickle cell disease.

With that belief about beta-thalassemia disease population other studies such as in sickle cell disease were designed with a focus on safety and today we will share those data with you as well.

We,also, recognize the potential use of ICL in children. So, we strategically planned and prospectively included a large number of pediatric patients in our key pivotal trials, almost 45 percent.

These are the three key trials that we will be discussing today that are the basis for the assessment of safety and efficacy of ICL670.

Study 107, 108 and 109; 107 is the pivotal controlled trial versus deferoxamine, DFO in beta-thalassemia patients.

Study 108 is the supportive trial in beta-thalassemia patients which also included patients with rate anemias. These two primary efficacy trials enrolled 770 patients of whom 480 patients received ICL.

Other than 107 and 108 the safety population includes patients from Study 109, a Phase II supported safety study in sickle cell disease and in this study we also collected secondary endpoints related to the efficacy measures and we also include Study 106 which is shown at the bottom as a footnote, a safety and kinetics study in which 40 pediatric beta-thalassemia patients were enrolled and these are also included in our overall safety population.

So, overall safety population for us analyzed includes 652 patients treated with ICL of whom 292 were pediatric. All these studies were of 1-year duration.

I would like to take a minute and note at this point something that may be on many minds here today. Why are we here even though our Studies 107, 108 did not meet the protocol specified statistical boundary for the primary endpoint? Let me assure you that today we will share with you clear and convincing evidence of efficacy of ICL based on meaningful secondary analysis.

These analyses are supported by consistent dose response seen in several secondary endpoints. This principle of documenting clinical effectiveness of new agents based on dose response is well recognized within the guidances that have been issued by the agency.

Dr. Marks will cover these in his presentation. In addition to Drs. Porter and Vichinsky, two experts as I mentioned in the field of chelation therapy we also are pleased to have a number of other experts who are here to assist us and the Committee with any questions.

Dr. Alan Cohen from Children's Hospital of Philadelphia is an expert in hemoglobinopathies. Dr. Richard Larson from the University of Chicago has expertise in the MDS arena. Dr. Raymond Hirschberg, from Harbor-UCLA Medical Center is a nephrologist who was a member of our external safety monitoring board for our clinical program and we have Dr.Lloyd Fisher from University of Washington who helped clarify any specific statistical issues that were brought up.

Now, I would like to invite Dr. Porter to come and present to you about iron overload, its complications and need for therapy.

Dr. Porter?

DR. ALLEN: We have a question first.

DR.BRITTENHAM: Before you begin I would like to ask another question that I think may be on many minds. That is where did the name Exjade come from?

DR. NANANG: Maybe I should ask somebody else who was looking at this to give you an idea about Exjade. Peter, do you want to comment?

DR.MARKS: Peter Marks from Novartis. I would say that this was a name that was come up with I believe and I did not come up with it myself, I believe because jade is a green mineral, ex taking the iron out of the green mineral. So, I think that is how it became Exjade. I apologize if there is some mistake in that but that is the best of my knowledge.

DR. ALLEN: Dr.Narang, one quick clarifying question. On my agenda I have got Dr.Marks speaking after Dr. Porter and then Dr. Vichinsky as the last speaker. Is that the order?

DR. NARANG: That is the order.

DR. ALLEN: All right, Dr. Porter?

DR. PORTER: Thank you very much. Good morning. I am going to talk about iron overload, its complications and the need for treatment. This is a scheme for iron distribution in a healthy human.

You can see that the majority of the iron is found in the erythron and that is to say circulating red cells and the bone marrow. This is present as hemoglobin.

Some is present in macrophages namely as ferritin at about .6 grams and the liver is a major source of storage iron as ferritin and hemosiderin.

A small amount of iron is present in other cells in the body in parenchyma particularly as myoglobin and also in key metalloenzymes such as ribonuclear(?) reductase and others.

Transferrin which is the major conduit of iron turnover in the body contains a very small amount of iron, about 3 milligrams but is essential for iron turnover. In fact, about 20 milligrams of iron is delivered to the erythron every day and a similar amount is destroyed by macrophages as red cells senesce. This iron is released back onto transferrin and this is the major iron turnover pathway.

A small amount of iron is absorbed from the gut about 2 milligrams each day and a similar amount is lost through the gut and through skin desquamation.

About 10 percent of all the iron turnover is directed to the liver which will take up iron in times of plenty and release it in times of lack of iron. Now, what happens with blood transfusions, each unit of blood contains about 200 milligrams of iron so that if we imagine the normal adult or the iron content of 3 to 4 grams when we start transfusing there is no way of excreting this iron. So, iron inevitably builds up at a rate which has been calculated between .3 and .7 milligrams per kilogram per day in transfusion-dependent patients.

This is equivalent to 4 to 10 grams per year in an adult patient. So, iron accumulation is inevitable with repeated blood transfusion. So, this is the scheme here. Here we see red cells being transfused at a rate of about 20 to 40 milligrams a day or .3 to .7 milligrams per kilogram per day, and the senescent red cells are broken down in macrophages. The iron is then released at a very much increased rate.

Transferrin then becomes saturated and once the transferrin is saturated there is nowhere for the iron to bind and iron is present in the blood as non-transferrin-bound iron.

This iron has a different pattern of uptake into different tissues from transferrin-mediated iron, and it is this iron which is responsible for iron loading hepatocytes predominantly but also importantly in other parenchymal cells.

So, we can see here parts of the body where iron is importantly distributed to, the anterior pituitary gland, the heart, the liver, pancreas, the gonads and also other endocrine glands such as thyroid and the parathyroid glands. The increased iron uptake from non-transferrin iron is taken into these tissues at increased rates and the increased amount of labile iron within these cells is potentially available to generate a number of free radicals including hydroxyl radicals and it is this which leads to tissue damage.

So, the complications of iron overload most importantly are cardiomyopathy with heart failure which in the pre-chelation era typically developed after the age of 10, between the ages of 10 and 20 so that in the pre-chelation era thalassemia patients typically died from cardiomyopathy by the age of 20.

Another important complication if iron overload is not controlled or treated is hepatic cirrhosis. Fifteen to 20 percent of patients develop diabetes mellitus and the infiltration of iron in the anterior pituitary leads to hypogonadotropic hypogonadism which leads to infertility and poor growth and sexual development.

What conditions are associated with transfusion iron overload? Beta-thalassemia major is the best described because on a worldwide basis this is numerically the most important group, less so in the United States.

So, most of our experience with the effects of iron overload have been gained with beta-thalassemia major. Transfusion typically begins within a year of birth and therefore the effects of the iron load are very important with respect to the anterior pituitary load.

Other types of chronic transfusion dependent anemias which begin in childhood have a similar range of effects in terms of iron loading. These include the very rare Fanconi's anemia, Diamond-Blackfan anemia and some congenital dyserythropoietic anemias and from what we can see there is no difference fundamentally in the effects of the iron loading in these conditions from beta-thalassemia major.

In the United States sickle cell disease is a very important group numerically and although transfusion is not required to maintain life it has become increasingly important to treat the complications and prevent them and Dr. Vichinsky will be talking more about that later.

Aplastic anemia and mild dysplasia are important transfusion-dependent causes of anemia which develop typically later in life and again develop important complications through this process.

Now, what is the current practice with respect to initiation of therapy in iron overload? When should it begin? As I have already said with repeated blood transfusions iron rapidly develops in the body and chelation therapy is typically begun after 10 to 20 blood transfusions or when the serum ferritin exceeds 1000 micrograms per liter.

In more difficult cases where transfusion has been sporadic and it is difficult to get an accurate transfusion record then measuring the liver iron concentration can be a useful measure to estimate body iron loading and in fact liver iron concentration is a very accurate way of measuring total body iron stores and this is elegantly shown by the study of Angelucci and coworkers who undertook quantitative phlebotomy in patients who had had bone marrow transplantations of beta-thalassemia major and they looked at the relationship between liver iron concentration by biopsy and quantitative iron stores, and you can see that provided adequate samples are taken by liver biopsy there is a very good correlation between these two variables and in fact you can use a mathematical formula to measure body iron stores from the measured LIC, liver iron concentration.

Now, what are the consequences of iron overloading in terms of the rate of iron loading and what does that mean in terms of when we begin treatment? On the horizontal axis here we see patients' age with thalassemia. On the vertical axis we see hepatic iron concentration and I will concentrate on the axis on the right.

Normal liver iron concentration is up to about 1.6 milligrams per gram dry weight and we know that from the pre-chelation era that there is a very rapid accumulation of iron in the body so that by the age of about 2, 7 milligrams per gram dry weight is achieved and within a year or 2 after that the threshold of 15 is reached and by the age of 10 about 30 milligrams per gram dry weight concentration is found in the liver, in the pre-chelation era.

Now, what are safe levels of iron in the body? We know that heterozygotes for hemochromatosis can sometimes reach levels as high as 7 milligrams per gram dry weight by the age of 50 and that these patients do not get complications of iron loading. They don't get hepatic fibrosis. They don't get diabetes. So, in principle this may be a safe level of iron or one to aim for.

We, also, know from a number of studies that patients who exceed levels of around 15 milligrams per gram dry weight have increased risk of complications. Studies show increased risk of cardiac disease and there is a study showing decreased survival in patients who have liver irons above this value.

So, in general the goal would be to keep levels below 7 at all times and if patients exceed 15 to try to reduce the liver iron quickly.

Now, liver iron concentration measurement is not always a convenient test and generally around the world the plasma ferritin has been the most frequently used measure or estimate of body iron loading and as you can see from the graph here there is a correlation between liver iron and plasma ferritin both in sickle and transfused thalassemia patients but that there is a considerable scatter and this scatter relates to a number of things such as inflammation which falsely raises serum ferritin. Ascorbate deficiency is falsely decreased and so on. So, there is a correlation. There is a scatter but there still is use in measuring plasma ferritin or serum ferritin.

Firstly the trend of serum ferritin over time reflects broadly the change in liver iron concentration and therefore sequential evaluation of ferritin provides a good index of whether the patient is taking that treatment. There are, also, a number of studies itemized here, A2E which show that maintenance of serum ferritin below 2500 significantly correlates with cardiac disease-free survival.

I will show one of these here. This shows cardiac disease and percentage of time with serum ferritin above 2500 and essentially if serum ferritins are kept below 2-1/2 thousand and survival is significantly better than if that goal is not achieved.

Now, when it comes to iron chelation therapy itself or the choice of the chelator what are the ideal properties we need? The first thing is to control body iron, to prevent body iron building up in the first place or if it has already developed then to reduce the iron burden, so-called "negative" iron balance.

Clearly if you start treatment early enough then iron balance studies, the balance of what goes in and what goes out would be sufficient. We want to prevent iron-mediate organ toxicity. We want the chelator to be simple and easy to use for the patient. As we will see later this is one of the drawbacks of deferoxamine. Once daily oral administration would be ideal. We would like a drug that has a sufficiently long plasma half life to justify its use once a day.

We would like the drug to be effective by itself. We don't have to have to give a cocktail of drugs to achieve our therapeutic dose and then we want the drug to have an acceptable toxicity profile. I will just expand a little bit on this. The experience with deferoxamine has been that in patients who are less iron overloaded and in patients who receive relatively high doses of the drug, relatively iron loading that the susceptibility to iron chelated mediated toxicity is greater and the target organs with deferoxamine have been growth, decreased growth in adolescents and children and retinopathy and hearing problems and also experience with animal models has shown that the general property of the chelator will be in less overloaded patients or animal species an increased propensity to chelator mediated toxicity.

So, this is a challenge in developing iron chelators. Finally, we want the chelator to be really relatively simple and easy to monitor. We don't want a drug where we have to do a blood count every week in order to assure its safety.

Now, the current therapy for iron overload in the United States is deferoxamine, the only drug available. Because of its short half life of only 20 minutes it must be given by continuous infusion and it needs to be given 8 to 12 hours every day at least 5 days a week and ideally 7.

This is very demanding for the patient. They have to put a needle in their abdomen. They have to hitch up to a infuser device for these periods of time and as we will see some patients fail to comply with this demanding regime and therefore an easier-to-take treatment is desirable.

This slide shows the relationship between survival and the ability of a patient to take their treatment a different number of days per year and it works out that if a patient takes their treatment 5 or more days a week their survival is excellent as shown by the yellow and white lines but if they fail to achieve this goal survival falls off very significantly and there are other papers clearly showing relationship between compliance with therapy and survival.

So, to summarize the medical need and transfusional iron overload is inevitable with repeated blood transfusions whatever the disease process, currently the only approved therapy for iron overload in the United States is deferoxamine which requires subcutaneous infusion for 8 to 12 hours 5 to 7 nights a week.

Compliance is a significant issue and patients in different centers may be not adequately treated. Inadequately treated iron overload leads to organ toxicity and this is related to lack of control of reactive iron and deposition of iron in key tissues.

This leads to developmental endocrine dysfunction and ultimately cardiac dysfunction resulting in early death.

Therefore, the need for an effective, well-tolerated and convenient oral iron chelator is clear.

I would now like to introduce Dr. Peter Marks from Novartis who will present the efficacy and safety of ICL670.

DR. MARKS: Thank you, Professor Porter. I am Peter Marks from Novartis and it is now my pleasure to present the efficacy and safety data on ICL670.

In my presentation on ICL670 I will describe the compound and go on to review the dose-finding studies, the large efficacy trials and other supportive studies that were conducted.

As you have heard from Professor Porter untreated iron overload causes significant morbidity and mortality. Novartis introduced the current standard of care, deferoxamine which has led to a reduction in the morbidity from iron overload. However, the regimen of slow subcutaneous infusion required for deferoxamine to be effective has proven quite challenging to patients. It has resulted in relatively poor compliance with therapy.

In order to address the limitations of deferoxamine Novartis has been working on the development of a safe and effective oral iron chelator. Of many compounds screened ICL670 was found to have the most promising efficacy and safety profile.

In preclinical studies it was found to enter cells and remove iron and to remove more iron per chelating unit than deferoxamine.

In terms of pharmacologic properties ICL670 is orally bioavailable and this facilitates administration as a disbursible tablet to patients of all ages.

In contrast to the 20-to-30-minute half life of deferoxamine the half life of ICL670 in humans is 8 to 16 hours and this facilitates once daily administration. The iron bound to ICL670 is excreted in the bile and eliminated in the feces.

In this diagram the chelation of iron with ICL670 is illustrated. Two molecules of ICL670 bind to 1 atom of iron. The iron chelator complex then acts as a vehicle for elimination of iron from the body through its excretion.

In this respect the principle of action of ICL670 is more straightforward than many other pharmacologic therapies. The goal is to administer a sufficient amount of the drug to remove a given amount of iron.

I will now briefly review the dose finding studies for ICL670. After a single dose pharmacology study was performed and determined the dose-limiting toxicity to be nausea at 80 milligrams per kilogram study 0104, a multiple-dose pharmacology study was conducted.

Individuals with beta-thalassemia major and iron overload as documented by a serum ferritin level consistently above 1000 were admitted to a clinical research unit. Patients were then randomized to receive ICL670 or placebo at ICL670 doses of 10, 20, or 40 milligrams per kilogram for 12 days.

Iron intake and excretion were carefully assessed by chemical measurement of the amount of iron in the diet and in bodily excretions.

For study 0104 here is the net iron excretion in milligrams per kilogram per day plotted on the Y axis against the dose of ICL670 plotted on the X axis.

The light blue shaded area represents the amount of iron excretion necessary to balance the iron intake of a regular transfusion regimen.

Throughout this presentation whenever I speak of regular blood transfusions I am referring to the equivalent of two to four units of packed red blood cells administered per month to an adult.

So, with placebo iron excretion was 0.038 milligrams per kilogram per day. This is equivalent to approximately 2 milligrams per day for an adult and this is consistent with published literature. ICL670 at doses of 10, 20 and 40 milligrams per kilogram were found to produce iron excretion that was proportional to the dose administered.

The dose of 20 milligrams per kilogram was the minimum dose necessary to remove the amount of iron administered for regular blood transfusions.

Next, a longer-term randomized dose finding trial was conducted. In this study patients with beta-thalassemia major and iron overload who received regular blood transfusions were randomized to receive ICL670 at 10 and 20 milligrams per kilogram daily or to receive a standard regimen of deferoxamine at 40 milligrams per kilogram 5 days a week.

In order to assess the effects of ICL670 on removal of iron repeatedly at intervals during the trial liver iron concentration was measured using the non-invasive technique of SQUID. This technology measures very small magnetic fields related to the presence of iron in tissues such as the liver.

The baseline characteristics of the three groups were similar and the median baseline liver iron concentration as measured by SQUID was 8 milligrams of iron per gram dry weight with a range of 5 to 15.

Iron intake during the study was the same in all three groups and was close to 3 units of blood per month. At the end of 12 months at the early dose of 10 milligrams of ICL670 it was able to maintain a stable liver iron concentration similar to baseline.

The daily dose of 20 milligrams per kilogram was able to reduce liver iron concentration to a similar extent as deferoxamine 40 milligrams per kilogram.

In the dose-finding trials it was found that ICL670 produced dose-dependent iron excretion. Comparable pharmacodynamic effect was observed when deferoxamine and ICL670 were administered at a ratio of two to one.

Although not shown here the two-to-one ratio was also supported by preclinical studies that were conducted. The ratio will be important as we go on to further discuss the clinical development registration program.

In the registration program beta-thalassemia major was used as the model disease for the demonstration of efficacy because this regularly transfused patient population showed the well-documented pattern of complications of iron overload.

Patients with other types of congenital or acquired anemia requiring blood transfusions were also enrolled primarily to assess the safety of the compound. Extrapolation of efficacy was felt to be reasonable given the fact that the mechanism of action of removal of iron is the same regardless of the underlying disease state.

One challenge for the clinical development program was the standardized endpoints for determining the efficacy of iron chelation therapy have yet to be established.

Serum ferritin is the parameter most commonly used in clinical practice for initiating and monitoring iron chelation therapy. However, in agreement with health authorities the evaluation of liver iron concentration by biopsy was to be more reliable as an indicator of total body iron burden in the context of a clinical trial.

As an alternative to liver biopsy in some pediatric patients and in adults with contraindications to liver biopsy SQUID was used. A validation substudy that was conducted in parallel as part of study 0107 compared the values of liver iron concentration determined by SQUID and by biopsy.

This study revealed that SQUID values were approximately half of those determined by biopsy and concluded that SQUID was most useful as a relative measure of change in liver iron concentration over time in our studies.

Study 0107, 0108 and 0109 comprised the three large studies submitted in the new drug application in support of the efficacy and safety of ICL670 in pediatric and adult patients.

Study 0107 was a randomized reference therapy controlled trial conducted to demonstrate the non-inferiority of ICL670 to deferoxamine in regularly transfused pediatric and adult patients with beta-thalassemia major.

Study 0108 was a supportive non-comparative trial conducted to assess efficacy and safety in a special patient population with beta-thalassemia and in patients with rare anemias and study 0109 was a randomized trial conducted primarily to assess safety of ICL670 in patients with sickle cell disease.

Now, the goal of the ICL670 development program was to treat patients across the full spectrum of iron overload. ICL670 doses were selected to minimize the potential for excessive chelation with a new agent whereas the deferoxamine doses were selected based upon those that were known to be effective.

Patients were assigned by the investigator to receive ICL670 doses of 5, 10, 20 or 30 milligrams per kilogram or corresponding deferoxamine doses in the range of 20 to 60 milligrams per kilogram. Patients with liver iron concentration values less than or equal to 7, randomized to receive deferoxamine were permitted to remain on the pre-study doses even if they were higher than those specified.

Such patients were already deemed to be receiving deferoxamine doses that were safe and effective.

Now, turning to the results of the registration studies I will review the one large well-controlled randomized trial comparing ICL670 to deferoxamine in patients with beta-thalassemia, study 0107.

Study 0107 is the large reference therapy controlled trial that was conducted to examine the safety and efficacy of ICL670. Indeed it is the largest prospectively conducted randomized clinical trial examining the efficacy of an iron chelator that has ever been performed.

Regularly transfused patients with beta-thalassemia major were randomized and then assigned to one of four dosing groups to receive ICL670 or deferoxamine.

Patient accrual took place in 12 countries at 65 sites from March through November 2003. Liver iron concentration was measured at baseline and after 1 year of treatment.

Liver biopsy was used to evaluate liver iron concentration in 84 percent of patients and SQUID was used in 16 percent of patients.

During the study regular blood transfusions continued and serum ferritin and other laboratory safety parameters were measured monthly.

In the absence of established guidelines for evaluating the success of iron chelation therapy external experts were consulted in order to develop such criteria.

There was agreement that patients with different baseline liver iron concentrations should have different therapeutic goals for iron chelation therapy over the course of 1 year.

The goal for patients with baseline liver iron concentrations less than 7 was to maintain liver iron concentration and for those with higher liver iron concentration the goal was to reduce liver iron concentration.

Reduction of liver iron concentration to less than 1 was felt to represent excessive chelation and such outcomes were therefore to be considered treatment failures.

Such non-parametric success criteria were used for definition of the primary endpoint which was the treatment success rate at 1 year.

A non-inferiority design was chosen for the comparison of ICL670 to deferoxamine with a margin of minus 15 percent for the lower limit of the 95 percent confidence interval in order to demonstrate that there was no clinically relevant loss of effect.

The primary efficacy analysis was to be performed on the protocol one population which included patients completing the study and patients discontinuing for safety or considered treatment failures for the purposes of success rate analysis.

The main protocol specified secondary efficacy analysis was designed to demonstrate the reduction of liver iron concentration in patients with baseline values greater than or equal to 7.

In addition the change in liver iron concentration and the change in serum ferritin values in the entire population were analyzed descriptively. Based upon an emerging understanding that patients with liver iron concentration values less than 7 may have been underdosed with ICL670 relative to deferoxamine a post hoc subgroup analysis of the primary end point was added, that of non-inferiority in success rate in the predefined population of patients with baseline liver iron concentration values greater than or equal to 7.

Five hundred and ninety-one patients were randomized in study 0107 and 586 received treatment on study. For the purpose of the primary efficacy analysis as already mentioned the per protocol 1 population of 553 patients was used and included patients completing the study and patients discontinuing for safety.

The secondary efficacy analyses looking at the change in liver iron concentration were evaluated in the protocol two population which included only patients completing the study since the end of study liver iron concentration values were required.

The secondary analysis for change in serum ferritin level was evaluated in the safety population. Now, turning to the data from the trial, the two treatment groups were relatively well balanced in terms of gender, race, age, liver iron concentration and serum ferritin. Of note, despite the fact that 97 percent of the patients in both arms that were receiving treatment with deferoxamine for at least 1 month prior to the study, the median baseline liver iron concentration was 11.

Such a high value indicates that many patients were at risk for complications at baseline. During the 1-year study patients on both arms of study 0107 received a similar number of blood transfusions and therefore had a mean iron intake of about 0.4 milligrams per kilogram per day.

This is the transfusional equivalent of about 39 units per year or 3-1/4 units of packed red blood cells per month for an average adult patient with beta-thalassemia.

Following randomization patients were assigned to ICL670 or deferoxamine doses according to the baseline liver iron concentration. About 60 percent of patients with baseline liver iron concentrations less than 7 were maintained on the pre-study deferoxamine doses as allowed by the protocol. These same patients received relatively conservative dosing of ICL670. This led to a ratio of deferoxamine to ICL670 doses in patients with liver iron concentrations less than 7 of 4 to 1, whereas for patients with liver iron concentrations of at least 7 the ratio was 2 to 1.

As previously mentioned the effective ratio of deferoxamine to ICL670 doses was found to be 2 to 1. This was not achieved in patients with the lower liver iron concentrations in study 0107.

Turning to the results the non-inferiority endpoint was not met in the overall population. The lower limit of the difference in the 95 percent confidence interval was less than the pre-specified margin. Factors that may have affected the outcome include the conservative dosing of patients with low baseline liver iron concentration values of 5 and 10 milligrams per kilogram and the maintenance of effective pre-study deferoxamine doses in the same group.

Looking at the change in liver iron concentration as specified in the original analysis plan a statistically significant reduction of minus 5.3 milligrams of iron per gram dry weight was observed in patients with baseline liver iron concentrations greater than or equal to 7. That is in those individuals receiving ICL670 at 20 and 30 milligram per kilogram doses this reduction was comparable in magnitude to that observed with deferoxamine.

When one looks at the change in liver iron concentration on the Y axis by dose of ICL670 or deferoxamine on the X axis a dose effect relationship is apparent. ICL670 doses of 5 and 10 milligrams per kilogram were associated with increases in liver iron concentration. Twenty milligrams per kilogram was associated with maintenance and 30 milligrams per kilogram was associated with a reduction comparable to the deferoxamine.

A similar dose response was not seen with deferoxamine likely because the doses administered to all but the highest dose group were similar.

Changes in serum ferritin levels paralleled the changes in liver iron concentration for both ICL670 and deferoxamine. Five and 10 milligrams per kilogram ICL670 doses were associated with increased serum ferritin levels. Twenty milligrams per kilogram was associated with essentially no change and 30 milligrams per kilogram was associated with reduced serum ferritin.

In addition to the protocol specified secondary analyses, a post hoc subgroup analysis of the primary endpoint was performed to look at the success rate in the 65 percent of patients with liver iron concentration values of at least 7.

These individuals were treated with 20 and 30 milligrams per kilogram ICL670 doses and the ratio of deferoxamine to ICL670 doses was 2 to 1.

As you see the success rates were similar in this population of 381 patients and in fact the pre-specified non-inferiority boundary for the overall patient population was achieved in this subgroup.

This was true regardless of whether the per protocol 1 or the intent to treat analysis was used. Now, we turn to the supportive studies.

Study 0108 was a non-comparative trial performed in transfused patients with beta-thalassemia who were intolerant or non-compliant with deferoxamine and in transfused patients with rare congenital and acquired anemias other than sickle cell disease such as myelodysplastic syndromes or Diamond-Blackfan anemia. Intolerance of deferoxamine was defined by adverse events such as allergic reaction and non-compliance was defined by documentation in the medical record and baseline liver iron concentrations greater than 14.

The general design of the trial was otherwise quite similar to study 0107 with the exception that there was no comparator arm.

In addition the percentage of patients assessed with SQUID in this trial was higher and a greater number of patients had contraindications to biopsy necessitating this.

The same primary efficacy endpoint was used for study 0108 as was used for 0107. There were no historical data on success rates with deferoxamine in this patient population. Therefore after consultation was experts a success rate of 50 percent was felt to be adequate for the demonstration of efficacy. The primary efficacy analysis was performed on the intent to treat population.

The secondary endpoints for study 0108 were the same as for study 0107 including reduction of liver iron concentration in patients with liver iron concentration greater than or equal to 7, change in liver iron concentration and change in serum ferritin levels. The same additional subgroup analysis of a primary endpoint performed in study 0107 was also performed in this trial.

The baseline characteristics, the beta-thalassemia patient population enrolled in study 0108 revealed that these individuals were on average older and had higher baseline liver iron concentration and ferritin values placing them at a higher risk of complications from iron overload.

The median liver iron concentration value of 18 milligrams of iron per gram dry weight can be compared to the median value of 11 in study 0107. This is consistent with a population of patients who had not received adequate chelation therapy. The most notable demographic feature of the rare anemia population in study 0108 was age.

Particularly notable was the median age of patients with myelodysplastic syndromes at 66 years. This accounts in part for the older median age of the overall rare anemia population.

As for blood transfusion data during the study although there were some differences by disease category as a group these individuals received close to as much iron intake in the way of blood transfusion as the thalassemia population.

This was the equivalent of about 3 units of packed red blood cells per month for an adult. The range of average daily doses administered to patients in study 0108 was similar to those administered to the patients on the ICL670 arm of study 0107.

The primary efficacy endpoint in study 0108 in the intent to treat population was not met as the lower limit of the 95 percent confidence interval was less than 50 percent. The same was true in the prospectively defined analysis in the per protocol 1 population consisting of patients who completed the study and those who discontinued due to safety.

This was probably due both to the con