FOOD AND DRUG ADMINISTRATION

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CENTER FOR DRUG EVALUATION AND RESEARCH

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ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

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MEETING

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Thursday,

April 26, 2001

The Committee met at 8:00 a.m. in the Versailles Rooms of the Holiday Inn Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. L. Barth Reller, Chairman, presiding.

L. Barth Reller, M.D. Chairman

Gordon L. Archer, M.D. Member

Dave Battinelli, M.D. Invited Guest

David Bell, M.D. Invited Guest

Joan P. Chesney, M.D. Member

Celia D.C. Christie-Samuels, M.D.,

M.P.H. Member

Alan S. Cross, M.D. Member

Barry Davis, Ph.D. Invited Guest

Steve Ebert, Pharm.D. Consumer Representative

Zachary D. Goodman, M.D. Invited Guest

Ralph Lazzara, M.D. Invited Guest

William M. Lee, M.D. Invited Guest

James E. Leggett, Jr., M.D. Member

Arthur Moss, M.D. Invited Guest

Barbara E. Murray, M.D. Member

Jeremy Ruskin, M.D. Invited Guest

David E. Soper, M.D. Member

Ciro Sumaya, M.D. Invited Guest

Ellen R. Wald, M.D. Member

Thomas H. Perez, M.P.H., R.Ph. Executive Secretary

I N D E X

by Dr. Reller 3

by Thomas Perez, M.P.H. 5

by Dr. Dianne Murphy 8

by Dr. Janice Soreth 12

by Dr. Jeremy Ruskin 17

by Dr. Douglas Shaffer 42

Introduction - Dr. Mindell Seidlin 55

Microbiology - Dr. Andre Bryskier 61

Human Pharacology - Dr. Vijay Bhargava 68

Clinical Efficacy & Safety - Dr. Bruno Leroy 77

ECG Analysis - Dr. Claude Benedict 97

Conclusions - Dr. Mindell Seidlin 112

Question and Answer Session

Clinical Efficacy - Dr. George Rochester 148

Resistant S. Pneumoniae - Dr. Alma Davidson 158

General Safety Profile - Dr. David Ross 165

Hepatic Effects - Dr. Edward Cox 183

Drug-Induced Liver Disease -

Dr. Zachary Goodman 196

FDA Presentation Summary - Dr. David Ross 209

Question and Answer Session 218

Open Public Hearing 255

Discussion of Questions and Vote 259

Adjourn 308

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

(8:00 a.m.)

DR. RELLER: Would everyone, please take their seats so we can begin our meeting? Good morning. I'm Dr. Barth Reller from Duke University Medical Center. I'd like to open today's meeting of the Anti-Infective Advisory Committee. We'll begin with introductions going around the table. To my right, Dr. Dianne Murphy.

DR. MURPHY: I'm Dr. Dianne Murphy. I'm the office director for ODE IV which has the antimicrobials.

DR. SORETH: Good morning, my name is Janice Soreth. I'm the acting director for the Division of Anti-Infectives with FDA.

DR. KORVICK: Joyce Korvick, acting team leader Medical Group.

DR. ROSS: David Ross, Medical Team Leader, Division of Anti-Infective Drug Products.

DR. SOPER: David Soper, Medical University of South Carolina in Charleston.

DR. CHRISTIE: Celia Christie from Pediatrics and Infectious Diseases University of the West Indies, Kingston, Jamica.

DR. WALD: Ellen Wald, University of Pittsburgh, School of Medicine, Pediatric Infectious Diseases.

DR. ARCHER: Gordon Archer, Virginia Commonwealth University in Richmond, Virginia.

DR. CHESNEY: Joan Chesney, the University of Tennessee in Memphis, Division of Infectious Diseases and Pediatrics and St. Jude's Children's Research Hospital.

DR. MURRAY: Barbara Murray, University of Texas Medical School in Houston, Adult Infectious Diseases.

MR. PEREZ: Tom Perez, Executive Secretary for the Anti-Infective Drugs.

DR. EBERT: Steve Ebert, Professor of Pharmacy, University of Wisconsin and Meriter Hospital, Madison.

DR. LEGGETT: Jim Leggett, Providence Portland Medical Center and the Oregon Health Sciences University.

DR. DAVIS: Barry Davis, University of Texas, School of Public Health in Houston.

DR. BELL: David Bell, assistant to the director for Antimicrobial Resistance, the National Center for Infectious Diseases at CDC.

DR. GOODMAN: Zachary Goodman, Hepatopathology Division of the Armed Forces Institute of Pathology.

DR. LAZZARA: Ralph Lazzara, University of Oklahoma, Cardiology.

DR. RUSKIN: Jeremy Ruskin, Cardiology, Massachusetts General Hospital, Boston.

DR. BATTINELLI: Dave Battinelli, General Internal Medicine, Boston University School of Medicine.

DR. LEE: Will Lee, UT Southwestern in Dallas, Hepatology.

DR. SUMAYA: Ciro Sumaya, School of Rural Public Health, Texas A & M University Health Science Center.

DR. RELLER: Thank you. We're delighted to have not only our members but guest experts who will be presenting at the meeting and participating in the discussions today. We'll now have our opening statement by Mr. Tom Perez, our Executive Secretary.

MR. PEREZ: Good morning. The following announcement addresses conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting. Based on the submitted agenda for the meeting and all financial interests reported by the committee participants, it has been determined that all interests and terms regulated by the Center for Drug Evaluation and Research present no potential for an appearance of a conflict of interest at this meeting with the following exceptions.

In accordance with 18 U.S.C. 208(B) full waivers have been granted to Drs. Gordon Archer, Barbara Murray and Ellen Wald. A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A30, The Park Lawn Building. In addition we would like to disclose for the record that Drs. Gordon Archer, Steven Ebert and James Leggett have interests which do not constitute a financial interest within the meaning of 18 U.S.C. 208(A) but which could create the appearance of a conflict.

The Agency has determined notwithstanding these interests that the interests of the government in their participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.

With respect to FDA's invited guests, there are reported interests which we believe should be made public to allow the participants to objectively evaluate their comments. Dr. Jeremy Ruskin would like to disclose that he and his spouse own stock in Pfizer and Merck. He also has received consultant fees from Pfizer and Roche and has lectured for Eli Lilly.

Dr. Barry Davis would like to disclose that he is the PI on an unrelated grant from Bristol-Myer Squibb and he is a consultant on unrelated matters for the steering committee for Merck and Glaxo Smith Kline. He is also consultant on unrelated matters for Pharmacia Corp. Data and Safety Monitoring Board and Pfizer's Data and Safety Monitoring Board for Alliance.

Dr. William Lee would like to disclose that he is a researcher for Glaxo Smith Kline, Bristol Myer Squibb, Roche and Schering Plough. He also has lectured for Roche.

Dr. Arthur Moss would like to report that he has and will consult for Abbott Labs on unrelated matters. He has also consulted on unrelated matters for Eli Lilly.

Dr. Ciro Sumaya would like to disclose that he owns stock in Glaxo Smith Kline and Pfizer. Thank you.

One more thing, actually two more things. In the event that the discussions involve any other products or firms not already on the agenda for with an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement under exclusion will be noted for the record. In addition, it has come to our attention that some of the materials that FDA typically puts up on the website were not made available till late yesterday evening. They typically go out the day before, hopefully, you know, as much as 24 hours before. We apologize for any inconvenience this may have caused anyone.

We have brought several copies of the background materials with us. They are available for anyone wishing to review them at the FDA table out front in the lobby. Again, our apologizes for any inconvenience this may have caused anyone. Thank you. DR. RELLER: Thank you, Tom. We shall next have opening remarks by Dr. Diane Murphy, who is the Director of the Office of Drug Evaluation IV.

DR. MURPHY: I want to again thank our committee members, our guests, sponsors and everybody who is here to listen to these deliberations because they -- the discussions today will involve topics that this committee in particular has dealt with a number of times. But, it always gets a little bit more precise when we have a product instead of a general topic. We have four issues that I think you will hear themes brought up that, again, don't just relate to this product. One has to do with the development of drugs to treat infections that are caused by resistant organisms and the need to make sure we have a pipeline of products that are being developed and yet at the same time that these products developed are used in a way that does not undermine our ongoing use of them and some people calls this prudent use.

For us what it relates to or where it is particularly important is because the patients who have resistant organisms will be small in number compared to the broad development plan that companies will have, how do we deal with these issues of prudent use of antibiotics when we have broad development plans. And there's a benefit to a broad development plan because it gives us a better picture of what the adverse event profile may be. And that's a benefit to everybody because as you know, the ability to detect signals, a particularly rare signal, is limited by sometimes our preclinical cause and certainly the size of them.

And we also know that our trials are designed in such a way that we often exclude populations because, again, they can only be so large, you need to be able to clearly delineate what's going on in a trial. However, once a product is approved, then that product is used by a population that may not have been included in the studies and appropriate use meaning for the right indication. I'm not talking about off-label prescribing. And that brings us to the issue of enhanced risk as far as what are the -- what are the characteristics of the population that may be taking products that are developed for a more general use.

And I think all of us understand that many of our older populations are on numerous products that may have interactions. And this has been an increasing issue for all the sponsors and for FDA and that happens to be Cytochrome P450 and the interplay between products that rely on these systems and their interactions with other drugs.

Many of the sponsors have attempted to address specific interactions and that's become an increasing part of our drug development request. However, again, populations that will be using this and other products often take multiple products of which it would be very difficult to ask a sponsor to develop every possible combination that a patient may be taking. So we have to look at the potential risks when we're looking at our risk benefit ratio, which is what we always do.

And the last thing that is another focus of this discussion and many of you have heard these discussions previously but we want to have some background information presented to you this morning and that's what we'll call the silent serious adverse events particularly if they're rare but how do we deal with adverse events such as QT and hepatic toxicity. You don't break out in a rash. You know, you don't -- you may not know you're having that complication. How do we deal with these in making our availability of products appropriate and making sure that we have come to the correct risk benefit assessment in our approval and in our availability of these products.

These are complex issues and we really do thank you for being here, for putting time and effort into preparing for this discussion because many of the things that we move forward on are evolving and your discussions are important in helping us expand how we think and how sponsors think about the development of products in this area. Thank you.

DR. RELLER: Thank you, Dr. Murphy. Next we'll have Dr. Janice Soreth, who is the acting Director of the Division of Anti-Infective Drug Products.

DR. SORETH: Good morning. Before I speak a little bit to the organization of presentation for our meeting today, I wanted to first make a quick apology to members of the advisory committee who may have experienced more than the usual difficulty in making travel arrangements. I think recently some of the rules may have changed, if not, in fact, the contract and it came however late, that there were, well, let's just say glitches. We promise you in the future we'll work very closely with you so that this experience is improved upon.

I wanted to talk a little bit today about the charge that is put before you as our Anti-Infective Advisory Committee and that charge is essentially to weigh in on the evidence that you'll see presented to you today by both our colleagues at Aventis as well as here at FDA on whether or not substantial evidence has been submitted to speak to both the efficacy of Ketek (Telithromycin) as well as safety.

In order to strike that balance, we have a couple of issues that you'll hear more about and that this committee has heard quite a lot about in the past decade or so for we have had no fewer than a half a dozen meetings product specific for antimicrobial agents that were requesting indications that included resistant organisms as well as at least three or four meetings in the past five years that have been non-product specific, speaking to the appropriate development scheme or schema for drugs seeking resistant claims and in the same breath trying to strike a balance with that, again, in the interest of the public health for what the prudent use of those antimicrobials would be.

Next slide. In addition to hearing a discussion of resistance previously as well as today, we will also be focusing on safety. I think it a fair statement that the independent FDA analyses that have been conducted on Telithromycin data are in agreement in general with those conducted by Aventis. We know in general that with regard to safety, clinical trials are not really powered to address those events which are uncommon or rare.

Instead clinical trials are powered in the realm of antimicrobial research to address efficacy issues. Should safety concerns arise anywhere in a development program, I think there are basically three options; stop, and that's usually what happens if the adverse events notes are of a very serious nature, like death. Short of that, when we're not dealing with a body count, but either clinical or laboratory adverse events, there are additional options and those include additional studies conducted premarketing that would shed further light on the elucidation of risk management to understand what the safety profile of a product would be for its intended use.

At other times, given a particular development program, one may choose to press on given the data that's been developed and try to put a drug on the market and in the setting of post-marketing have inquiry either in the setting of additional trials or active surveillance so to speak, to understand the use of the product, the safety of the product in the setting of general use. We know that our Phase III trials attempt to tell us that information but at the end of the day we also know that the experience with concomitant drug use and co-morbidities is sometimes a small experience in Phase III trials, even if the Phase III trial is relatively large. The devil is in the details.

Exposure for a product that would target respiratory infections such as you'll hear today is one with potentially very, very broad use with millions of prescriptions potentially written in a single year. Next slide.

What are some of the lessons learned at the agency with regard to safety? I would offer that we have learned through experiences with Mibefradil or Posicor, Terfenadine, Durac, et cetera, that once prescribing patterns are established for a drug, it becomes very, very difficult to change those patterns. Next slide, please.

So to that end, we need to do it right and we need to do it right the first time because again, I think that is in the best interests of the public health and it is also in the best interest of what I think of as the marketing half-life of a product. Next slide, please.

When in need, steal from a better writer. Dr. Temple published a paper in JAMA in 1999 that spoke to alternative means of looking at and gathering safety information for new drug development and I quote from that paper,

and by such it referred to a previous point of modest risk, that which was not necessarily common, somewhere between common -- certainly less than common to rare,

And I would submit to you that for many, if not most of the antimicrobial products that have come before this committee and come before us in the agency, we typically are looking at broad use. Only relatively recently in the setting of development of drugs for resistant bacteria have we begun to talk a lot about prudent use equalling less than very broad use, again, in order to try to preserve those products. Next slide.

And finally again from the paper in JAMA authored by Dr. Temple, "If a question is important", and I would add if a question is important particularly with regard to safety, "answering it may well be worth the cost and the effort".

We're going to hear this morning presentations that are essentially a QT Primer 101 by Dr. Jeremy Ruskin followed by an FDA presentation that will take us through a tour of some of the post-marketing data speaking to Torsades de Pointes and finally wrapping up the morning will be presentations on Ketek from Aventis. We'll break for lunch and then come back and hear presentations from FDA underlining where we, I think, see eye to eye on the efficacy data in general but perhaps not clearly as much on safety and finally wrap up with a discussion and a vote by the committee.

I thank you for your attention and turn the podium back to Dr. Reller.

DR. RELLER: We now look forward to the presentation of Dr. Jeremy Ruskin.

PRESENTATION OF DR. JEREMY RUSKIN

DR. RUSKIN: Good morning. I was asked to give a very basic introduction to this issue of QT prolongation and Torsades and that's what I will attempt to do but let me apologize in advance to the many people in this room who are already well familiar with these data. This is obviously a complex and difficult subject from a regulatory perspective and I certainly don't have any answers to it. What I can hope to do perhaps is help frame some of the discussion that will follow as we hear the data and talk about these issues.

This is an example of the problem that everyone is concerned about. This is a polymorphic ventricular tachycardia occurring in the setting of a long QT interval and in this particular situation it's occurring in the setting of a bradycardia, which was the circumstance under which Torsades was first described. In fact, it was first reported in the setting of complete heart block and we have learned over the years that bradycardia is one of the most potent predisposing conditions to the occurrence of this form of tachycardia.

Now, what I'd like to do in this slide is make an analogy between the occurrence of drug induced Torsades with non-antiarrhythmic drugs and a lightening strike and the analogy is based on the fact that -- it's not going to work. So much for my tricks with PowerPoint. There was text. The text for this slide basically said that this is a rare event, very rare, potentially life threatening however and very difficult to predict in any individual despite the fact that we are aware of risk factors and can define some of those risk factors.

There it is. The issue of QT prolongation and Torsades spans many disciplines and that -- I think that is familiar to everyone who has looked at these data and these include cardiac electrophysiology, pharmacology, genetics, and both clinical practice and regulatory medicine and we'll, obviously, be confronting all of these areas as we talk about the data. What I'd like to do in the next several minutes then is say a few words about the mechanisms of QT prolongation and Torsades, talk a little bit about how drugs effect that QT interval, say a few words about some specific agents that serve as illustrative examples of the problem that we're grappling with, emphasize some of the risk factors associated with drug induced Torsades and also then mention at least a few comments about the clinical and regulatory implications.

This is a partial list of drugs that have been shown to prolong the QT interval. Many of these have been associated with rare instances of Torsades. The list is actually incomplete and I show it just to emphasize one, the very large number of agents that do effect cardiac repolarization and two, the fact that these agents span almost every therapeutic discipline in medicine, or at least certainly many of the major ones including neurology, allergy, cardiology, infectious disease and psychiatry.

There are two major syndromes, if you will, of long QT, the first being congenital which we are not going talk about today except in passing and second the acquired long QT syndromes which is clearly the topic of interest today, the major cause of which at least for the purposes of today's discussion are drugs. But it's important to emphasize that drugs are not the only cause of acquired long QT and this has implications when one talks about multiple risk factors and these include bradycardia, electrolyte abnormalities and certain forms of heart disease including hypertrophy and congestive heart failure in which repolarization is intrinsically abnormal.

This slide is shown just to illustrate the fact that cardiac electrical activity is comprised of a fairly heterogenous group of action potential configurations and durations. But in the normal situation, the heterogeneity exists within fairly tight boundaries and when that heterogeneity is exceeded either as a result of a drug or some pathologic state, we have an environment in which arrhythmias can occur and one form of these arrhythmias is Torsades de Pointes which we'll focus on today. The major interest with regard to today's discussion focuses not on depolarization but rather on repolarization which results from a complex series of events that involves many ion channels. But for the purposes of today's discussion and particularly with reference to drugs that cause Torsades, one can simplify this and this is a gross over-simplification, to a discussion primarily of three channels, the sodium channel which is responsible for depolarization, and then the calcium channel which is responsible for the plateau phase of the action potential and then repolarizing potassium currents, in particular the rapid and slow components of the delayed rectifier current.

It turns out, and this will come up repeatedly, that almost all of the drugs that are known to cause Torsades in fact, effect this channel. And it's also important to emphasize that the duration of the action potential, which is what determines the duration of the QT interval, is a complex inter-play of all of these channels and it is possible to prolong the action potential duration by interfering or inhibiting the outward movement of potassium from the cell.

One could also enhance inward movement of calcium thereby prolonging the plateau phase and if the sodium channels fail to inactivate when they normally should, it's also possible to prolong action potential duration. But the primary mechanism by which this occurs in clinical practice with the drugs that we use, is a result of block of the IKr current. The question of why IKr is so sensitive to a drug inhibition is not completely understood but there are some fascinating data from Dr. Sanguinetti's lab in Utah which are based primarily on structural analyses of the -- of IKr, of HERG and suggest that this channel has a particularly large vestibule in the pore region, that's an intra-cellular receptor obviously, in which potassium is pumped from inside the cell to the outside of the cell.

This pore region and, particularly the vestibule of this pore region, is unusually large compared with other channels and for that reason appears to have a certain degree of non-specificity to it with regard to its capacity for drug trapping. So many, many drugs in fact will effect IKr and this is largely a concentration dependent phenomenon. If you give enough of many, many drugs, you will get an effect on IKr. The question really is what is the potency of that effect and how does it translate at therapeutic concentrations into an effect on the QT interval in humans.

The mechanism of Torsades de Pointes is not completely understood but there are important observations that have come to light in the last five to seven years that suggest that while early after depolarizations which is a focal mechanism and was previously thought to be the primary mechanism, is probably not responsible for the arrhythmia itself, that is the sustained arrhythmia, but rather it is likely due to a form of reentry within the wall of the ventricle muscle. And this is a copy of a figure from a manuscript by Charles Antzelevitch, who has done some seminal work on examining different layers within the left ventricular myocardium and demonstrating that in fact, action potential characteristics in the epicardium, mid-myocardium and endocardium are quite different and that this heterogeneity within the wall of the muscle may be in part responsible for susceptibility to drug induced effects and the occurrence of Torsades.

These are recordings also from a paper from Antzelevitch's lab demonstrating that the mid-myocardia layer, the so-called M cells generally have significantly longer action potential durations than cells within the sub-epicardium and in the endocardium and in addition, these M cells appear to be more sensitive to rate effects particularly slowing of the rate, and to drugs which inhibit IKr than either the endocardium or the epicardium. And remember we talked earlier about the issue of heterogeneity. When one has heterogeneity within the wall of the muscle or any other place in the heart, one has a potential substrate for a re-entrant arrhythmia and this is just a cartoon that created by lifting these action potential figures from one of Antzelevitch's papers, lining them up with the epicardium, mid-myocardium and endocardium and if one gets significantly long enough prolongation within the mid-myocardial layer, such that this area is unresponsive for a longer period of time than either the epicardium or the endocardium, the potential for re-entry exists.

And one of the proposed mechanisms of Torsades is as follows. A ventricular premature beat perhaps due to an early after depolarization may arise anywhere within the heart and I've just placed it in the endocardium. These can arise from the mid-myocardium or from the His-Purkinje system and this ventricular premature beat occurs with timing such that when it conducts into the mid-myocardial layer, it encounters refractoriness because of the long action potential duration in this portion of the ventricular wall, and therefore, it blocks.

It then travels around this zone of block for a sufficient period of time to reach some portion of the mid-myocardium that has recovered and once it does that, it can excite the mid-myocardial layer, reach the epicardium and then descend again through the wall of the heart, resulting in a re-entrant arrhythmia. And there are very good animal models demonstrating that this is capable of producing what we see in clinical Torsades, that is a polymorphic VT varying configuration.

In fact, if one thinks of these as rotors, three dimensional rotors, that may migrate through the wall of the heart, it's not hard to imagine how the kind of polymorphic VT that we see in drug induced Torsades could be produced by this form or re-entry. Now what about the QT interval? The QT interval, as you all know, is an electrocardiographic measurement. It's made from the onset of the Q wave to the end of the T wave and is taken to represent repolarization. In fact, it represents both a combination of depolarization because it includes the QRS complex and repolarization. And it's important to emphasis that drugs or pathologic states that prolong the QRS duration may, in fact, effect the QT interval and if we were going to be purests about it, we would probably measure the JT interval but in clinical practice and drug development, that is not done.

It's also important to emphasize that this is not an easy measurement to make with a high degree of accuracy. The little boxes on those EKG's are 40 milliseconds. The calipers are about 20 milliseconds wide, half a box or a little less than that and there is tremendous variability both in the way that it's measured and also in the measurement itself within any individual over the course of 24 hours. So the techniques that are used to measure QT intervals and to assess the effects of drugs need to be extremely precise and this is not an easy undertaking.

Automated QT analysis has been used in a number of programs. I don't think it's used much any more. We all look at EKG's that show us QT interval measurements and while they are often quite reliable in the setting of normal T waves at physiologic heart rates, they are unreliable at extreme of heart rate and certainly in the presence of abnormal T waves or prominent U waves. In addition, the automated analyses tell us nothing about the TU wave complex morphology, a feature of these EKG's that is extremely important to pay attention to because drugs, in fact, may alter the QT -- excuse me, the TU morphology as their only sign of an effect on IKr and I've seen situations in which a significant QT effect has been missed entirely because of failure to pay attention to morphological changes.

So these EKG's have to be analyzed by people who are expert at doing it and if they're done by technicians, they need to be over-read carefully by cardiologists. This is an electrocardiogram from an entirely asymptomatic young individual who turns out to have a genetic abnormality that is a polymorphism of an HERG, an IKr abnormality, and the evidence of that is in lead two, in which there is a splayed, notched T wave with a fairly large U wave. This morphological change is fairly typical of one form of the congenital long QT syndrome, the one that effects IKr and it's also not uncommon with drugs that have very significant effects on IKr.

This QT-U complex -- this pointer is on way out. If you have a backup, I'd be very grateful. This QT-U complex is distinctly abnormal but if you didn't notice this, and simply looked at the automated analysis, you'd see a QT of 400 and a QTc of 401. In fact, those numbers are wrong and in addition, there is no comment at all -- thank you -- about the morphologic abnormality which is really the only way to detect this problem.

Sorry about that. Thanks. The QT interval is a variable phenomenon. It is highly labile and one of the most important influences on the QT is heart rate. You can see that the QT interval prolongs at slow heart rates and shortens at high heart rates. There's a direct relationship between cardiac cycle length and QT; the slower the cycle length, the longer the QT, the shorter the cycle length, the shorter the QT and in order to make comparisons at different times of day or under different circumstances, one has to use correction formulae that take into account the effective rate on the QT interval in any one individual.

In the vast majority of development programs, and certainly in clinical medicine, the formula that's used is the Bazett Formula which is the QT interval, the absolute QT divided by the square root of the RR interval that precedes that measured QT. And in the general population, this averages somewhere around 380 to 400 milliseconds, probably closer to about 380 milliseconds. The problem is that the Bazett formula is extremely limited. It falls apart at high heart rates and at very low heart rates and it is, in fact, probably the least accurate of all the formulae that are available. It was kind of defined into existence about 70 or 80 years ago based on 39 patients who were reported by Bazett and because it was the first description of this correction, it has stuck, but it is clearly a problem and one that I would at least argue should be abandoned.

There are many other formulae, including Fridericia, which uses the cube root baseline correction formula and a host of linear and non-linear regression formulae that can be used to correct for heart rate. I'm not aware of a perfect way of doing this. This is an area where the state of the art has not yet been defined and it is certain influx. I think the only important point I would emphasize is that the Bazett formula has very major limitations and particularly in the setting of drugs that increase heart rate may result in very misleading QTc intervals, that is over-estimates of the QTc interval.

The formula tends to over-correct, that is give you a longer corrected QT when the heart rate goes up. The normal range for intervals is listed here and for males it's somewhere under 430, females under 450. Clearly prolonged is greater than 450 in males and greater than 470 in females and this gender difference is important, not terribly well understood, but what is clear is that females tend to have longer QTc intervals at baseline and are also generally more susceptible to the effects of IKr blocking drugs and in fact, much if not most of the drug induced Torsades that occurs tends to occur in women and I'll show you some data on that in just a minute. In fact, I'll show it to you here.

These are data from two separate series. This series was reported by Makkar in 1993 in which he analyzed 332 cases of anti-arrhythmic drug induced Torsades de Pointes in which either a QT or a QTc interval was measured around the time of the event. And what he found was that about 90 percent of the patients who were described in these series had corrected QT intervals of greater than 500 milliseconds and of those in whom the QT but not the QTc was reported, about 80 percent had a QT greater than 500, suggesting that the degree of QT prolongation particularly when it exceeded 500 milliseconds, may be important in defining a subset of patients at increased risk for Torsades.

A similar analysis in 189 cases of Torsades with non-anti-arrhythmic drugs turned up virtually the same numbers. That is the vast majority of reported cases had QTc's or QT's greater than 500 milliseconds at the time of the event. There is, however, a potential reporting bias here and one has to be very careful about interpreting these data because we don't know what the denominator is in fact, investigators may be somewhat biased away from reporting cases in which the QT is not markedly prolonged. There's no way to know that with certainty but these are the best data we have.

These are the gender distributions in both series with anti-arrhythmic drugs. Seventy percent of the events occurred in women, 30 percent in men and with non-anti-arrythmics it looks essentially exactly the same and this is obviously important in a drug development program wherein assessing the potential risks of a drug you have to have data on sufficient numbers of women to determine whether there is a gender difference because clearly this is a risk factor for drug induced Torsades.

Now, what about some specific agents or at least classes of agents? I've divided them into two categories and I think about drugs in terms of two categories; those in which the therapeutic effect of the drug is directly tied to its IKr blocking properties and if you don't have the IKr effect you don't have the therapeutic effect and these are the anti-arrhythmic drugs, a least a partial list of the anti-arrhythmic drugs that exert this effect and we understand and accept the fact that Torsades de Pointes is part and parcel of using these agents. Most of them have an incidence of Torsades that is in the range of one percent and sometimes a little higher.

What's more important for the purposes of today's discussion and what creates the regulatory conundrum that everybody is facing these days are the low risk drugs, that is drugs in which the therapeutic effect is entirely independent of the IKr blocking properties of the drug, where in situations in which the IKr blocking effect is an undesirable side effect of the drug and in which the risk of Torsades is very low, that is less than .1 percent and often two orders of magnitude less frequent than that. And these include drugs that you're familiar with, antihistamines, antibiotics, antiviral agents, psychotropics and many, many other agents.

The occurrence of drug induced Torsades de Pointes generally with the latter class of drugs and that's all I'm going to focus on for the rest of this discussion, that is the drugs in which Torsades is an extremely rare occurrence, the occurrence of TdP in that situation is rarely a result of the use of the single agent by itself in a perfectly normal patient. It is more commonly due to the combination of a mild to modest drug effect on IKr in the setting of an effect amplifier. And this is a challenge because it's very hard to study all of these and two, it's extremely difficult to predict them in any population or any one individual over the course of time and these include bradycardia, electrolyte abnormalities, heart disease, particularly hypertrophy or congestive heart failure in which we know IKr is down regulated and action potential durations are long to start with, atrial fibrillation in which irregular cycle lengths predispose to the occurrence of Torsades particularly in the setting of anti-arrhythmic drugs, female gender, undetected mutations in the HERG gene, which codes for IKr. We know now that there are individuals out there who have phenotypically normal EKG's and who are asymptomatic yet who carry mutations in the HERG gene and are susceptible to polymorphic ventricular tachycardia and sudden death and these patients, while probably not numerous, are probably when exposed to IKr blocking drugs, significantly more sensitive than those who don't have these mutations.

High doses of drugs, metabolic inhibitors that result in pharmacokinetic interactions and pharmacodynamic interactions with other drugs that cause IKr blockade. This is just an example of the impact of hypokalemia on potency of IKr blockade. This is from Dan Roden's lab, showing you some examples of -- excuse me, these are concentration effect curves on IKr and let's just look at quinidine for a moment. This would be the IC50, the concentration of quinidine required to produce 50 percent block of the channel and you can see that at eight millimolar potassium, the IC50 is 3.8. This falls to 0.4. That is an order of magnitude change in potency at a potassium concentration of one millimolar. So electrolyte abnormalities can unmask a potentially very serious effect that would not be seen in the setting of normokalemia.

Metabolic interactions are obviously critically important. These were eluded to by -- in the introductory comments by previous speakers. In particular many IKr blockers are either CYP450 substrates and some of them are CYP450 inhibitors and that creates the potential for interaction both in the gut wall and in the liver and terfenadine is a good example of that and I'll come back to that in just a moment. In addition, elimination may also be an important issue particular in the setting of drugs that are renally excreted like Sotalol and Dofetilide. Renal dysfunction may predispose patients to markedly elevated plasma concentrations and increased risk of QT prolongation and Torsades.

This is just a partial list of 3A4 inhibitors to emphasize that they span a fairly broad spectrum of therapeutic classes and with many of these drugs and in particular grapefruit juice, which effects gut 3A4, the effect of these agents on the enzyme systems may long outlast the presence of the drug in the body. This is just a partial list of drugs that cause Torsades. All of them are IKr blockers and I show it just to emphasize that most of them are also either 3A4 substrates or inhibitors. It's an unfortunate combination of properties.

Here's an example of this kind of interaction, Terfenadine, well-known to everybody in this room, a drug with rather modest effects by itself when used at indicated -- at recommended doses of 60 milligrams BID, the effect trough on the QT interval was about 6 milliseconds, at peak about 18 milliseconds when given alone, but in the setting of a potent CYP3A4 inhibitor, there were marked increases in plasma Terfenadine concentrations and profound effects on the QTc in the range of 80 milliseconds. This is a drug that is subject to very significant first pass metabolism. Terfenadine largely disappears by the time its passed the liver and the active metabolite effects of Fenadine is, in fact, the drug with the antihistaminic effect but the QTc liability is related to the parent compound.

And if the parent compound is not metabolized in the gut or the liver effectively and the body sees large concentrations of it, this is the impact. This just emphasizes the difficulty in detecting this kind of risk. Trefenadine was prescribed more than 100 million times during the time that it was on the market. During the course of its development, it appeared to have relatively modest effects on the QTc interval by itself, but in the presence of Ketoconazole, marked increases in QTc, a clear-cut risk of Torsades and an increased risk of sudden death which led ultimately to the withdrawal of this agent.

Another example is Cisapride, which was also recently withdrawn. This is a modest IKr blocker with an effect on QTc, that's under 10 milliseconds. It is a CYP3A4 substrate and in the setting of CYP3A4 inhibitors, patients were exposed to markedly increased concentrations of the drug. Again, very difficult to detect any risk in the development program, more than 30 million prescriptions written for the drug, no arrhythmia signal and a very large data base review or in the NDA, yet between '93 and '99 there were 270 cases of serious arrhythmias of which 70 were fatal reported to FDA and ultimately the drug was withdrawn.

If one simply looks at these numbers, there's an adverse event rate here of less than one in 100,000, obviously impossible to detect in any drug development program and very difficult to detect even with post-marketing surveillance. Let me just come back then to this so-called multiple-hit hypothesis with drugs that have mild to modest effects on the QTc. It requires more than the drug alone to produce problems and we've listed those and discussed them earlier. This is a list of drugs withdrawn because of Torsades de Pointes and again, most of these drugs had relatively modest effects on the QTc when used alone but had some sort of metabolic liability associated with them and they include Trefenadine, Sertindole, Astemizole, Grepafloxacin and Cisapride.

QT prolongation is a significant issue in the overall scheme or drug monitoring. This is a table extracted from a Government Accounting Office report in January of this year which listed 10 drugs that were withdrawn from the market between January 1997 and December of 2000 specifically focusing on evidence of greater health risk in women and, in fact, eight of these 10 drugs had were associated with greater risk in women than in men, but I show it just to emphasize that of the 10, the most frequent cause for withdrawal was Torsades which was the cause in four of these 10 agents. So this is not a minor issue from a regulatory perspective.

With regard to screening drugs in a development program, and I'm going to skip through this very quickly because you will see and hear this data and I think everybody in the room is familiar with them, it is important to understand the effects of all new agents on IKr probably as well as on the calcium and sodium currents and also to assess in vitro action potential duration effects and this can be done in a number of systems. What's critical is that all of these parameters be evaluated over a very wide range of concentrations, preferably around 1000 fold. One can't always do that for technical reasons but that should be the target. These things should be assessed over a very wide range of heart rates and wherever possible, it's important to characterize the effects of metabolites on these parameters as well. A number of other in vitro models have been used including the left ventricular wedge preparation which I described to you, the profused rabbit heart and a host of in vivo models of Torsades including conscious and anesthetized rabbit models and a canine AV block model.

It's important to emphasize, however, that none of the pre-clinical approaches can exclude with certainty some risk of QT prolongation and Torsades and the bottom line is always the QT effect in humans. When one looks at the QT effect in patients or volunteers, we examine and the committee will be looking at these data today, both mean and mean max changes compared with placebo. This is effect on QT and QTc in particular, categorical analyses, that is percentage of patients who have prolongations of 30 to 60 milliseconds or greater than 60 milliseconds and outliers with QTc's of greater than 450, 470 and 500 milliseconds.

What's particularly important and often very difficult and I think this is a major challenge to sponsors, is to focus as much as possible on special populations, particularly patients with various forms of heart disease, hypertension, congestive heart failure and hypertrophy and coronary artery disease. In addition, it's very important that development programs have sufficient number of females in their studies to evaluate the differential effects of these agents on QTc with regard to gender.

Other aspects that one looks at in a development program include the occurrence of Torsades de Pointes which you almost never see in the kinds of drugs that we're talking about, the incidents of other ventricular arrhythmias, the incidents of syncope and the incidents of sudden death. Dizziness is often listed as well. I think that's a highly non-specific symptom and one that can't be used with any degree of comfort to point to the occurrence of a cardiac arrhythmia.

Finally, let me just re-emphasize then the critical importance of pharmacokinetic and pharmacodynamic interactions which can be assessed and then the potential for drug gene interactions which at the moment we are unable to assess. I think we've covered and let me just conclude with this slide which emphasizes that when one examines the potential liability of an agent with a modest effect on QT, a whole host of issues need to be considered, including the pre-clinical finding but most important the QT effects in humans, the adverse event profile, which we've discussed and all of these have to be evaluated in the setting of the therapeutic target. One's tolerance for some risk is likely to be higher in the setting of a life-threatening problem than it is in the setting of a non-life threatening problem.

The relative efficacy of the drug, as well as unique advantages need to be considered as do alternative options that may have a different and perhaps a somewhat better safety profile. And finally, when these are then evaluated a risk benefit assessment has to be constructed and the challenge, obviously here is we're reasonably good at assessing benefit, but in this particular situation not terribly good at assessing risk because we have a measurement, the QTc, which is a long way from the issue at hand, that is the occurrence of Torsades de Pointes and sudden cardiac death.

Let me just conclude by saying that there is no way to exclude risk with agents that have modest effects on the QTc interval. The other side of that coin, however, is that if we eliminated all drugs with some effect on the QTc interval, we would profoundly reduce our therapeutic armamentariums in many areas of medicine, in particular cardiology, infectious disease, psychiatry and oncology.

Thank you.

DR. RELLER: Thank you, Dr. Ruskin, for that telling tutorial. Our next speaker will be Dr. Douglas Shaffer, who will present the FDA post-marketing review of Torsades.

PRESENTATION OF DR. DOUGLAS SHAFFER

DR. SHAFFER: Good morning. It is my pleasure to present results of a post-marketing analysis regarding macrolide antibiotics and Torsades de Pointes completed by Sarah Singer and myself. We used the following outline. First, I will identify the goal and rationale for the presentation this morning.

Second, I will focus on the post-marketing analysis. The majority of the time will be dedicated to a descriptive analysis of the adverse event reporting system or AERS data base. I will present data from IMS Health in an attempt to describe macrolide utilization and finally I will briefly present reporting rate comparisons among the macrolide antibiotics incorporating a negative control. Finally, I will conclude with summary and conclusions.

The goal of this analysis is to systematically evaluate post-marketing data and attempt to provide the advisory committee with a descriptive overview of Torsades de Pointes and association with macrolide antibiotics. Two properties identified in the KETEK advisory committee packet and shared by the macrolide and microbials, specifically Clarithromycin and Erythromycin will be incorporated into results presented today.

First, the pharmacokinetic property, cytochrome P450 3A4 metabolism and second, the pharmacodynamic property of concentration related lengthening of the QTc or corrected QT interval.

While Telithromycin has not been marketed in the United States a post-marketing analysis now is warranted. This is recognized by the following quote for the European Society of Cardiology Policy Conference addressing iatrogenic QT prolongation and Torsades de Pointes. "Of concern is the interval usually measured in years from the marketing of these drugs to initial recognition of their association with QT interval prolongation and/or Torsades de Pointes. It is in the public's best interest to begin considering any potential for Torsades de Pointes sooner rather than later.

Considerable time and attention is warranted to randomize control trial data and drug development. However, we are well aware in the practice of medicine that adverse events often ignore the randomized control trial. It is important to keep in mind this presentation is in the context of the post-marketing setting. I would like to propose the following hypothetical scenario.

Consider a 61-year old female receives a broad spectrum antibiotic for acute sinusitis. The antibiotic undergoes hepatic metabolism and also has the potential to prolong the QT interval. After one drug, one patient, the controlled environment of the clinical trial abates and confounding variables become significant. This hypothetical situation may result in QT prolongation and ultimately a pro-arrhythmic milieu. From here we can postulate three outcomes. By far and most common, there is not pathophysiologic event, that is the patient takes the antibiotic without adversity rarely and as we just heard approximately less than one percent, the patient may experience a non-sustained arrhythmia. Even more rarely, the patient may experience cardiac sudden death. Our analysis today will be focusing on these confounding variables and presenting the patients that fall into the non-sustained arrhythmia and cardiac death categories.

Finally, as introduction to our AERS analysis, I would like to present a representative AERS report. Approximately one-third of our cases presented with a syncopal episode or near syncope. From there, the patient is seen in the emergency room where an ECG is obtained and QT prolongation is documented and ultimately Torsades. We commonly observe three outcomes; first, drug discontinuation and resolution; second, rapid deterioration and treatment, for example, with magnesium or other NCCLS protocol and rarely we do observe death.

I will now present results of our descriptive analysis of the AERS data base. We queried the AERS data base using four individual macrolide drugs as the exposure; Azithromycin, Clarithromycin, Dirithromycin and Erythromycin. We used the preferred term, Torsades de Pointes as the outcome of interest and since Torsades was not coded prior to 1995, we used the ventricular tachycardia for this time period. We included all reports regardless of nationality or routed administration.

In our description analysis our aim was to capture as much data and as many reports as possible. We excluded duplicate reports or reports prior to 1995 without Torsades de Pointes in the text. We systematically extracted pharmacoepidemiological data from each case report. PC SAS was used for analyses.

Our search query resulted in 268 reports being reviewed, 112 were excluded and 156 were analyzed and I will be presenting the details of this 156. Overall Erythromycin accounted for the majority of Torsades de Pointes reports, 53 percent. This was followed by Clarithromycin, 36 percent, Azithromycin, 11 percent. There were no reports of Torsades de Pointes associated with Dirithromycin which may be reflective of its relatively little utilization as I will show later. Twenty-eight percent of reports included an intravenous route of administration and 25 percent of the reports were of foreign nationality, a statistic that is not on this slide.

This is the first in a series of four slides where I will present pharmacoepidemiological data extracted from the AERS reports. For orientation, the variable of interest will be presented in the first column and the corresponding statistic, mean and standard deviation or frequency will be in the second column. Where indicated and appropriated at the bottom of the screen, I will provide the proportion of AERS reports providing information for the variable interest. For example, 93 percent of our cases reported information regarding age, 94 percent regarding gender, far less regarding race, 16 percent and weight was available in 26 percent of the reports.

Given this, the majority of Torsades de Pointes reports were primarily from older female patients. The mean age was 61 years and 70 percent of the reports providing gender were female. While very limited reports provided the data, those providing information, 60 percent were Caucasian and the mean weight was 152 pounds.

Approximately one-third of the AERS cases provided ECG data. Of this, 59 percent identified the QTc. The mean baseline QT in our AERS' analysis was 432 milliseconds. This is within normal limits for females and at the border upper limit of normal for males. The mean event QT were the QT Antecedent two or associated with the Torsades de Pointes report was 594 milliseconds and the mean change was 172 milliseconds. The interval between the initiation of the macrolide drug and the reported event was a mean of four days with three outliers greater than 120 days being excluded.

While we cannot assign causation and our aim is not to assign causation. Fatalities were reported. Fourteen outcomes of the 156 reports ended in a fatality. We also extracted data regarding co-morbid risk and co-morbid disease states. Forty-two percent of the AERS reports included any evidence of cardiac disease the most frequent cardiac disease reported was congestive heart failure, 23 percent. Renal disease and hepatic disease were both less frequent, 11 and 6 percent respectively. Hypokalemia or hypomagnesemia was present on 17 percent of the reports and hypokalemia alone on 15 percent.

Finally, we extracted data regarding concomitantly administered or concomitantly reported drugs and the mean number of drugs concomitantly administered or reported on our case series was four with a standard deviation of three and a range of zero to 15. We also evaluated two mutually exclusive classes of drugs or drug combinations. First, we looked for evidence of a drug interaction focusing on contra-indicated drug interactions using the product labels as guides.

In preview, this in general involves Erythromycin or Clarithromycin and a combination of Astemizole, Cisapride, Penazide or terfenadine. Thirty-one percent of the AERS reports had evidence of this contra-indicated drug interaction. In addition, after this, we further evaluated the reports to see if there was evidence of drugs or drug classes known to prolong the QT interval in uses less similar to that seen in the introduction. An additional 22 percent of the reports included drugs known to prolong the QT interval. This pie chart demonstrates the three resulting categories of AERS reports. In maroon, as I've just indicated, 31 percent of reports met the criteria for a drug interaction or contra-indicated drug interaction. In addition, 22 percent of the reports had evidence of drugs or drug classes known to prolong the QT interval. This leaves basically half, 47 percent, of the reports listing the macrolide drug as the sole suspect.

I would like to further describe the maroon section of the pie chart or the contra-indicated drug interaction section. As I mentioned, we defined this as Clarithromycin and Erythromycin and a combination of four drugs. As you can see, Cisapride accounted for the vast majority of drug interactions noted in our analysis. This was followed by Terfenadine and Astemizole. Two points should be noted.

First, Astemizole specifically is not a drug interaction with Clarithromycin but is with Erythromycin. Second, as just pointed out, these three drugs have been removed from the market. The second portion of our analysis involves data from IMS Health. We queried IMS Health's National Prescription Audit Plus to estimate macrolide drug utilization. We evaluated retail outpatient prescriptions dispensed focusing on oral formulations only since the formulation being considered today as oral.

I will present the data in two manners. First, I will use a figure to describe the representation of annual drug use and second, we will use this data in comparison of relative estimated reporting rate ratios. For this ratio, we consider the reports or numerator and we consider only domestic oral formulation or outpatient reports. Drug utilization will serve as a surrogate analytic population or denominator and we will use cefuroxime as a negative control.

This figure depicts annual macrolide antibiotic utilization with total prescriptions from zero to 35 million on a Y axis and years from 1993 to 2000 on the X axis. As you can see in the light blue line, Erythromycin use has steadily declined since the introduction of the newer macrolides. Clarithromycin, in a dark red or maroon appeared to plateau in 1996 and has a gradual decline since then. In contrast Azithromycin, a drug with five-day dosings, similar to a dosing we may see today has benefited from a marked positive trajectory and has only experienced a potential plateau in the last year.

Dirithromycin is not on the graph and this is due to its relatively low utilization averaging less than 500 prescriptions dispensed yearly. Finally, we proceeded to compare report utilization ratios within the macrolide drugs using Cefuroxime as a negative control. To do this we considered reports only of domestic oral formulation, outpatient origin and used 1993 to 2000 utilization after the drug listed in the first column reports follow in the second column, utilization in the third column and finally the report utilization ratio in the last column. I will focus on the last column.

Clarithromycin has the largest report utilization ratio among the macrolide antibiotics when considering domestic oral-formulation and outpatient reports only. This was followed by Erythromycin and then Azithromycin and Cefuroxime was used as our negative control. We are limited in the degree of certainty that can be placed upon these estimates due to the use of a surrogate analytic population and reporting biases known in the spontaneous system. From this slide, we propose to conclude that Clarithromycin had the greatest reporting ratio among the macrolide antibiotics and this was approximately nine times that of the negative control.

In summary, macrolide associated Torsades de Pointes reports are from primarily older female patients. Concomitant diseases and drugs are prevalent in potentially modifiable risks. Erythromycin overall accounts for most reports. Clarithromycin has the greatest reporting rate when considering domestic outpatient oral cases and accounting for drug utilization and finally Clarithromycin and Erythromycin Torsades de Pointes reporting rates are nine and three times that of Cefuroxime respectively.

Limitations must be addressed in considering results presented. First are those limitations germane to the spontaneous reporting system. These include adverse event recognition and report data quality. Torsades de Pointes is a difficult adverse event to capture. We evaluated each report individually in an attempt to assure reporting accuracy. However, without an ECG rhythm strip or data from telemetry we cannot have 100 percent certainty.

We must also consider the influence of biases. Market time and market environment are biases that should be considered. We did not adjust for secular trends. Rather we propose to let the data speak freely and consider these results in light of biases and the implication they may hold. Under-reporting is a well-known bias with spontaneous reports ranging anywhere from one to 10 percent of adverse events making it to the FDA depending on the severity.

I propose that we should consider a competing bias as well. We cannot overlook the potential bias in Clarithromycin reports due to the Cisapride received. As I showed, Cisapride was the most common drug interaction and overall in our data base accounted for approximately one-fifth of the reports. It is possible among the macrolide drugs that Clarithromycin received relatively more reports. We cannot make inferences regarding missing data and this addresses the specificity of spontaneous reports. An example is Telithromycin. We do not see reports of Torsades de Pointes with Telithromycin. However, it would be inappropriate to conclude that there is no association.

And finally, we are unable to establish causation in this type of analysis. Our goal was to present a descriptive overview. And last, reporting rate estimates are not synonymous with incidents rates. I propose, however, there are several advantages to consider. We systematically proceeded with pharmacoepidemiological data extraction within this class to an extent not previously seen before. This is a cost efficient analysis. In clinical research today we must recognize the need for cost efficiency. Spontaneous reports are a relatively cost efficient means for this type of analysis.

Regarding best available evidence, it is not always possible to turn to the randomized control trial or large cohort study particularly when evaluating rare potentially fatal outcomes. The AERS data base is arguably among the best available for not only single generation but descriptive and qualitative analyses as well.

Finally, we provided a detail analysis of individual drugs in the post-marketing setting. This series of case reports offers a descriptive overview of tangible data unavailable in the clinical trial. In conclusion, Telithromycin, the first of a new class of antimicrobials related to macrolides interacts with cytochrome P450 metabolism and prolongs the QT interval.

Recognition of the potential for Torsades de Pointes should clearly be acknowledged. And monitoring of post-marketing data and development of risk management strategies would be critical if the drug was marketed in the United States.

Thank you. And I would certainly like to take the opportunity to state that our AERS data base is in part dependent on the quantity and quality of reports submitted and we certainly encourage use of this valuable asset. Thanks.

DR. RELLER: Thank you, Dr. Shaffer, for that balanced review. We will now take a short break but please reconvene at 9:35 promptly to begin the sponsors' presentations.

(Whereupon, the meeting went off the record at 9:21 a.m. and went back on the record at 9:38 a.m.)

DR. RELLER: I should like to introduce Dr. Mindell Seidlin, Vice President for Clinical Development of Anti-Infectives Aventis. Dr. Siedlin.

INTRODUCTION OF DR. MINDELL SEIDLIN

DR. SEIDLIN: Thank you, Dr. Reller. Good morning, ladies and gentlemen. It is my privilege to introduce the Aventis presentation on Telithromycin, the first Ketolide. This is the agenda for the Aventis presentation. The introduction will focus on the need for new antibiotics in this era of increasing resistance. Subsequent presentations will detail the mechanism of action and in vitro microbial profile and human pharmacology of the drugs. The clinical efficacy and safety with special discussion on the ECG findings will follow. I will then summarize the unique features of Telithromycin which represents and advance in antimicrobial chemotherapy and address current therapeutic needs in this area.

Clearly, the emergence of multi-resistant respiratory pathogen, particular streptococcus pneumoniae have driven the need for new drugs in this area. Currently, physicians who perceive their patients to be at risk for drug resistant respiratory infections have only one or two classes of drugs to choose from. Availability of new drugs with novel mechanisms of action will reduce the resistance pressure on existing classes. While the emergence of multi-resistant strains is a key driver of medical needs in this area, we must not lose sight of the other elements for successful therapy of respiratory infections. Out-patient therapy is moni-therapy. New respiratory antibiotics must be effective against the full range of pathogens responsible for these infections; common, atypical and intra-cellular.

Ideally, they should be effective when administered with a brief simple regiment that can facilitate patient compliance and minimize drug exposure. Brief regiments which do not lead to misdoses in sub-therapeutic levels may limit further resistance. Recent policy statements by both the World Health Organization and the United States Department of Health and Human Services have included recommendations on development of new antibiotics in addition to judicious use of existing agents.

New drugs for community respiratory tract infections must be effective against the full range of relevant pathogens and must reach sufficient concentrations at the site of infection. Streptococcus pneumoniae is key because it is the most common pathogen but also the one most associated with serious sequelae and bacteremia. Rapid and cidal activity against sensitive strains of the pneumococcus may reduce the likelihood of emergence of resistant strains.

The other typical bacterial species which are associated with these infections include Hemophilus influenza and moraxella catarrhalis, both of which now include many beta lactamase positive strains. Achievement of adequate levels in plasma and particularly for pneumonia an extracellular fluid are important when treating these infections. The importance of atypical and intracellular pathogens is increasingly being recognized. In these inceptions, intracellular levels of drug are key.

Let us now turn to the clinical relevance and impact of resistance. Demonstration of the clinical impact of penicillin resistance was first observed in patients with pneumococcal meningitis. Due to relatively poor penetration of many beta lactams across the blood/brain barrier, even strains with intermediate levels of resistance to penicillin failed therapy in this indication. As the prevalence of high level resistance increased in the late '90's, outcome studies began to demonstrate impact of penicillin resistance on mortality, suppurative complications and other clinical adverse outcomes. It's important to remember in this context that some 60 percent of penicillin resistant pneumococci are also resistant to other classes of drugs.

The first cases of clinical failure of patients with Erythromycin resistance streptococcus pneumonia who were treated with macrolides were reported in the early '90's. At that time, there were few isolates with MICs greater than or equal to 4. Recently there have been an increasing number of reports. All of the reports in the latter part of the '90's have occurred in patients whose organisms have MICs of 8 or more. In contrast to the situation with penicillin and beta lactams, where high plasma levels can be achieved with increasing doses of the drug, increasing doses of macrolides to achieve plasma levels that will cover MICs of 8 or more in simply not feasible.

This slide shows data that was kindly shared with us by Dr. Cynthia Whitney at the CDC. In the left-hand panel, you can see the increasing frequency of Erythromycin A resistance among sterile sites of pneumococcus. In 1999, 20.3 percent of these isolates were Erythromycin A resistant. In the same year 16 percent were penicillin G resistant. The panel on your right shows the frequency of MICs of 8 or more in these same isolates. This demonstrates that not only has the frequency of Erythromycin resistance increased but the level of resistance has increased as well.

Here is the dilemma faced by physicians who must prescribe for out-patients with bacterial respiratory tract infections. Let's take community-acquired pneumonia as an example. Current Infectious Disease Society of America guidelines suggest that if a patient is not at risk for drug resistant streptococcus pneumonia, there are three options; macrolides, tetracyclines or flouroquinolones. If, however, the physician judges that the patient is at risk for drug resistance streptococcus pneumonia, the options reduced to one, flouroquinolones. The lack of options will further increase resistance pressure on this class. Further, there are no options for patients intolerant to that class.

Telithromycin is the first key light. It has excellent pneumococcal activity. This is crucial because in addition to being the most common bacterial respiratory pathogen, it is the one most associated with serious consequences. Telithromycin retains activity against Erythromycin A and Penicillin G resistant strains of the pneumococcus and is effective against all of the key community respiratory pathogens. The pharmacokinetic profile support a brief simple therapeutic regiment which will facilitate patient compliance.

This slides lists the indications that were proposed for Telithromycin. The mechanism of action and in vitro anti-microbial profile will now be presented by my colleague, Dr. Bryskier.

PRESENTATION OF DR. ANDRE BRYSKIER

DR. BRYSKIER: Good morning. It will be a pleasure for me now to share with you our current knowledge on the anti-bacterial activity and the mode of action of Telithromycin new Ketolide. Ketolide will synthesize and design to overcome Erythromycin A resistance within gram-positive cocci. This figure illustrates the structure of a Ketolide. The Ketolide are composed of three parts; the lactone ring, a 3-keto function and a Cll-C12 carbamate residue substituted by a long side chain.

Now, I want to share with you the property issue for this chemical structure. Here you have the cladinose, a natural sugar. If you remove the cladinose and by chemical modification you obtain the 3-keto function. The name came from the 3-keto function the Ketolide. Most important, the property you obtain with the 3-keto function as a following, first, high stability in acidic environment. After six hours of contact of pH1 95 percent of the Telithromycin activity remain.

Second, the anti-bacterial activity against erm-containing strains remain. Inability to induce macrolide lincosamine strepogramine-B resistance. Now, the second part of the structure. The C11-C12 carbamate residue substrated by a long side chain, you obtain the innovation of this compound. The C11-C12 gives you the following; reduced impact of efflux mechanism of resistance; second, enhanced antibacterial activity against gram- positive bacteria; third, govern intracellular accumulation and efflux in phagocytes and most important the mode of action.

I will call your attention of the mode of action. The first to know we are really on the front of the knowledge and the science with the mechanics of action and resistance to macrolide and Ketolide today. Telithromycin inhibits protein synthesis. Second, Telithromycin deplete ribosomes contained in bacterial cells. Let's have a look on protein synthesis. Protein synthesis is the protein produced in bacterial ribosome. Ribosome are constituted by two subunits, small one 30S and a big one 50S subunit. The target for Telithromycinis located on the 50S subunit. One side is the peptidyl transferase site and especially in rRNA place, a subunit of ribosome constituted by protein and rRNA.

As molecular, the peptidyl transferase is constituted by three parts. In 23S rNRA you so-called six domains. Two domains constitute the peptidyl transferase site, Domain V, Domain II and the link with another rRNA, the fifth rRNA. The difference between Erythromycin, Clarithromycin and Telithromycin is where the drug is fixed. When the drug enter in the pocket, here you have a fixation on Domain V through the desosamine, an amino sugar, Erythromycin, Clarithromycin, Azithromycin. Telithromycin also entered the desosamine so Telithromycin is also fixed on Domain V but the difference, there is a very long side chain, a carbamate side chain. This carbamate side chain allows you to be fixed on Domain II.

So the difference, you have a double fixation on the peptidyl transferase sites. Now, the depletion of the ribosomal contained. Inhibition of ribosomal subunit formation, 30S subunit, 50S subunit gives you this big ribosome system. With Erythromycin A, you have inhibition and abnormal protein form within 50S subunit. These proteins are destroyed and you have a depletion of ribosome. Telithromycin also acts on the 50S subunit but the difference, you have a double blockage, 30S subunit is also blocked. And I remind you that the 30S subunit is also the place where the protein synthesis is processed, so that means that you have a deep depletion and a total blockage of your synthesis and the consequence is that the drug is bactericidal. What is a consequence of a double binding?

So first, we explain that the mode of action is due to the C11-C12 side chain. Also overcoming mechanisms of resistance is partly due to this chain. If you have a methylation for instance on the Domain V, Erythromycin is unable to be fixed and the drug is no more active. So you have a resistance to Erythromycin and a cross-resistance with other like Erythromycin and Clarithromycin. Telithromycin could be also blocked in Domain V but a second arm on Domain II and Telithromycin retain activity against Erythromycin air resistance organisms.

Telithromycin is also active against another mechanics of resistance to Erythromycin efflux by another way. The drug is pumped out, when you have a poison in the cells, the cells wants to pump out the drug to survive. The blood is able to pump out Erythromycin A due to a high affinity to the pump, but the low affinity is for Telithromycin and you don't have this problem, so activity retained for Telithromycin. And that's a type of mechanism of mutation on protein, ribosome protein and Telithromycin retained activity for exactly the same problem with the C11 - C12 side chain.

Telithromycin is today the most active drug against pneumococci. On this shot, this work was done by NCCLS methodology and it was done by Gary Doern. And here you have Telithromycin. Telithromycin is more active than Clarithromycin, Azithromycin, Levofloxacin, as seen here, and Linezolid.

There's an anti activity that is a third property of this C11-C12 side chain is not only an anti-activity but also the drug is active against strep pneumonia resistance to other compounds which act on S. pneumoniae. Here you have comparison between Telithromycin and Clarithromycin. It's very evident that even if you have an efflux of macrolide and lincosamine streptogramine-B resistance, Telithromycin retain activity.

We have explored other drugs. When a S. pneumoniae is resistant to Cefotaxime, to Penicillin G, Tetracycline, Cotrimoxazole, Ofloxacin, Telithromycin retained activity and is highly active. So there is no cross-resistance between all these drugs and Telithromycin.

A fourth, very important, among this class of antibiotic it is the first time that we have a drug with a rapid bactericidal activity at an MIC level. So what is important, you have a very quick drop of three or more logs after four to six hours of contact. But at 24 hours with a mode MIC around 0.01 to 0.03 microbial we end up with Telithromycin against S. pneumoniae, we still have a bactericidal activity. So with 800 milligram per day, you cover the 24 hour period and you expect to have a bactericidal activity. All this in vitro data will confirm in vivo in animal model. Disseminated infection, lung infections in mouse and we use Erythromycin susceptible and Erythromycin resistant micro-organisms with different mechanisms of resistance, erm and mef. In a survey in North America only one strain about 2,000 -- out of 2,000 MIC of four, Telithromycin was about 4 so only one strain. So it is today a very rare occurrence.

But Telithromycin is not only a drug for S. pneumoniae. It covers many micro-organisms and mainly all the bugs which are involved in respiratory tract infections; S. pneumoniae, S. pyogenes, H. influenzae, moraxella catarrhalis, and S. pyogenes, Legionella pneumoophila, C. pneumonliae and atypical mycoplasma. The data you have here, I share with you were obtained also by NCCLS methodology.

The other very important point which is related and linked with the section is intracellular accumulation. With Telithromycin you have an accumulation or concentration in the cells in phagocytes with a ratio between 350 and 400 times. But the drug is also eliminated. Forty-five percent of the drug is pumped out in one hour period, so no accumulation in the cells. But accumulation of concentration in cells doesn't mean activity. So bioactivity is very high with Telithromycin demonstrated in C. pneumonaie, bactericidal activity, Legionella pneumophila in many models, S. pneumoniae and other intracellular pathogens. For S. pneumoniae it was demonstrated in the model two that it was the only compound that stabilized the cells, not as a compound we tested. We have tested quinolones, we have tested macrolides, and it is the only one who are able to do that. Even rifampin is not able to do that.

So to sum up the antibacterial activity and the mechanics of action and resistance to Telithromycin; Telithromycin is the first Ketolide, a new class of antibiotics. Telithromycin exhibits antibacterial activity against S. pneumoniae, resistance to other antibiotics. Telithromycin is able to overcome Erythromycin A resistance and achieve our targets.

Important bactericidal activity is obtained with the major respiratory pathogens. Doesn't induce MLSb macrolide, lincosamine, streptogramine -3 resistance. A low frequency of selection of resistance was noted in cellular passages. And it's active against all resistance pathogen with other drug. Thank you. Now I will ask Vijay Bhargava to continue with pharmacokinetics.

PRESENTATION OF DR. VIJAY BHARGAVA

DR. BHARGAVA: Thank you, Andre. Good morning. I will outline the key clinical pharmacology data for Telithromycin. Doses ranging from 800 to 3200 milligrams were given in this program to establish the pharmacokinetic and safety profile of Telithromycin. Safety aspects of Telithromycin in clinical pharmacology will be discussed by Dr. Benedict.

First, I will present the key plasma and tissue characteristics. Second, I will present the disposition profile and exposure profiles when these pathways are blocked either by drug interaction or impairment of an eliminating organ. And third, I will present support for the dose that was used in the Phase III trials.

This slide shows the pharmacokinetics after an 800 milligram single dose and as multiple doses to steady state in healthy volunteers. Absorption is rapid as seen in both cases as seen by the t max. The maximum concentration after single dose is similar to that seen after steady state in concentrations over two microgram per mL are achieved. Trough levels and area under the curve increase upon multiple dosing and steady state was rapidly achieved after the second or third dose.

There is a bi-expediential elimination with terminal half-life of seven to 10 hours. This profile is reproducible and representative of that scene in healthy volunteers and in patients. This slide shows the tissue concentrations of Telithromycin in patients when dosed with 800 milligrams once a day to steady state. In the three tissues here, adequate concentrations were rapidly achieved and are detectible for at least 24 hours. Patient data for the important target tissue epithelial lining fluid is from the laboratory of Honeybourne and Wise where similar data for other drugs has been reported. Levels in the ELF as high as 14.9 microgram per mL were observed. In other tissues high levels of Telithromycin were also achieved.

Regarding other key pharmacokinetic characteristics, absolute viable ability of Telithromycin is high at about 60 percent in both the young and elderly subjects. Protein binding is approximately 70 percent meaning that binding interactions are unlikely. Pharmacokinetics between men and women were similar and no food interaction was observed with this drug.

In the next few slides, I'd like to show you the multiple pathways of Telithromycin disposition. I will also present exposure profiles in population where these disposition pathways can be impaired. After an oral dose, over 90 percent of the drug is absorbed through the gastrointestinal tract. Prior to reaching systemic circulation about 33 percent of the drug is metabolized in the liver or gastrointestinal tract resulting in a systemic bioaviability of 57 percent. Once the drug reaches systemic circulation it can be eliminated by the GI tract or biliary secretion about seven percent, it can be renally eliminated as unchanged drug in the urine, about 13 percent.

Telithromycin can also be metabolized in the liver and excreted as several metabolites that add up to about 37 percent. The metabolites of Telithromycin are equally mediated by cytochrome P450, mainly 3A4 and non-cytochrome P450 pathways. Non-cytochrome P450 pathways are rarely associated with clinically relevant drug interactions or inhibitions. In clinical studies, the non-cytochrome P450 metabolite was not inhibited with Ketoconazole or in hepatic impairment.

Since the exposure of Telithromycin to CYP3A4 isozyme is limited, its potential for increased exposure when this pathway is blocked is minimal. This contrast with other drugs such as Cisapride and terfenadine where CYP3A4 is the primary isozyme for elimination. The effect of Telithromycin when given with or without 3A4 inhibitors on cardiac repolarization will be discussed by Dr. Benedict. Two other important points regarding Telithromycin metabolite to note; first SYP2D6 is not involved in its metabolism and secondly, due to minimal exposure metabolites do not contribute to the activity.

In the next few slides I will show you the exposure in populations where one of the disposition pathways could be impaired. Having established that the contribution of CYP3A4 is limited, we wanted to validate this in clinical studies with several drugs that are known to be potent inhibitor of this enzyme. This slide shows the effect of Ketoconazole , one of the most potent CYP3A4 inhibitors on the pharmacokinetics of Telithromycin at steady state to mimic the clinical situation. Area under the curve increased two-fold. Importantly the increase in C max which may be more relevant to safety was less at about 1.5 fold. As indicated earlier, this contrast with drugs where CYP3A4 is the primary pathway, for example Cisapride levels increased eight-fold and terfenadine levels 16 to 73-fold when they are co-administered with Ketoconazole.

With other potent inhibitors such as itraconazole, we saw a lesser interaction and also very importantly with grapefruit juice, we saw no change in exposure of Telithromycin. Regarding hepatic impairment, the maximum concentration in AUC values indicated no change in exposure after a single dose of Telithromycin. Interestingly the renal clearance of Telithromycin in subjects with hepatic impairment increased about 60 percent when compared to the age and sex matched controls in this study.

A multiple dose study in patients with hepatic impairment has been completed and data recently shared with the agency. Similar to the single dose results, in this multiple dose study where 800 milligrams once a day was administered for seven days, exposure did not change in the hepatically impaired subjects either on day one or on day seven. Increases in renal clearance of Telithromycin were also seen in this study both at day one and day seven in subjects with hepatic impairment compared to the age and sex match control. Similar findings for Clarithromycin have been documented.

Pharmacokinetics were investigated in subjects with different degrees of renal impairment. The Cmax and AUC increased about 1.5-fold in the group with creatinine clearance of 11 to 40 mils per minute and lesser increases were observed with the group creatinine clearance of 41 to 80 mils per minute. Thus, we have now seen that when a Telithromycin elimination route is blocked the risk of increased exposure is limited due to the multiple pathways.

One other point regarding the limited risk of exposure for Telithromycin due to drug interaction is its high absolute bioavailibility of about 60 percent. Inhibition of first past metabolism with Telithromycin will result in less than a two-fold increase unlike drugs with low bioavailability for example, Semvastatin and Cisapride and Terfenadine where changes of six to eight-fold or greater are observed.

Next we will look at Telithromycin in the elderly. The Phase I data are outlined in your briefing document and show that the elderly have a modest increase when compared to the young. Data shown here are from our Phase III study in community- acquired pneumonia patients where risk factors for increased exposure may have been present -- were present, for example, concomitant medication, infections or decrease renal and/or hepatic function.

When comparing the CAP patient under 65 to over 65, we see a 1.4-fold increase in AUC and more importantly, a 1.2-fold increase in Cmax which was lower. The safety of Telithromycin in the elderly will be discussed by Dr. Leroy and Dr. Benedict.

The next few slides illustrate data that was used to establish the dose and regiment for the clinical efficacy trial. Telithromycin was evaluated using the well-known mouse thigh infection model in Professor Craig's unit. The pharmacologically effective dose was similar irrespective of the frequency of dosing. That is, when similar doses were given, divided into three, six, 12 or 24 hours, the outcome was similar.

Area under the curve over MIC and Cmax over MIC were better predictors of efficacy than time over MIC. This indicated that the efficacy of Telithromycin is concentration dependent like that of azithromycin rather than time dependent like that of clarithromycin. Therefore, this model indicated that a once daily dose that would achieve adequate Cmax and AUC values would be efficacious in the clinical studies.

Once the pharmacokinetic, pharmacodynamic data were established, the human dose was chosen so that the unbound AUC over MIC values would be similar to or higher than the AUC over MIC values at the effective dose in mice. Eight hundred milligram given once daily met this criteria. In addition, as shown earlier, the tissue concentrations after the 800 milligram dose in Phase I studies were adequate to achieve the MIC 90 for S. pneumonia. Hence, the doses predicted by the model were validated by levels observed in humans after the 800 milligram Telithromycin given once daily.

A few points need to be made regarding the dose selection in H. flu. Contrary to the S. pneumonia situation, there is no well-validated model for predicting the therapeutic dose for lower respiratory tract infection caused by H. Flu. Non-typable H. Flu is rarely isolated in the blood stream of infected patients. Hence, the drug levels in respiratory tissues are important in the treatment of this pathogen. The ELF levels of Telithromycin after the 800 milligram dosed once a day exceed the MIC value for H. Flu.

Plasma and extra cellular concentration of Telithromycin are higher than those for Azithromycin which is one of the better in vitro macrolide for H. Flu. The efficacy of the chosen dose will be discussed by Dr. Leroy.

In summary, Telithromycin rapidly achieved the targeted plasma and respiratory tissue concentrations. Telithromycin has a well characterized and reproducible pharmacokinetic profile with a high bioavailability. Telithromycin has multiple pathways for elimination and its metabolism by CYP3A4 is limited. It is significantly metabolized by non-cytochrome P450 pathway and also eliminated as unchanged drug, unlike other drugs where CYP3A4 interactions have been an issue.

Pharmacokinetic and pharmacodynamic data were used to support the 800 milligram dose given once daily during the clinical efficacy program. Thank you and I'd like to turn it to Dr. Leroy.

PRESENTATION OF DR. BRUNO LEROY

DR. LEROY: Thank you, Vijay. My subject now is the clinical efficacy of Telithromycin in respiratory infections and I will start with the common element of study design and then cover efficacy in each of the four indications. The dose of 800 milligrams was chosen for all indications. And in this program we also studied the efficacy of short five-day treatment cause for common infections other than pneumonia. This was based on the potent in vitro activity of Telithromycin as well as its high and prolonged diffusion in tissue.

The benefit targeted with the short treatment duration was an improve patient compliance as well as a decrease of antibiotic exposure. In the pneumonia trials, a seven to 10 days regiment was maintained to insure that enrollment will not be biased to want patients with mild diseases. Some key elements of the study design was standardized across studies and indications. There were five study visits and you know in accordance to the FDA drug guidelines for Anti-Infectives, the test of cure was performed at the post-therapy visit between day 17 and day 21.

In studies where five-day Telithromycin was used, a placebo peer at five days was added in order to maintain the blind and the test of cure was performed in the studies at the same time after the start of treatment in both groups. And this was the most stringent approach allowing to capture the early relapses.

This approach was also recommended by the FDA. There were three main analysis populations. The mITT population corresponds to the intent to treat population excluding subjects who did not have the disease or did not receive treatment, the PPc corresponds to the mITT excluding subjects who had major protocol violation or an indeterminate response and this was the primary analysis population in all indications except in tonsillitis/pharyngitis and I will focus on this population during the presentation. Results of the mITT analyses, which are presented in the briefing document, were consistent with the PPc analyses. The protocol population was the primary analyses for tonsillitis/pharyngitis. Let us first consider the efficacy of Telithromycin in community acquired pneumonia. There were three controlled double blind comparative studies; 3001 compared 10 days of Telithromycin with 10 days of amoxicillin high doses, one gram three times daily. This comparator is increasingly considered as the best therapy in countries with high prevalence of S. pneumonia resistant to penicillin. 3006 compared 10 days of Telithromycin with 10 days Clarithromycin given 500 milligrams twice daily and 3009 was performed with Trovafloxacin as a comparator because of its efficacy against resistant strains of S. pneumonia.

This study was stopped before the planned sample size was reached when the FDA restricted the use of Trovafloxacin because of post-marketing safety concerns.

Three open-label studies were also performed, 3000 designed to obtain some pharmacokinetic data in patients with pneumonia. 3009 open-label which was performed only in South Africa, was aimed at gathering additional cases of S. pneumonia resistant to Erythromycin or penicillin and in this study consolidation on chest x-ray was required in all patients at entry. This study was an extension of 3009 with Telithromycin but no subjects of 3009 were included in 3009 open label.

Data from a dose comparison study performed in pneumonia in Japan 2105 will be also presented in agreement with the FDA. In total, more than 1300 subjects were treated with Telithromycin for pneumonia.

Looking at criteria associated with an increased severity, we can see that risk factors for morbidity summarized here for the mITT population were well balanced between Telithromycin and the comparative groups in comparative studies. And turning now to the pool of Telithromycin patients, you can see that the significant numbers of outpatients at risk of complication were included in the program. For example 16 percent of subjects had a fine score of three and a above, 56 subjects had an associated pneumococcal bacteremia. And this to our knowledge is one of the highest number of pneumococcal baceterimia submitted in an NDA for an oral antibiotic.

Therefore, we believe that the upper end of severity expected for outpatients with pneumonia in the community has been well-captured in this program.

On this slide the bar represents the cure rates with Telithromycin in blue and the comparator in gray. And at the bottom of the bars are the study numbers and the comparator used. At the top of the bars are the cure rates and the 95 percent confidence interval of the difference.

Analysis of the PPc population demonstrated equal balance between Telithromycin and high dose Amoxicillin and Clarithromycin with clinical cure rate with Telithromycin of 95 percent in studies greater than one and 81 percent in studies greater than six. In both studies the lower bounds of the confidence interval was well within trial limits.

In 3009 versus Trovafloxacin both treatments gave high cure rates exceeding 90 percent. However, the planned size was not reached for the reason explained earlier. But the results also support efficacy of Telithromycin in this indication. Clinical cure rate in the uncontrolled studies were consistent with the comparative studies and of note in study 3009 open-label where consolidation was required at entry, the cure rate was high with 94 percent in the PPc population.

In the Telithromycin group the clinical cure rate by pathogens for the most frequently isolated organism varied between 87 percent and 95 percent with the highest rate observed for S. pneumonia. Stringent serology criteria were used for the diagnosis of atypical pneumonia, which are detailed in the briefing document. Only patients with no common pathogens were considered for this diagnosis and the cure rate was over 90 percent for these pathogens.

Interestingly, 12 subjects were diagnosed with Legionella infection by serology or antigen soluble and these number of -- these pathogens are less observing of patients than in those hospitalized patients, but still ought to be considered as they represent a threat in the out-patients with pneumonia. All these 12 subjects were cured. This table summarizes the efficacy in the out-patients most likely to develop complications. In the Telithromycin group the cure rate, a test of cure, was high, 90 percent and above in elderly subjects. In subjects with Pneumococcal bacteremia in the PPb population, any subjects with fine score greater or equal to three.

Of particular note is the outcome of serving subject with Pneumococcal bacteremia. Efficacy in this subject may result from the combination of the excelling in vitro activity of the Telithromycin as well as its substantial plasma results and we believe that that differentiates Telithromycin from isolates compound giving low class labels and that it provides a high level of confidence in the treatment of out-patients with pneumonia in the community.

Now we will turn to the outcome in subjects with resistant isolate of S. pneumonia who are treated with Telithromycin. A summary of the results obtained in Western and Japanese studies are shown on this slide. And looking first at all resistant pathogens including both single and multiple pathogen infections, we can see that 19 strains were resistant to penicillin, 16 of which were associated with clinical cure, 25 strains were resistant to Erythromycin, 21 of these strains were associated with a clinical cure and of note, a total of 18 strains resistant to Erythromycin had an MIC greater or equal to 8 microgram per ML and 15 of these strains where associated with a clinical cure.

Results for infections due to single pathogens are given below with similar cure rates to single and multiple infections. If we look at the sub-set of subjects with resistant S. pneumoniae and documented bacteremia the number are limited but still substantial given that these were out-patients treated orally. Seven out of the nine subjects with S. pneumonia resistant to penicillin or Erythromycin were cured.

In one of the two subjects categorized as failure which are counted in all the rolls, and these subjects had an S. pneumonia resistant to both Penicillin G and Erythromycin A, the S. pneumonia was eradicated from the blood with a documented negative blood culture and an improvement of clinical symptoms. But these subjects had a secondary infection with SRAs isolated in urine leading to the prescription of an anti-infective.

In summary, efficacy was demonstrated with seven to 10 days of treatment with Telithromycin in pneumonia due to common and atypical pathogens. Cure rate in patients with pneumonia, with S. pneumonia and Legionella pneumophila which are the two pathogens associated with the risk of morbidity, were excellent. Efficacy was demonstrated in subjects with S. pneumonia resistant to Penicillin G or Erythromycin A and efficacy was also shown in the most vulnerable of patients such as the elderly, subjects with pneumococcal bacteremia and subjects with Legionella pneumophila.

I will now present the results obtained in subjects with acute exacerbation of chronic bronchitis. Two control studies were performed. Study 3003 compared five days of treatment with Telithromycin to 10 days of treatment with Amoxicillin/Clavulanic acid given 500 milligram three times daily and this was performed in subjects with the documented bronchial obstruction by lung function tests.

In 3007 the comparator was Cefuroxime axetil given 500 milligram BID for 10 days and patients were enrolled in these studies with a criteria of exacerbation type one or two. In the PPc population of both studies the clinical cure rate after the short five-day treatment with Telithromycin was equal to the longer 10-day treatment with the comparators, Amoxicillan/Clavulanic acid or Cefuroxime axetil.

In the PPb population which was selected according to strict criteria, clinical cure rate by pathogens with Telithromycin ranged from 68 to 100 percent. In the pooled population for both studies the cure rate was slightly lower for H. influenzae than for other pathogens. This was true also for the comparative treatment. As explained in the briefing document, this lower rate for H. influenzae was due mainly to the lower eradication rate observed in study 3003 in patients with community -- with COPD and documented obstruction.

In 3007 the eradication rate with Telithromycin was higher than with Cefuroxime axetil. For atypical pathogens, the clinical cure rates exceeded 90 percent in the 11 subjects with chlamydia infection diagnosed by serology with a four-fold increase of IGG. Looking at the out-patients most likely to develop complications in this indication efficacy was high in the elderly patients, in patients with one or at least two risk factors and in patients with bronchial obstruction.

To summarize, Telithromycin 800 milligrams given for five days once daily is effective in the treatment of acute exacerbation of chronic bronchitis due to these pathogens in patients with exacerbation requiring antibiotic treatment that is to say with type one or two. Efficacy was also observed in the out-patients most likely to develop complications at trials, the elderly and patients with documented obstruction.

Let us now turn to the acute sinusitis indications. Three studies were performed to support this claim. Study 3002 compared five days and treatment and 10 days of treatment with Telithromycin and this study was performed in patients and all the patients had bacterial documentation by sinus puncture. Study 3005 had three treatment groups, five-day and 10-day Telithromycin and 10 days with Amoxicillin/Clavulanic acid, 500 milligram given three times daily. Finally a second comparative study, 3011, was performed comparing Telithromycin for five days with Cefuroxime given for 10 days and this study also included bacterial documentation at entry.

In the comparative studies equivalence was demonstrated between Telithromycin for -- given for five days and the two goal standard in the Amoxicillin/Clavulanic acid and Cefuroxime axetil. Cure rates after five and 10 days with Telithromycin were also equivalent in study 3005 and in study 3002. Clinical cure rate by pathogens were high and comparable for the five-day and 10-day treatment regimen with Telithromycin for all targeted pathogens in this syndications with rates over 85 percent for S. pneumonia and H. influenza.

This slide summarizes the results obtained in subjects with S. pneumonia resistant to Penicillin G or Erythromycin which are of increasing prevalence in the syndication in the U.S. in our experience. Focusing first on the large population of subjects with single and multiple pathogen infections in the pool five and 10 days treatment with Telithromycin, which have been shown to have the same efficacy for the other pathogens, 11 out of 13 subjects with strains resistant to Penicillin G were cured. Eighteen out of 21 subjects with transference to Telithromycin A were cured and effectiveness was also shown in the five-day treatment group and in single pathogen infections although the numbers -- the experiments involves smaller numbers.

In summary, Telithromycin given at 800 milligram once daily for five or 10 days is effective in the treatment of acute sinusitis due to the main pathogens isolated in this indication. Telithromycin also proved to be effective against S. pneumonia resistant to Penicillin A or Erythromycin A. An important point to make for this indication is that equal balance was demonstrated in two controlled comparative studies between Telithromycin given once daily for a short treatment duration of five days and a standard treatment given two to three times daily for 10 days.

Telithromycin represents therefore, an effective alternative in this indication where the number of antibiotics demonstrating in vitro activity against all the key pathogens I related is becoming limited.

I will now summarize briefly the experience in tonsillitis/pharyngitis due to S. pyogenes. Two controlled studies were performed comparing Telithromycin for five days with Penicillin G given 500 milligram three times daily for 10 days or Clarithromycin given at 200 milligrams twice daily for 10 days. This was the main study performed to support the claim in this indication. Equivalence in efficacy which is the primary end point in this indication was demonstrated between the five day Telithromycin and the 10 day treatment with Penicillin VK or Clarithromycin. Reasons for type of therapy are given in the briefing document and confirmed the equal balance between Telithromycin five days and the two comparators used indicating that the short treatment duration with Telithromycin was not associated with a higher rate of relapses.

To summarize, Telithromycin, 800 milligram once daily given for five days is effective at treating tonsillitis/pharyngitis and is equivalent to the standard 10-day treatment with Penicillin VK or Clarithromycin given two to three times daily respectively. Eradication of S. pyogenes with the short five-day treatment duration given once daily is of particular importance in this indication where in practice compliance to a full 10-day treatment is rarely observed as a clinical symptoms result particularly in the adolescents.

This review has shown that the efficacy of Telithromycin given at 800 milligrams once daily was consistent in 13 Phase III studies across four indications where compared to a broad range of comparators that are well-recognized for their efficacy. A short treatment duration with Telithromycin given once daily for five days was effective in three respiratory tract indications and equivalent to 10 days of treatment with comparators given two to three times daily.

The most recent of efficacy within the treatment duration consistently non-pneumonia indication is important because this short treatment duration may favor better compliance resulting in increased efficacy and also it may decrease the potential to select resistant strains that can be savored misdoses at the end of a prolonged treatment.

In pneumonia, Telithromycin given for seven or 10 days showed excellent efficacy but most of all in this indication Telithromycin was effective in the out-patients most likely to develop complications. In pneumonia it was elderly subjects and subjects with pneumococcal bacteremia or Legionella infections, in chronic bronchitis, elderly subjects or subjects with significant obstruction.

Finally, Telithromycin was effective in patients with S. pneumonia resistant strain to Penicillin G or Erythromycin A with cure rates over 80 percent in pneumonia and acute sinusitis. I will now present the key 50 results of Phase III studies starting with an overview of the adverse event profile and for this I will focus on treatment related events observed in controlled studies. Then I will discuss the serious adverse events followed by key results of laboratory investigations and the review of ECG analysis will be presented separately by Dr. Benedict.

The safety population included all subjects who received at least one dose of study medication and had a subsequent safety assessment. And that's shown here to the left, a total of 3,265 subjects were analyzed with approximately two-thirds of them in controlled studies. Number of men and women were equal and the population of elderly subjects was substantial with 372 subjects analyzed. In addition, 95 subjects are aged 13 to 18 year olds were also included.

This table shows treatment emergent adverse events considered possibly related to the study medication and observed in more than two percent of the subjects. Gastrointestinal events were the most common events observed with Telithromycin with a slightly higher frequency than in the comparable groups in particular for diarrhea and nausea. But most of these events were mild or moderate in intensity and mild cases accounted for most of the difference between Telithromycin and the comparatives. Also added to this table is the rare event of blurred vision observed with Telithromycin in 0.5 percent of subjects and events were generally mild and resolved during treatment. An association with trouble in accommodations of subject, especially in high doses in Phase I studies, points to what is a condition of transient myopia as reported for example, with some of the compounds -- marketed compounds.

Overall the adverse events observed in both Telithromycin and the comparatives were generally mild and moderate in intensity and rate. Discontinuation due to adverse events were low with Telithromycin at about five percent for all events. In both treatment groups, gastrointestinal events were the most frequent events leading to discontinuation. This graph shows the percentage of subjects with diarrhea on each day of treatment, focusing on Telithromycin, Clarithromycin, Cefuroxime axetil and Amoxicillin/Clavulanci acid. Note that the prevalence of diarrhea with Telithromycin is lower than for Amoxicillin/Clavulanic acid which is one of the most widely used antibiotic treatment of out-patients with respiratory tract infections. It is slightly higher than that of Clarithromycin and Cefuroxime axetil.

Considering the distribution of treatment related adverse event by age group, events in both treatment groups were less frequent in the elderly subjects and in subjects age 13 to 18 years old than in the population of young adults. Eleven deaths reported for all treatment groups in the entire development program. In the controlled studies two deaths occurred with Telithromycin and four deaths with the comparatives. There were five deaths in the uncontrolled studies, all in the pneumonia indication. None of these deaths were considered treatment related and the overall rate of deaths in pneumonia patients in the Telithromycin group was around 0.5 percent with corresponds to the expected rate of death in pneumonia in the out-patients. There was no imbalance between Telithromycin and the comparatives in the occurrence of serious adverse events considering all events, all treatment related events and the rate of all treatment-related events was low at .04 percent for Telithromycin and .02 percent for the comparatives as it is expected for oral antibiotics.

In the uncontrolled studies the rate of serious adverse events was similar. In one of the uncontrolled studies a 53-year old male treated for pneumonia in Finland was enrolled with a normal transaminase at baseline and also elevated eosinophilia at baseline. He had a history of diabetes, asthma and three previous courses of macrolide in the previous year. Four days after the end of treatment he had an episode of gastritis similar to what was observed in several members of his family but this episode was followed by fever and transaminase increased with a peak eight days at approximately 1500 unit per liter. The biopsy showed centrilobular process and plasma cell infiltration with those inner fields.

Transaminase returned to baseline levels approximately eight weeks later and then the subject presented a second episode of transaminase increase nine months after the first episode with a peak at around 1300 units per liter. Biopsies performed seven weeks after the peak transaminase showed plasma cell infiltration and fibrosis.

In summary these subjects with transaminase increase at baseline and eosinophilia increase at baseline presented two episodes of transaminase increase with return to baseline after the first episode and a second episode occurring nine months later and to our knowledge there has been no published report of drug induced liver injury or two distant episodes were triggered by one drug intake.

Therefore, we believe it is unlikely that Telithromycin is the etiology of the hepatitis episode observed in this patient. Looking at treatment related hepatic adverse events reported in comparative studies, we can see that they were well balanced between Telithromycin and comparatives with an occurrence of two percent in both groups. Also there was no imbalance in the occurrence of event leading to discontinuation. The effect on hepatic enzymes was also evaluated in detail in Phase III studies and increasing transaminase greater than three times the upper limit of normal as summarized here in controlled studies.

As you can see the rate of transaminase increase was similar between Telithromycin and the comparatives at .05 percent and -- for Telithromycin and .04 percent for the comparatives in subjects with normal transaminase at baseline and 8.5 percent for Telithromycin, 11.1 percent for the comparatives in subjects with elevated transaminase at baseline which were mainly enrolled in pneumonia studies.

In these subjects there were no case with transaminase increase of greater than three times the upper limit of normal and bilirubin greater than 1.5 times the upper limit of normal. These graphs show -- allow a more precise comparison of the different level of increase in transaminase during the course of the study between Telithromycin and the comparatives. I'm presenting the subjects with normal transaminase at baseline were less likely to have confronting factors that complicate interpretation.

And since transaminase increase is frequently observed in pneumonia, we've analyzed the subject in controlled pneumonia studies and non-pneumonia studies separately. We can see a small difference in the transaminase increase above two times the equivalent of normal similar to what is observed with a macrolide but no signal above three times the upper limit of normal.

To summarize, Telithromycin was generally well tolerated with a pattern of adverse events similar to that of macrolides. Frequency of the transaminase events was slightly higher with Telithromycin than with comparatives but within the range expected for antibiotics. The adverse event profile was similar in different age groups and the rate of transaminase elevation was similar to the comparators.

Finally, and most importantly, the rates of serious adverse events and discontinuation were low and similar to the comparators. I'd like now to hand it over to Dr. Benedict.

PRESENTATION OF DR. CLAUDE BENEDICT

DR. BENEDICT: Good morning. I would now present the second part of the safety update, the ECG analysis. Macrolides have been associated with changes in cardiac repolarization. Telithromycin was -- has structural similarities and derived from macrolides. Because of this we performed an extensive pre-clinical and a prospective clinical investigation of the potential effect of Telithromycin on cardiac repolarization and compared it to different comparative macrolides and non-macrolides in our program.

This program was designed in accordance with the EU guidelines and FDA recommendations. Let me now first present to you the pre-clinical data. We performed extensive evaluation of the pre-clinical properties of Telithromycin. This included binding to the different membrane ionic channels, interaction with cloned channels particularly the Ikr or HERG channel but also Kv1.5 and Ikr. We also performed studies in isolated human atrial cells, studies in rabbit Purkinje fibers under different conditions of hypokalemia, different anti-arrhythmic drugs and in the presence of low pacing rates of bradycardia as well as interaction studies with Sotalol and quinidine. We also performed studies in awake animals.

The results of these studies are summarized in your briefing document but here I would like to especially present the data on Ikr or HERG channel. This slide gives the results of four different variables for some of the commonly used antibiotics except maybe Sparfloxacin. The first column is oral dose, the second the peak free plasma concentration, the third, the concentration required to inhibit the HERG channel by 50 percent and fourth, a ratio that relatively ranks these compounds by the amount that is required for 50 percent inhibition which is the plasma concentration that would be achieved.

Please note Telithromycin falls between Clarithromycin and Erythromycin. Please recall from Dr. Jeremy Ruskin's presentation, he said we need to also know not only the effect of the parent compound on the Ikr channel, but also its metabolite. We also looked at the effect of metabolites on the Ikr channel and even at 300 micromolar concentration, the effect was less than 20 percent inhibitory activated.

Let me now turn and present the Phase III data. As sponsor, we feel we have done a large extensive program in Phase III. We have gathered an unusually large number of patients. We have looked at the QT changes. In addition to that, we have also gathered PK/PD relationship in over 1500 subjects. ECGs were performed, pre and on-therapy usually days 3 to 5 when a steady state was reached. As indicated by Dr. Ruskin, it's important to read these electrocardiographic changes carefully. Therefore, it was all read by a single reader who was blinded to the treatment assignment and read in a random order.

There were approximately 1800 subjects in this group. Recall the emphasis or the need to know the information in patients with high risk factors. Our study program had fairly relaxed inclusion criterias, therefore, we were able to capture a large number of patients with high risk factors. In addition, about two/thirds of the way through the program, after safety review, the inclusion criterias were eliminated except for some drugs and congenital QT prolongation giving us a total of about 600 subjects to evaluate which will be presented subsequently.

QT was measured as the longest and the shortest interval from the 12 leads averaged and corrected by the heart rate using the Bazett's formula. To place the data in perspective, we are giving the data here as QTc but your