> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTIVIRAL DRUGS ADVISORY COMMITTEE (AVAC) MEETING**
>
> Tuesday, May 13, 2003
>
> 8:00 a.m.
>
> Holiday Inn Gaithersburg
>
> Two Montgomery Village Avenue
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Roy M. Gulick, M.D., M.P.H., Chair
>
> Tara P. Turner, Pharm.D., Executive Secretary
>
> MEMBERS
>
> Victor G. DeGruttola, Sc.D.
>
> Janet A. Englund, M.D.
>
> Courtney V. Fletcher, Pharm.D. (Consumer Rep)
>
> Princy N. Kumar, M.D.
>
> Wm. Christopher Mathews, M.D.
>
> Kenneth E. Sherman, M.D., Ph.D.
>
> Lauren V. Wood, M.D.
>
> ACTING INDUSTRY REPRESENTATIVE (Nonvoting)
>
> Eugene Sun, M.D.
>
> CONSULTANT (Nonvoting)
>
> Joel Morganroth, M.D.
>
> CONSULTANTS (Voting)
>
> Douglas G. Fish, M.D.
>
> D. Roger Illingworth, M.D., Ph.D.
>
> Peter R. Kowey, M.D.
>
> Rory P. Remmel, Ph.D.
>
> Thomas R. Tephly, M.D., Ph.D.
>
> Ronald G. Washburn, M.D.
>
> PATIENT REPRESENTATIVE (Voting)
>
> Matthew Sharp
>
> FDA
>
> Debra Birnkrant, M.D.
>
> Mark Goldberger, M.D., M.P.H.
>
> Kendall Marcus, M.D.
>
> Lisa Naeger, Ph.D.
>
> C O N T E N T S
>
> [Page]{.underline}
>
> Call to Order: Roy M. Gulick, M.D., M.P.H. 3
>
> Introduction of the Committee 4
>
> Conflict of Interest Statement: Tara Turner, Pharm.D. 6
>
> Opening Remarks:
>
> Debra B. Birnkrant, M.D. 11
>
> Evaluation of QT Interval:
>
> Joel Morganroth, M.D. 17
>
> **Sponsor Presentation**
>
> **Bristol-Myers Squibb Company**
>
> Introduction:
>
> Elliott Sigal, M.D., Ph.D. 43
>
> Clinical Development Program and Clinical Trial Results:
>
> Steven M. Schnittman, M.D. 47
>
> Cardiac Electrophysiology Evaluations:
>
> John H. Lawrence, M.D. 78
>
> Characterization of Hyperbilirubinemia:
>
> Michael Giordano, M.D. 88
>
> Characterization of Lipid Profile:
>
> Michael Giordano, M.D. 97
>
> Overall Risk/Benefit and Conclusions:
>
> Elliott Sigal, M.D., Ph.D. 106
>
> **FDA Presentation**
>
> Kendall Marcus, M.D. 109
>
> Tom Hammerstrom, Ph.D. 112
>
> Lisa Naeger, Ph.D. 129
>
> Kendall Marcus, M.D. 139
>
> Questions from the Committee 160
>
> **Open Public Hearing**
>
> Rob Camp 213
>
> Jules Levin 219
>
> Charge to the Committee/Questions for
>
> Discussion 221
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. GULICK: Good morning and welcome. I am Trip Gulick from Cornell
> University. I am pleased to welcome everyone to today\'s Antiviral
> Drugs Advisory Committee Meeting.
>
> We will start off by introducing the members of the Committee. We will
> start with Dr. Sun over in this corner. Please state your name and
> your affiliation.
>
> **Introduction of the Committee**
>
> DR. SUN: Eugene Sun, Abbott Laboratories.
>
> DR. MORGANROTH: I am Joel Morganroth, a cardiologist in Philadelphia
> associated with eResearch Technology and the University of
> Pennsylvania.
>
> DR. KOWEY: Peter Kowey. I am an electrophysiologist and cardiologist
> at Thomas Jefferson University and Lankenau Hospital in Philadelphia.
>
> DR. FISH: Douglas Fish, Division of HIV Medicine, Albany Medical
> College.
>
> DR. WASHBURN: Ron Washburn, infectious-disease doctor from LSU in
> Shreveport.
>
> DR. ILLINGWORTH: Roger Illingworth, a lipid specialist from Oregon
> Health and Science University in Portland, Oregon.
>
> DR. REMMEL: I am Rory Remmel, Department of Medicinal Chemistry,
> University of Minnesota, specialties in clinical pharmacology and AIDS
> drugs and drug metabolism.
>
> DR. TEPHLY: Tom Tephly, University of Iowa, Department of
> Pharmacology.
>
> DR. MATHEWS: Chris Mathews, University of California, San Diego.
>
> DR. FLETCHER: Courtney Fletcher, University of Colorado Health
> Sciences Center.
>
> DR. TURNER: Tara Turner, Executive Secretary for the Committee.
>
> MR. SHARP: I am Matt Sharp. I am a thirteen-year survivor of AIDS.
>
> DR. ENGLUND: Janet Englund, Pediatric Infectious Diseases, University
> of Washington and Fred Hutchinson Cancer Center.
>
> DR. KUMAR: Princy Kumar, Georgetown University, Washington, D.C.
>
> DR. DeGRUTTOLA: Victor DeGruttola, Harvard School of Public Health.
>
> DR. HAMMERSTROM: Tom Hammerstrom, statistician, FDA.
>
> DR. NAEGER: Lisa Naeger, microbiology reviewer, FDA.
>
> DR. MARCUS: Kendall Marcus, medical reviewer, FDA.
>
> DR. BIRNKRANT: Debbie Birnkrant, Division Director, Division of
> Antiviral Drug Products, FDA.
>
> DR. GULICK: Thank you. Tara Turner will now read the
> conflict-of-interest statement.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: The following announcement addresses the issue of conflict
> of interest with respect 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 and information provided by the
> participants, the agency has determined that all reported interests in
> firms regulated by the Center for Drug Evaluation and Research present
> no potential for a conflict of interest at this meeting with the
> following exceptions.
>
> Dr. Joel Morganroth will be permitted to participate in the
> committee\'s discussions. He is excluded from voting.
>
> Dr. Roy Gulick has been granted a waiver under 18 U.S.C. section
> 208(b)(3) because his employer receives research funding from two
> competitors. Each firm provides less than \$10,000 a year. And, for
> serving as a consultant to two competitors. He receives less than
> \$10,000 a year from each firm.
>
> Dr. Courtney Fletcher has been granted waivers under 208(b)(3) and 21
> U.S.C. section 355(n)(4) for owning stock in a competitor valued
> between \$25,001 and \$50,000.
>
> Dr. Ronald Washburn has been granted waivers under 18 U.S.C. 208(b)(1)
> and 21 U.S.C. section 355(n)(4) for owning stock in two competitors.
> The first stock is valued from \$25,001 to \$50,000 and the second
> stock is valued from \$50,001 to \$100,000.
>
> Dr. Peter Kowey has been granted a 208(b)(3) waiver for consulting for
> two competitors. He receives less than \$10,000 a year from one and
> between \$10,001 to \$50,000 a year from the other firm.
>
> Dr. Roger Illingworth has been granted a 208(b)(3) waiver for
> consulting for a competitor for which he receives from \$10,001 to
> \$50,000 a year. And, for speaking for a competitor for which he
> receives from \$10,001 to \$50,000 a year.
>
> Dr. Kenneth Sherman has been granted a waiver under 21 U.S.C. section
> 355(n)(4) for owning stock in a competitor worth between \$5,0001 and
> \$25,000.
>
> Dr. Victor DeGruttola has been granted a 21 U.S.C. section 355(n)(4)
> waiver for owing stock in a competitor valued at less than \$5,000.
>
> Dr. Princy Kumar has been granted a 21 U.S.C. 355(n)(4) waiver for
> owning stock in two competitors. The first stock is worth from \$5,001
> to \$25,000 and the second is worth less than \$5,000.
>
> A copy of these waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30, of the Parklawn Building. The signed disclosure statements are
> available for public review at this meeting.
>
> Lastly, we would also like to note for the record that Dr. Eugene Sun
> is participating in this meeting as the Acting Industry
> Representative, acting on behalf of regulated industry. Dr. Sun is an
> employee of Abbott Laboratories.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants have a financial
> interest, the participants are aware of the need to exclude themselves
> from such involvement and their exclusion will be noted for the
> record.
>
> With respect to all other participants, we ask, in the interest of
> fairness, that they address any current or previous financial
> involvement with any firm whose product they may wish to comment upon.
>
> Thank you.
>
> DR. GULICK: Thanks very much.
>
> I am now going to turn to Dr. Catherine McComus from the University of
> Maryland who is going to tell us about a project that is going on in
> today\'s meeting.
>
> DR. McCOMUS: Thank you and good morning. My name is Katherine McComus.
> I am a faculty member at the University of Maryland. I am here today
> to ask for your assistance on a study that I am conducting with
> collaborators at the Food and Drug Administration that examines
> conflicts of interest and FDA advisory-committee meetings.
>
> This study is being conducted across several centers at the FDA and at
> multiple meetings. It is an attempt to gain an idea of what people
> understand and know about the procedures that the FDA uses to monitor
> and manage real or potential conflicts of interest of its
> advisory-committee members.
>
> So I am responsible for all of these grey questionnaires that are on
> your chairs in the audience and I have also distributed a separate
> questionnaire to advisory-committee members. I am two short, but I
> will get you tomorrow.
>
> I would like to ask that you take about fifteen minutes today, if you
> have an opportunity to complete the questionnaire. There is a box at
> the registration desk where you can drop it in. If you don\'t have a
> chance to complete it today, there is a business reply envelope and
> you can complete it later and mail it back to me postage-paid. I will
> also be around today and tomorrow for those of you that are here
> tomorrow to answer any questions that you may have about the study.
>
> Again, thank you very much for your time. Your responses are very
> important. They increase the validity and reliability of the results
> and really will help us to offer recommendations on how we can improve
> overall satisfaction with the advisory-committee function.
>
> Thank you.
>
> DR. GULICK: Thanks. I think an informed consent is not required.
>
> DR. MCCOMUS: No, but it has followed institutional review-board
> procedures.
>
> DR. GULICK: We had one committee member joining late. Dr. Wood, could
> you just introduce yourself and your affiliation?
>
> DR. WOOD: Good morning. Dr. Lauren Wood, National Cancer Institute.
>
> DR. GULICK: Thanks.
>
> We will turn now to Dr. Birnkrant from the agency for some
> introductory remarks.
>
> **Introductory Remarks**
>
> DR. BIRNKRANT: Good morning.
>
> \[Slide.\]
>
> I would also like to welcome our advisory-committee members,
> consultants and guests to today\'s advisory-committee meeting on
> atazanavir, Bristol-Myers Squibb\'s once-a-day protease inhibitor for
> HIV treatment.
>
> At this point, I would like to commend Bristol-Myers Squibb for their
> drug-development program for atazanavir. They not only conducted
> studies in treatment-naive subjects but also in treatment-experienced
> subjects and used comparators such as nelfinavir, efavirenz and
> Kaletra, all widely used in potent protease inhibitors to have a
> better understanding of how this drug fits into the armamentarium of
> drugs for HIV treatment.
>
> \[Slide.\]
>
> Prior to beginning my comments on today\'s topic, I would also like to
> commend the FDA reviewers for their time and efforts in preparing for
> this advisory committee. They had to review more than nine clinical
> studies and more than forty clinical pharmacokinetics biopharmaceutics
> studies as well as other data in preparation for today\'s meeting and
> in order for us to take a regulatory action within a six-month time
> period.
>
> With regard to the current marketed protease inhibitors, there are
> six; two formulations of saquinavir, ritonavir, indinavir, nelfinavir,
> amprenavir and ritonavir-boosted lopinavir. This class of drugs, the
> protease inhibitors, have class effects that include metabolic
> dysregulation manifested by lipid elevation, lipodystrophy and cases
> of diabetes and hyperglycemia.
>
> \[Slide.\]
>
> How, then, is atazanavir the same and how is it different compared to
> other protease inhibitors. Well, with regard to class effects, and you
> will be hearing a lot about this morning, treatment with atazanavir
> resulted in less of an increase in lipid parameters compared to
> nelfinavir in Phase II studies.
>
> This favorable finding was confirmed in Phase III clinical trials.l
> However, cases of lipodystrophy and diabetes were still seen in the
> atazanavir database.
>
> \[Slide.\]
>
> How else is atazanavir the same and how is it different compared to
> other protease inhibitors on the market? The most common adverse event
> seen in the database was hyperbilirubinemia. This was investigated
> extensively and found to be associated with UGT 1A1 inhibition which
> is similar to that seen with indinavir. However, the incidence of
> hyperbilirubinemia with atazanavir was much greater occurring in more
> than 75 percent, all grades 1 through 4, and grades 3 through 4 ranged
> between 20 and 50 percent whereas the incidence with indinavir is
> about 10 percent.
>
> With regard to cardiac conduction, atazanavir had dose-dependent and
> concentration-dependent effects on the TR interval that were generally
> mild and reversible. In addition, there were effects seen on the QT
> interval and this will be discussed more extensively by the applicant,
> the agency and our consultant, Dr. Morganroth.
>
> With regard to resistance, atazanavir has a unique resistance profile
> in naive subjects. Dr. Lisa Naeger will elaborate on this.
>
> \[Slide.\]
>
> With regard to efficacy, this was an extensive database that was
> reviewed for today\'s advisory-committee meeting. The agency reviewed
> two principal studies, study 034 in naive subjects that contained
> 48-week data and used efavirenz as a comparator. Study 043, which was
> conducted in treatment-experience patients and used Kaletra as a
> comparator, extensive data from Phase II trials 007 and 008 with
> rollover studies that contained more than 48-week data.
>
> Given that we received for review 48-week data in the naive patient
> population and more than 48-week data in Phase II trials as well as
> 24-week data from 043, would we consider taking a regulatory action on
> this application. This application will be considered for traditional
> approval as opposed to accelerated approval because, as you are all
> familiar with our paradigm with regard to accelerated approval, we
> generally only review 24-week data and the applicant has exceeded
> this.
>
> I would also like to comment on Study 045 which was conducted in a
> different population that is highly treatment experienced. Because
> this used a different regimen\--that is, a ritonavir-boosted
> regimen\--and because only 16-week data were submitted for review,
> this study will only be considered for a safety review as opposed to
> efficacy.
>
> So, just to summarize, the agency considered the two principal studies
> 034 and 043 as well as Phase II clinical trials 007 and 008 plus their
> rollover studies as we prepared for today\'s advisory-committee
> meeting with regard to efficacy. With regard to the safety that we
> will be presenting, we considered all the clinical trials in the
> database.
>
> \[Slide.\]
>
> So what we will be asking the advisory committee today will be issues
> related to the safety and efficacy of atazanavir and, as the advisory
> committee deliberates, we will ask them to consider the adverse-event
> profile of this drug; namely, the hyperbilirubinemia seen with
> atazanavir, effects on cardiac conduction and effects on metabolic
> parameters including lipid effects.
>
> In addition, we will be asking the committee to comment on the results
> in the clinical trials seen in the various populations studied as well
> as a resistance assessment.
>
> \[Slide.\]
>
> Turning to the agenda for today\'s committee meeting, following my
> remarks, Dr. Morganroth will be presenting a primer on evaluation of
> QT intervals. This will be followed by the Bristol-Myers Squibb
> presentation which will then be followed by clarifying questions.
> After our break, the FDA will present\--Drs. Marcus, Hammerstrom and
> Dr. Lisa Naeger will give the FDA presentations. This will be followed
> by questions.
>
> After lunch, there will be an open public hearing at approximately 1
> o\'clock. I will then give the charge to committee and this will be
> followed by questions to the committee.
>
> Thank you very much.
>
> DR. GULICK: Thanks, Dr. Birnkrant.
>
> We will turn now to Dr. Morganroth to give us a primer on the
> evaluation of the QT interval.
>
> **Evaluation of the QT Interval**
>
> DR. MORGANROTH: Good morning.
>
> \[Slide.\]
>
> I am not sure what a primer is but I will be happy to give you a few
> minutes of some experience and background in the QT interval which is
> obviously something you have all been aware of as an important issue
> in the development of noncardiac drugs and particularly relevant to
> the safety issues.
>
> \[Slide.\]
>
> The reason that the QT interval was such a hot topic and is of such
> importance for developing drugs in terms of their safety profile is
> because of the concern that drugs that prolong the QTc duration on the
> electrocardiogram increase the risk of an uncommon to rare event known
> as torsades de pointes, which is a polymorphic ventricular
> tachyrhythmia that sometimes can be asymptomatic but often can lead to
> syncope and occasionally be fatal in a fair number of cases.
>
> Most of the cases in the literature are thought to occur at fairly
> prolonged durations of the QT interval. The normal is around 440
> milliseconds but not all cases are greater than 500 milliseconds as
> many clinicians might think.
>
> \[Slide.\]
>
> This is an example of torsades de pointes that the division provided
> me that really shows the twisting of the pointes. It is obviously a
> very fast rhythm that would not likely provide sufficient output of
> blood to keep the brain happy for a while and that would, of course,
> cause the CNS symptoms to death.
>
> \[Slide.\]
>
> Prolongation of the QT interval by noncardiac drugs is the commonest
> cause of drug delays in development, nonapprovals and withdrawal from
> the market. So I learned in January, when Dr. Temple provided that
> information\--I thought it was something more likely to do with the
> liver but it turns out that QT is now risen to the top of the list.
>
> Here is a example of the types of drugs that have been withdrawn from
> the market in the last several years. You can see they span a great
> number of therapeutic categories.
>
> \[Slide.\]
>
> The probably prototypic noncardiac drug that caused everyone to focus
> in on the QTc interval as am important safety feature was terfenadine,
> a non-sedating antihistamine, when one looks at the effect, the
> magnitude of the effect, on the QTc duration at the usual clinical
> dose, was approximately 6 milliseconds. That was determined solely by
> the use of digital-manual ECG analysis after the drug was on the
> market and there were many cases of torsades, prolonged QTs and death
> reported.
>
> It turns out, however, that this is the average change over the extent
> of exposure. If one looks at the maximum change at either Tmax or
> probably around Cmax, it is around 18 milliseconds. These numbers are
> important because the magnitude of effect is related, one thinks, to
> the degree of risk and there are now some regulatory suggestions about
> how much that magnitude imparts to risk in terms of determining a
> risk/benefit duration.
>
> With metabolic inhibition of the parent compound, terfenadine, and
> prohibiting it going to its acid metabolite, there can be as much as a
> 50 to 100-millisecond effect in such individuals. With only the
> reduction of minimal symptoms as the benefit and the potential risk of
> torsades, death, the drug was removed from the market, particularly
> since the acid-metabolite, fexofenadine, does not bear any of the
> blockade of the HERG channel or QTc effects.
>
> \[Slide.\]
>
> There are many drugs in many categories that are known to affect the
> QTc interval. I have listed them here on the board. They are very
> widespread. I have only given a few examples of each. The list
> actually fills a board. There are over 100 drugs that have been
> reasonably well characterized.
>
> Some of the drugs have been released on the market in the last couple
> of years that are clearly ones that prolong the QT interval because of
> risk/benefit relationships being ones that permit such use.
>
> \[Slide.\]
>
> The primary effect of the drugs that generally affect the QTc interval
> on the electrocardiogram as demonstrated in that therapeutic list is
> by blocking the IKr HERG-related ion channel. This effect is a primary
> effect. However, a prolongation of the QTc interval doesn\'t affect
> cardiac function. The heart operates as a pump perfectly well, causes
> no symptoms, and, under the presence of some modifier will, in fact,
> generate torsades.
>
> That modifier can be a Form Fruste HERG mutation, someone with a
> subclinical primary prolonged QT syndrome and the two together can, of
> course, tip the person over the hill and produce torsades.
>
> Obviously, if you can also mimic such effects with bradycardia that
> prolongs that QT or metabolic conditions like hypokalemia,
> particularly ischemia, atrial fibrillation. Women tend to be more
> sensitive to QTc drugs. Their slope is larger in terms of the amount
> of drug and the degree of the QTc prolongation. Obviously, concomitant
> use of drugs that also prolong the QT in combination is probably an
> important common cause of this torsades effect in the market.
>
> \[Slide.\]
>
> Now, the ECG is complicated in terms of the various aspects that you
> will be dealing with. The PR interval, which is the AV-nodal
> conduction, is something that will be discussed today because this
> drug that is under consideration does affect conduction. It has an
> effect on calcium ions and, perhaps, a small effect on the sodium ion.
>
> The QT interval which begins at the beginning of the QRS and ends at
> the end of the T-wave, the so-called QT, is made up of the
> depolarization and repolarization\--JT is the repolarization
> phase\--and, therefore, one might ask why aren\'t we dealing with JT
> if we are interested in repolarization as the effect of the potassium
> channel, principally.
>
> QRS and the QT interval has been the historic measurement technique
> and is the best we have. No one believes, in fact, that the QT
> interval that is measured simply on the 12-lead electrocardiogram is a
> great index of what is going on with the ion channels and the
> potential cardiac safety risk, and there are many proposals for
> looking at various forms of areas and parts of the T-wave and the ST
> T-wave segment.
>
> However, clinically, the QT interval is what is commonly validated
> because of all the historic drug effects that have been determined by
> that simple method. Of course, we have a great deal of regulatory and
> clinical experience, epidemiologic experience, with that simple
> measurement. So, until one has more validated information on using
> what is likely to be a better measure of cardiac repolarization than
> the QT, we are sort of stuck with that.
>
> But there are lots of different proposals out there as to what could
> be used but we are really left, as I said, with the QT interval.
>
> \[Slide.\]
>
> In November of 2002, the FDA and Health Canada printed the new concept
> paper which is one in a series of three regulatory guidances stemming
> from 1996 when CPMP, the European FDA equivalent, published its Points
> to Consider in this field. Health Canada produced its draft guidance
> in March of 2001. As these guidances have come along, they have become
> more granular, more recipe-like, in terms of detailing how one wants
> to determine cardiac safety as measured by the electrocardiogram.
>
> I think that has happened because, despite the 1996 Points to
> Consider, there has been continued lack of robust definitive
> understanding of ECG effects during many development programs.
>
> The guidance document, or the concept paper, in November 2002 is under
> review in ICH. I have just taken a couple of comments from it that I
> thought were relevant. First is that there is a great request, if you
> will, or urgency, to record ECGs digitally, process them digitally and
> store them digitally, rather than on pieces of paper with all the
> obvious limitations that paper has compared to electronic data.
>
> The specificity of using a central ECG laboratory, very much like
> everyone does with blood tests, is obvious because of the great
> variability of methods of reading and determinations of morphological
> interest.
>
> Paper ECGs are fine when digital is not possible or practical. These
> can easily be digitized or digitally dealt with as analysis. It is
> clear from all the guidance documents that one should be using a
> manual method of determining the duration of the intervals, PR, QRS,
> QT, heart rate, on a digitizing board or with electronic digital data
> on screen with electronic calipers.
>
> The possibility of using automatic computer readings of interval
> duration which are widely understood to not be accurate except in
> perfectly normal electrocardiograms may be fine for safety analysis.
> They tend to overread and give longer numbers and shorter numbers and
> so, for screening for safety at the sites during the clinical trials,
> that is quite appropriate. But for centralized data, I think the
> manual data is important.
>
> These are principles that, perhaps, you will look at when you
> determine whether the definitive trial that Bristol-Myers has
> conducted today\--I think is called 076\--how well they followed some
> of these principles.
>
> The guidance document, also, and this is really the biggest change
> from any of the previous ones, is actually suggesting\--probably the
> word \"require\" is not out of place\--an intense or thorough or
> definitive Phase I trial to rule out a 5-millisecond effect for all
> bioactive agents and even for any agent that is on the market that is
> brought back for a new indication or for a principal change.
>
> The reason for this is because one really needs to determine whether
> the drug has a QTc liability or not in order to enter that into your
> risk/benefit analysis. It is very difficult, because of the large
> degree of spontaneous variability, to be very definitive about that in
> studies with small sample sizes that are traditionally done in Phase I
> or in Phase III with limited ability to get electrocardiograms where,
> also, particularly in this particular therapeutic group, it is very
> difficult to have negative controls, placebo controls.
>
> The important design features that have been added to this and one
> that has been somewhat controversial is the requirement of using assay
> sensitivity, a positive control, that one of the arms in this
> definitive trial should be a drug known to produce a 5-millisecond
> effect on the QTc duration so that, if you think your drug is the same
> as placebo\--that is, having no effect on the QTc, in the same study,
> one must show that you were able to detect the 5-millisecond effect of
> a positive control drug.
>
> This, of course, really does produce assay sensitivity and make the
> data very easy to be definitive, to be certain about the design
> characteristics.
>
> The final addition, to show you the concern of the agency about this
> issue of QTc effects, electrocardiographic effects of new drugs, is
> that here is an instance where the FDA now wishes to see, particularly
> for definitive trials, the actual raw data. They want not just the SAS
> tables with the results, if you will, of the study, but they actually
> want to have sent in the EKG wave forms, digitally sent in and
> annotated so one can see where the central laboratory actually
> measured the Q and the T-wave because the end of the T-wave, as you
> all know, is not so easy. That is why the manual measurements are
> required. That, of course, should be in XML.DTD file. That was
> published in the Federal Register just a few days ago for comment, the
> final form that they want to see this in.
>
> \[Slide.\]
>
> This slide is probably the most important one to consider as you
> review 076 and as you review trials in general to determine whether
> they are definitive or not because the issue about QTc duration is
> there is such a high degree of spontaneous variability in QTc
> durations from almost minute to minute, the average being about
> 75 milliseconds in an individual over a day, yet if we are looking for
> a small signal that might have clinical significance at 5 or 10
> milliseconds from a regulatory perspective, how does one overcome
> these sources of variability?
>
> The first way to do that is to make sure that you have an ECG
> measurement method that is accurate. You want to get accurate data.
> Again, that speaks to the manual, digital validated method. The second
> issue is to make sure you correct for the QT interval. Remember that
> the QT interval varies with heart rate so, if you start with someone
> who has a tachycardia and you give them a drug like an antibiotic and
> you let their fever and their pneumonia get cleared up, and they now
> have a slower heart rate, they are going to have a longer QT by
> definition because, as the heart rate slows, the QT increases.
>
> So it is very important to correct the QT to the QTc. One of the
> biggest issues you need to look at today is what correction formula is
> the one to use and which is the appropriate one in order to determine
> whether the QTc as found is correct or not.
>
> The next issue is how many measurements you make. It is absolutely
> inadequate to do one EKG at baseline and one EKG on drug which is
> often typically done. What you need to do, and I believe the frequency
> has to cover clearly the extent of exposure of the drug and its
> metabolites, account for diurnal variation. Therefore, you need EKGs
> very similar to a PK profile, at least 10 to 20 a day in the range at
> baseline and then, of course, at steady state or at first dose if it
> is only a single-dose-appropriate study.
>
> The sample size, in order to have enough power to detect 5
> milliseconds because of the high variance is usually at least 30
> patients per arm. Usually, I would recommend 40 because half the
> population it would be nice to be women because they do have increased
> sensitivity and, therefore, you would have 20 women and 20 men to be
> able to do a gender analysis.
>
> Volunteers are fine. One doesn\'t have to try to put in heterogenous
> patients with the disease under study. It is very difficult to do such
> large studies with the target population. We believe that if you, with
> a definitive study in volunteers, see no QTc effect, no effect on
> cardiac repolarization, then the likelihood of seeing it in
> higher-risk patients such as ones with cardiac disease should be very
> remote.
>
> Important in a trial is to look for dose effects. The doses selected
> for the drug under consideration should be at least two to look at a
> dose effect. One of the doses should be able to cover the expected or
> theoretical, I should say, maximum concentration that might occur in
> the public.
>
> For example, if a person takes an extra pill and happens be on a
> metabolic inhibitor, or two, for the drug, one needs to be certain
> that they have evaluated that potential concentration. That usually
> means that the second dose has to be at least three to five times, as
> a guideline, the therapeutic dose. If you can get up to 10X, then the
> potential of this supertherapeutic dose covering any potential
> exposure is very clear.
>
> Finally, you need control groups. Without a placebo, it is difficult
> to determine the effects of spontaneous variability. I have already
> mentioned the importance of the positive control for assay
> sensitivity.
>
> \[Slide.\]
>
> The corrected QT interval is an important controversial topic. I will
> tell you that I think there is going to be a great deal of resolution
> about this, or at least a lot more data than we currently have, at the
> end of this month when the GU and Cardiorenal Advisory Committee have
> a public meeting to discuss two applications in which all of these
> correction formulas that are on this slide were actually applied in a
> positive-controlled, negative-controlled, definitive QT dataset.
>
> The Bazett\'s correction formula is what is traditionally, in all the
> EKG machines that everyone uses in healthcare because that is sort of
> the historic standard, there is no one, I believe, that would argue
> that this is the correct, or the best, or the preferred, correction
> factor.
>
> That is important for this committee because I believe that the
> Bazett\'s formula data should be looked at with minimal interest. The
> maximum interest should be on the Fridericia\'s formula, particularly
> for drugs that have an impact on the heart rate. Any drug that
> increases the heart rate, the Bazett\'s is particularly not a good
> correction factor and the Fridericia\'s tends to be a very good
> correction factor. At the end of this month, we will have some
> comparisons of Fridericia\'s versus others.
>
> When you get to the ISS phase, the integrated summary of safety in an
> application, you have the opportunity to actually look at all of the
> pretreatment ECGs that were obtained in the disease entity under
> consideration and you can calculate the correction factor that is
> useful for the population.
>
> This was first done, from my experience, by neuropharm in the
> antipsychotic area where, in schizophrenics, they found that the
> correction formula of 0.37 was the best method for correcting the QT
> data in that particular disease entity.
>
> What I am talking about is that the QTc equals the QT over the heart
> rate as measured by the RR interval raised to an exponential power.
> There are linear regression formulas and probably 30 other types of
> formulas.
>
> Fridericia\'s is cubed root of the RR, or 0.33. If you use a
> population base, you might find it to be, as I just said for
> schizophrenics, 0.37 and for others it could be 0.28 or 0.41.
>
> Finally, and most people in this field believe that you should take,
> in fact, individuals, every single individual in a clinical trial, and
> determine their correction formula and apply all the ECGs for that
> individual by that individually defined correction formula.
>
> To do that, you need 50 to 100 ECGs prior to therapy. The applications
> that are being discussed at the end of this month at Cardiorenal, in
> fact, did that. They had enough EKGs off therapy in their group that
> they were able to do individual-based correction formulas.
>
> It is felt, of course, that this should be the most accurate, should
> be the most definitive, for a definitive Phase I trial. I think we
> will be seeing whether that, in fact, is true or whether one can use a
> simpler fixed formula.
>
> \[Slide.\]
>
> This is just the crowded figure that\--what you are trying to do is
> this is as the heart rate slows, your QT interval on the Y axis
> increases. What you want to do is get this cloud to be as flat as
> possible with your correction formula.
>
> \[Slide.\]
>
> The final couple of slides are to talk about the statistical analysis
> that should be done with this data. There are lots of different
> possibilities, as you can imagine. In the November 2002 concept paper,
> there are a couple of pages listed of everything that has been seen.
>
> I must warn you that point-to-point analysis is very dangerous because
> if you only have one EKG at 10:00 a.m. and you think that is relevant
> to the 10:00 a.m. on drug because you think that is where Tmax is,
> that is okay to look at Tmax and Cmax. That makes common sense. But if
> you only have one EKG at each of those time points, of course you have
> lost your power to eliminate variability and, therefore, your degree
> of definitiveness obviously erodes.
>
> So, central-tendency mean change, in my opinion, takes half the
> weight. You want to know what the mean change on the drug is
> compared\--placebo-corrected to see if there is an effect or not an
> effect.
>
> If your mean change is 0, you don\'t really have an effect, I,
> personally, have never seen an outlier that is necessarily correct,
> true, except in very unusual circumstances. So, if you do have some
> very small effect on the QTc, the cardiac repolarization, then, of
> course, the outlier analysis is half the weight or, in some people\'s
> opinion, three quarters of the weight because what you are really
> interested in is how many people are going to be severely affected by
> the blockade of their HERG channel, if that is the mechanism.
>
> Here, the principal categorical analyses\--there are many you could do
> from normal to abnormal. Many of them are very sensitive. Many are
> maybe too specific. But these are the ones that I think are most
> relevant; maximum mean change to see what the maximum effect is any
> time, not just at Cmax because it may be a metabolite. There may be
> tissue penetration. 30 to 60 milliseconds is a fairly sensitive, maybe
> too sensitive, meaning a lot of people on placebo will have this
> effect.
>
> Greater than 60 tends to be due to drug in most cases, particularly if
> you have adequate measurements, frequency and quality, but
> occasionally placebo patients may have this. How many people get new
> 500 milliseconds that are not having them at baseline or changes in
> their TU waves, another important analysis, to determine whether or
> not you have any abnormalities in morphology.
>
> Don\'t expect to see or make an argument that because I didn\'t see
> torsades in my 3,000 patients that that means anything because the
> rate of torsades that one would see, even for a drug like the
> terfenadine, was probably less than 1 in 100,000 so you need an awful
> lot of patients to say that you have excluded the possibility of
> clinical events.
>
> \[Slide.\]
>
> This is the current guidance from both Europe and the United States in
> terms of what the mean change, whether this is probably maximum mean
> change or Cmax change across the extent of the exposure is a little
> bit uncertain. Less than 5 milliseconds, everyone would agree, if you
> are in 0 to 5 millisecond mean central-tendency change, you can pretty
> much ignore that.
>
> If you are over 20 milliseconds, you have got to have an awfully good
> argument to why you are thinking of putting this drug on the market
> because there is usually, in such drugs, a very high rate of torsades,
> at least the regulatory experience is such. Then, of course, anything
> between 5 and 20 is under a great deal of debate is to what the
> risk/benefit ratio is.
>
> Most would say that 5 to 10 milliseconds for a drug that has
> reasonably strong benefit would be something of minimal concern, we
> still call it \"not clear risk,\" where 10 to 20, everyone says, is
> uncertain. Ziprasidone is an example of the drug with approximately a
> 14-millisecond or so effect that was put in the market because of its
> benefit/risk ratio.
>
> \[Slide.\]
>
> In the final slide, we will just summarize the overall cardiac safety
> analysis. It is not really totally defined by one trial although the
> new definitive Phase I trials that are being requested are, of course,
> going to be the one to look at the most. 076 in this case meets some
> of the these principles.
>
> The preclinical data is something that is trumped by adequate clinical
> data, meaning if you have a HERG-positivity and you do a definitive
> trial and it is negative, it is now believed that one would ignore
> that preclinical data in terms of risk because in the targeted
> species, man, you have shown that the drug does not have this risk.
>
> The thorough Phase I trial, as I said, is not only important to define
> the principal degree of cardiac risk but, of then, of course, one
> still needs to look at electrocardiograms in the target population in
> Phase II and Phase III but, if the Phase I definitive trial is
> negative, those ECGs can be pretty routine. If it isn\'t, one needs to
> consider more intense monitoring in Phase II and III.
>
> Finally, at the time of the ISS, one puts together all of the data and
> makes it relatively easy to come to a judgment.
>
> Thank you very much for your attention.
>
> DR. GULICK: Thanks, Dr. Morganroth.
>
> Are there any quick questions from the committee for Dr. Morganroth?
>
> Mr. Sharp?
>
> MR. SHARP: I will just start off here. I just wondered if there are
> any other antiretroviral drugs that cause QT prolongation. I noticed
> the list of some of the prophylactic drugs. I was wondering about
> other antiviral drugs.
>
> DR. MORGANROTH: I believe that ritonavir is known to prolong the QT.
> It is also a fairly, if not the most potent, blocker of 3A4, an enzyme
> that is used for the metabolism of many of these drugs. I am not an
> expert in the HIV area in terms of history with past drugs, so I
> don\'t know the regulatory history. Perhaps someone else on the
> committee could comment on that or maybe someone from the agency.
>
> DR. GULICK: Dr. Birnkrant?
>
> DR. BIRNKRANT: We periodically scan our postmarketing database for
> adverse events related to cardiac conduction, et cetera. It is an
> active process for us. So we are constantly looking for this type of
> signal. To date, basically, there are cases here and there but there
> is a lot of confounded data along with those cases. At this point,
> that is all I am prepared to say but we are actively looking for those
> types of signals.
>
> DR. GULICK: Dr. Kumar.
>
> DR. KUMAR: Could you comment on how, for the clinician, the places
> that we have seen problems with drugs known to prolong the QTc
> prolongation are patients who are on diuretics and then develop
> hypokalemia or hypermagnesemia. How can we assess that when clinical
> trials, most of these patients are usually healthy people who are not
> on diuretics or anything else that can prolong the QTc interval?
>
> DR. MORGANROTH: If you are asking how can you assess whether a drug
> that you are using affects the QTc when you take care of a patient and
> you eliminate, for example, hypokalemia or other issues, the answer
> is, in my opinion, that you can\'t very easily, can you, because you
> really need almost, like we discussed, a definitive trial that is very
> large, that is very controlled, that has a lot of ECGs before drug and
> on the drug. In a clinical setting, you don\'t really have that luxury
> because you hopefully may have an EKG before you started the drug and
> you might do an EKG for whatever reason on the drug, maybe, perhaps,
> to look to see if there is an effect.
>
> But, in an individual patient, that is difficult to do. For example,
> in the oncology area, which is where this becomes relative, perhaps
> even in your area, when you have cytotoxic drugs and you can\'t do a
> controlled trial\--you can\'t give it to normal volunteers and it is
> often difficult to use placebo in oncology patients. There, you have
> to do an outlier equivalent analysis.
>
> That would be to see if there is a major change in the QTc duration.
> For example, 60 milliseconds would suggest that you are seeing a QTc
> effect. If your baseline was 400 and you are now 460, that might be an
> effect. You would want to sort of do a couple more ECGs to see if that
> doesn\'t go away quickly, within a few minutes, because it possibly
> could, if it is just variability.
>
> So it is difficult, without doing a definitive trial, to be certain. A
> 60-millisecond effect, a new 500-millisecond effect, would be what you
> would be concerned about. So anything over 500, you would be very
> concerned or 60 milliseconds, you might consider a drug, would be the
> best answer.
>
> DR. GULICK: Yes?
>
> DR. KOWEY: Can I just respond to the other question about other
> antiviral drugs? Almost all the protease inhibitors do have an effect
> on IKr. I don\'t think that we have\--as Joel was intimating, I don\'t
> think we have the kind of clinical-trial data that would tell us how
> much of that translates into a QT-prolonging effect.
>
> But I would be surprised if the other protease inhibitors didn\'t have
> this effect based on the relative potency of their effect on IKr. In
> fact, the drug we are looking at today is probably one of the weakest
> of the IKr blockers within this family of agents.
>
> So I think it is probably a yes to your question.
>
> DR. GULICK: Okay. Thanks for that. Just to remind the committee, we
> are going to have lots of time to get into this later. I will take one
> last question from Dr. Wood.
>
> DR. WOOD: I was just wondering if you could comment on QT intervals in
> the pediatric population, if there are any changes developmentally?
>
> DR. MORGANROTH: The pediatric population, in my experience, has been
> obviously insufficiently studied in general and particularly for the
> QT issues of drugs. I have seen two or three trials attempting to do
> this in pediatrics and I don\'t have sufficient data to really give
> you any generalizations or comments. But it is perfectly reasonable
> and easy to do. Of course, EKGs are noninvasive. You can do them.
>
> I think as more pediatric trials are done and more intense concern
> about safety issues in children are raised with this we will be able
> to get the data. Right now, it is just an area that has, in my
> opinion, sufficient data to know how one can translate adult findings
> into pediatrics. It is assumed to be the same.
>
> DR. GULICK: Thank you, Dr. Morganroth.
>
> Just to remind everyone, we will have lots of time to go into more
> details and Dr. Morganroth is on the committee today so we can seek
> his advice later.
>
> Two additional members joined the table, so please introduce
> yourselves and state your affiliations. Dr. Sherman and Dr.
> Goldberger.
>
> DR. SHERMAN: Ken Sherman, University of Cincinnati.
>
> DR. GOLDBERGER: Mark Goldberger from the Office of Drug Evaluation IV
> at FDA.
>
> DR. GULICK: Thank you.
>
> We will turn now to the sponsor presentation from Bristol-Myers
> Squibb.
>
> **Sponsor Presentation - Bristol-Myers Squibb**
>
> DR. SIGAL: Good morning.
>
> \[Slide.\]
>
> My name is Elliott Sigal. I am Head of Development for Bristol-Myers
> Squibb. I would like to thank the committee for this opportunity to
> describe our clinical studies on atazanavir.
>
> In the early 80\'s, when physicians were first seeing patients with
> what was later named AIDS, I don\'t think they ever would have
> imagined we would be here today discussing the challenges and
> opportunities that have arisen because of the chronic nature of HIV
> therapy.
>
> As patients live longer, drug therapies need to have new resistance
> patterns, better side-effect profiles and dosing that supports
> extended use. Because of these challenges, HIV AIDS remains a disease
> for which new and improved therapies are important.
>
> \[Slide.\]
>
> Atazanavir is a new addition to our armamentarium for the treatment of
> this disease and for meeting these challenges. It has a distinct
> resistance profile. Resistance is infrequent but, as you will see, we
> have characterized a signature mutation that we believe has
> opportunity for preserving future treatment options.
>
> Unlike other protease inhibitors, atazanavir has far less effect on
> cholesterol and triglyceride levels. Its favorable lipid profile
> potentially reduces the need for concomitant medicines. Finally,
> atazanavir offers once-daily dosing which reduces, importantly, the
> pill burden for these patients.
>
> These attributes, along with an acceptable safety tolerability profile
> and demonstrated efficacy, address what we see today as important
> medical needs. We designed atazanavir\'s development program to
> establish its ability to meet these needs.
>
> \[Slide.\]
>
> A substantial clinical program with over 2500 subjects studied and
> 1500 patients treated with atazanavir has demonstrated the efficacy
> and safety of atazanavir. This program has studied a wide variety of
> HIV-infected individuals including treatment-naive,
> treatment-experienced and pediatric patients.
>
> Studies have demonstrated efficacy extending past two years. In
> addition to the Phase II and Phase III trials, patients have received
> atazanavir through an early-access program. As you heard, part of the
> process of bringing a novel therapy into treatment is the
> characterization of its safety profile and to do so comprehensively.
>
> As part of BMS\'s ongoing safety program, we have worked to examine
> any effects on cardiac electrophysiology. In addition, we have
> examined and characterized the effects of bilirubin. We have then
> worked extensively with the FDA and our experts to determine the
> implications of these results.
>
> To further explore these findings today, we have arranged to have
> available to you outside experts to respond to any questions and
> supplements to our company presentation. Our list of experts is on the
> following two slides.
>
> \[Slide.\]
>
> They are available to you and prepared to comment on specialty areas
> of HIV resistance, lipid levels in HIV infection, cardiac
> electrophysiology issues.
>
> \[Slide.\]
>
> HIV clinical paradigms and hyperbilirubinemia.
>
> \[Slide.\]
>
> Based on our program, we are seeking an indication for the treatment
> of HIV in combination with other antiretroviral agents for the
> treatment of HIV infection. This indication has evolved through our
> discussions with the agency.
>
> \[Slide.\]
>
> The presentation of the clinical program will begin with Dr. Steve
> Schnittman. Steve will describe the clinical-development program and
> clinical-trial results.
>
> Because of the evolving norm, as you heard, to extensively
> characterize the electrophysiology effects of all new chemical
> entities, Dr. Jack Lawrence, one of our cardiologists, will speak to
> these issues. You will hear our conclusion that we think atazanavir
> has no significant effect on QT interval.
>
> Dr. Michael Giordano will describe the drug\'s effect on bilirubin and
> characterize its lipid profile. I will then return to present a brief
> summary of benefit/risk.
>
> Dr. Schnittman?
>
> **Clinical Development Program and**
>
> **Clinical Trial Results**
>
> DR. SCHNITTMAN: Thank you, Elliott, and good morning everyone.
>
> \[Slide.\]
>
> My role today is to present the atazanavir clinical-trial program and
> show how the program supports the safe and efficacious use of
> atazanavir in a diverse HIV-infected patient population. First, the
> intrinsic properties of atazanavir will be described including ADME
> features, a summary of drug-drug interactions, and early findings in
> the program that guided dose selection for Phase III clinical trials.
>
> The bulk of the presentation will be clinical-trial results. Study
> findings in the antiretroviral treatment-naive patient population will
> be described including information regarding overall viral
> susceptibility and the distinct resistance profile for atazanavir that
> is emerging.
>
> Next, we will review the data in treatment-experienced patients. These
> patients face problems with emerging HIV resistance and
> treatment-associated comorbidities, and we will be presenting data
> from two trials in diverse experienced-patient populations.
>
> Before presenting the pivotal clinical studies, let\'s briefly review
> the ADME which provided critical information to guide clinical-study
> design and the drug-drug interaction profile that is essential for the
> proper and safe use of atazanavir.
>
> \[Slide.\]
>
> Atazanavir is rapidly absorbed. Food increases atazanavir exposure and
> decreases the intersubject variability. Therefore, atazanavir should
> be administered with food. Atazanavir protein binding of 86 percent is
> in the mid-range for PIs. Atazanavir is primarily metabolized in the
> liver. It is a substrate and a moderate inhibitor of CYP3A4 with a Ki
> in the mid-range of PIs.
>
> Thus, atazanavir may have the potential to alter the clearance of
> drugs that are metabolized by CYP3A4. Furthermore, atazanavir may have
> its metabolic clearance altered by drugs that have the potential to
> inhibit or induce CPY3A4.
>
> These characteristics of atazanavir metabolism drove the drug-drug
> interaction program and provided guidance for the safe and efficacious
> use of concomitantly administered medicines.
>
> While not metabolized by the enzyme, atazanavir is also a competitive
> inhibitor of UGT 1A1, like indinavir, but quantitatively more
> significant. This inhibition of bilirubin glucuronidation was a
> consideration in our dose selection.
>
> Finally, atazanavir is primarily eliminated in the feces with minimal
> urinary excretion and has an elimination half-life of about seven
> hours.
>
> \[Slide.\]
>
> The drug-drug interaction profile for atazanavir was evaluated in a
> series of clinical-pharmacology studies. The entire program is in your
> briefing document in Appendix 1 beginning on Page 214. But summarized
> here are the complete recommendations.
>
> This evaluation included drugs that are commonly taken by HIV-infected
> patients. No modification in dosing for atazanavir or coadministered
> drug was noted in many cases. There are certain drug-drug interactions
> that have potentially important PK or PD effects because of CYP3A4
> interactions.
>
> These include drugs whose dosing should be modified due to
> atazanavir\'s inhibition of CYP3A4 including saquinavir,
> clarithromycin, rifabutin, diltiazem and oral contraceptives. Some of
> these will be further described in the Special Topics part of the
> presentation.
>
> Other drugs require atazanavir dosing modifications because of either
> CYP3A4 induction, as seen with efavirenz, or with CYP3A4 inhibition as
> seen with ritonavir. Finally, atazanavir should be separated in dosing
> from buffer formulation ddI and, although not studied, this may be
> expected to apply to antacids in general.
>
> \[Slide.\]
>
> To select the dose for the Phase III studies in treatment-naive
> patients, a combination of pharmacokinetic and pharmacodynamic data
> was analyzed, integrated and assessed. This single figure sums up our
> overall rationale for dose selection. It displays the steady-state
> concentration curve over a twenty-four hour dosing period in the fed
> state for atazanavir at 400 milligrams.
>
> The Cmin or trough at the far end of the curve is the PK parameter
> that best correlates with antiviral activity of atazanavir, and this
> is true for protease inhibitors as a class. For atazanavir 400
> milligrams once a day, the trough in patients is a mean of about 150
> nanograms per ml.
>
> In addition, we provide the estimated protein-adjusted EC90s for
> atazanavir as a cluster of dots. These data were determined from 93
> consecutive antiretroviral-naive subjects who were randomized to this
> study. Given the median estimated protein-adjusted EC90 of 14
> nanograms per ml, the ratio of mean Cmin to adjusted EC90 is in excess
> of 10.
>
> This provides a PK cushion throughout the dosing period for the range
> of virus susceptibilities encountered in a naive patient population.
> Other PK and PD assessments, as well as safety and efficacy
> evaluations, in the large dose-ranging Phase II clinical studies 007
> and 008 further support the dose selection of atazanavir 400 QD for
> treatment-naive patients. This is consistent with the accepted
> convention of HIV therapeutics that one should pick the highest
> tolerable dose.
>
> \[Slide.\]
>
> Two weeks of atazanavir monotherapy demonstrated a dose-related mean
> RNA decline. This is consistent with hollow-fiber in vitro modeling
> demonstrating the adequacy of doses of 400 milligrams QD or greater.
>
> The Phase II studies also demonstrated a nonlinear dose relationship
> to Cmin with a large increase in trough level from 200 to 400
> milligrams and much smaller increases in the trough with doses above
> 400 milligrams. Importantly, the Cmins for 200 milligrams were
> inadequate relative to the median EC90 in naive patients.
>
> \[Slide.\]
>
> Elevations in bilirubin are dose-related, best correlate with Cmin and
> doses of 500 and 600 milligrams were associated with significantly
> greater elevations in bilirubin of at least five times the upper limit
> of normal and did not appear to offer additional efficacy.
>
> \[Slide.\]
>
> Confirmation of the efficacy of the 400-milligram dose of atazanavir
> as compared to nelfinavir was demonstrated by the solid virologic
> response over 48 weeks from the two large Phase II studies 007 and
> 008. The 400-milligram once-daily dose provided the best balance of
> maximizing antiviral efficacy while minimizing the risk of potential
> adverse events.
>
> \[Slide.\]
>
> Therefore, atazanavir 400 milligrams was chosen as the optimal dose to
> be evaluated in Phase III studies in treatment-naive patients. I will
> now provide the results of Study 034, the pivotal Phase III study in
> antiretroviral-naive subjects.
>
> \[Slide.\]
>
> 034 was an 810-subject, double-blind, double-dummy active controlled
> multinational study that randomized subjects to either atazanavir 400
> once daily or efavirenz 600 once daily. Subjects on both arms received
> zidovudine plus 3TC BID as a fixed-dose combination.
>
> Please note, nucleoside changes were not permitted in the study.
> Efavirenz was the selected comparator as it is the standard of care in
> treatment-naive patients.
>
> \[Slide.\]
>
> The baseline characteristics of the subjects enrolled in Study 034
> were well balanced overall. Of interest, more than one-third of the
> subjects enrolled were female. Two thirds were non-white. The median
> HIV RNA was 4.9 logs with over 40 percent of subjects having greater
> than 100,000 copies HIV RNA.
>
> Of note, retention was high with 82 percent of subjects remaining on
> study through Week 48. The similarity of virologic efficacy between
> the atazanavir and efavirenz regimens is demonstrated in the next
> slide.
>
> \[Slide.\]
>
> The primary endpoint for the study was the virologic response through
> 48 weeks which is the proportion of subjects below 400 copies per ml
> RNA. This is an intent-to-treat analysis, non-completers equal
> failure, based on the most recent FDA-proposed algorithm for virologic
> response. The figure demonstrates that both treatment regimens are
> highly active.
>
> \[Slide.\]
>
> The primary analysis, virologic response, below 400 copies through 48
> weeks, atazanavir, shown in green, was similar to the efavirenz
> regimen and statistically noninferior. The response rates were 70
> percent and 64 percent respectively.
>
> For the secondary endpoint of virologic response through 48 weeks for
> LOQ50, the response rates were 32 percent and 37 percent respectively
> and they also met the criteria for similarity. These data demonstrate
> the durable efficacy of the 400-milligram, once-daily, dose of
> atazanavir in antiretroviral-treatment-naive patients relative to a
> widely accepted standard of care.
>
> Subpopulation analyses for the principal efficacy parameters confirm
> consistent between-treatment comparisons based on gender, race, region
> and HIV RNA level. For subjects with baseline RNA less than 100,000,
> virologic responses were comparable between treatment regimens, as
> seen on the left, and this comparability was also seen for treatment
> regimens for subjects with baseline RNA greater than 100,000, seen on
> the right.
>
> \[Slide.\]
>
> In order to understand the development of resistance in naive patients
> with virologic failure, phenotypic and genotypic determinations were
> performed by Virologics and LabCore respectively. Samples from
> patients with protocol-defined virologic failure in Study 034 and who
> had viral loads of greater than 1,000 copies per ml were assayed.
>
> Resistance develops infrequently in atazanavir patients meeting the
> protocol definition of virologic failure. Working down the column, 26
> of 69 atazanavir virologic-failure patients were able to be pheno- and
> genotyped. Of these 26, only 6 demonstrated decreased susceptibility
> to atazanavir\--i.e., greater than 2.5 times the control, EC50.
> Notably, all six of these isolates had the I50L substitution.
>
> In addition, the only genotypic changes consistently seen in isolates
> from patients experiencing virologic failure in antiretroviral naive
> studies has been the I50L substitution. Across the naive-patient
> studies, decreased susceptibility to atazanavir occurs infrequently,
> being observed in 2 percent of all subjects and about 11 percent of
> atazanavir treatment failures.
>
> \[Slide.\]
>
> In PI treatment-naive subjects who develop virologic failure in Phase
> II and III studies, 23 on-study resistant isolates have been assessed
> and all have the I50L signature mutation. Furthermore, each of these
> I50L-containing isolates demonstrates atazanavir-specific resistance
> with decreased viral fitness and maintained or enhanced susceptibility
> to all other PIs tested.
>
> These features of the I50L genotype are promising with respect to
> preserving the PI class and preserving future treatment options.
>
> \[Slide.\]
>
> We also looked at CD4 cell counts as a marker for immunologic response
> in O34. CD4 cells increase substantially and throughout the study
> duration. The mean increase at Week 48 was 176 cells on the
> atazanavir-containing regimen, 160 cells on the efavirenz-containing
> regimen, each of which contained ZDV 3TC.
>
> These data support the durable efficacy of atazanavir 400 relative to
> a potent standard of care.
>
> \[Slide.\]
>
> The safety and tolerability of atazanavir was also carefully assessed.
> Adverse events seen in the 034 study are presented in the slide and
> demonstrate the overall safety and tolerability profile of atazanavir.
> Rash and dizziness were more common on the efavirenz regimen whereas
> jaundice and scleral icterus were more frequent on the atazanavir
> regimen. The jaundice and scleral icterus were not associated with
> hepatotoxicity and reflected benign elevations in unconjugated
> bilirubin.
>
> This will be addressed in detail by Dr. Giordano.
>
> \[Slide.\]
>
> The ability of heart regimens to provide durable efficacy and safety
> to patients is of paramount importance. To this end, the atazanavir
> program has continued long-term dosing and monitoring of patients in
> order to provide this information.
>
> One such study is the 008/044 Phase II rollover. Subjects who were
> enrolled in the 008 dose-ranging study and who had successfully
> completed the trial and were virologically stable were eligible to
> enter this extended dosing phase and to continue in one of three arms,
> either atazanavir 400 on the left, atazanavir 600 in the middle, or
> switch from nelfinavir to atazanavir 400 each in combination with
> continued d4T/3TC.
>
> \[Slide.\]
>
> The cohort of subjects on atazanavir 400 that enrolled in 044 received
> a median cumulative treatment of about 109 weeks. The virologic
> response was sustained and durable for subjects treated with
> atazanavir 400, shown in green, 82 percent for LOQ 400, 50 percent for
> LOQ 50 and was comparable to patients treated with atazanavir 600,
> shown in blue. Of note, virologic suppression was maintained for those
> who switched from nelfinavir to atazanavir 400.
>
> These long-term extension results support the durable efficacy of
> atazanavir 400.
>
> \[Slide.\]
>
> These same patients have also demonstrated continued immunologic
> responses over time. We observed substantial CD4-count increases of
> about 350 cells for the atazanavir 400-milligram arm beyond two years
> further supporting the sustained efficacy of this dosing regimen.
>
> We conclude from studies in antiretroviral treatment-naive subjects
> the following.
>
> \[Slide.\]
>
> In a large adequate and well-controlled Phase III study, the
> 400-milligram dose of atazanavir has been shown to be safe and highly
> efficacious over 48 weeks relative to the non-nuc efavirenz. These
> findings are supported by those in two large Phase II studies in which
> atazanavir was shown to be safe and as efficacious as the PI,
> nelfinavir.
>
> Furthermore, the extended follow up of patients in the Phase II
> studies supports the durable efficacy and safety beyond three years of
> dosing with atazanavir 400. Resistance to atazanavir develops
> infrequently in treatment-naive patients and, when it does, the I50L
> signature mutation consistently appears which may preserve future
> therapeutic options.
>
> \[Slide.\]
>
> In addition, and to be presented by Dr. Giordano, atazanavir
> demonstrates no increase in cholesterol and triglycerides with less
> need for lipid-lowering agents.
>
> \[Slide.\]
>
> Having demonstrated safety and efficacy in antiretroviral-naive
> patients, let\'s turn our attention to the experienced patients. We
> will begin with the rationale for dose selection and then the clinical
> data in support of the safety and efficacy of atazanavir in these
> patients.
>
> \[Slide.\]
>
> Treatment-experienced patients are heterogeneous for several reasons.
> These patients have been exposed to a variety of combination therapies
> and for varying periods of time. The virus in these patients generally
> has decreased antiretroviral susceptibility with a variety of
> mutations.
>
> Several strategies were explored; atazanavir, 400 milligrams
> unboosted, atazanavir boosted with ritonavir and atazanavir combined
> with a second PI with a nonoverlapping resistance profile. In current
> clinical practice, most PIs are boosted with ritonavir in order to
> enhance PK.
>
> However, there are features of the atazanavir profile that prompted
> our looking at unboosted atazanavir in experienced patients.
>
> \[Slide.\]
>
> The strategy for unboosted atazanavir 400 in treatment-experienced
> patients who only failed a single PI was based on the fact that
> atazanavir susceptibility was maintained in 86 percent of viral
> isolates resistant to one or two PIs. In addition, we determined the
> 400-milligram once-daily dose mean trough level of 150 was
> significantly above the EC90s of many of these experienced patient
> virus isolates.
>
> Together, this information supported the trial of an unboosted
> 400-milligram atazanavir dose as a single PI for a Phase III study in
> patients who previously failed a single PI. This is the 043 study.
>
> \[Slide.\]
>
> Such patients were randomized to receive either atazanavir at 400 once
> daily unboosted or lopinavir boosted with ritonavir twice daily.
> Lopinavir/ritonavir was the selected comparator as it is the standard
> of care in treatment-experienced patients.
>
> Each of these dosing regimens was combined with two nucs to which the
> patient was phenotypically sensitive. Of note, one-third of the
> subjects selected D4T ddI and one-third of subjects selected abacavir
> plus a second nuc. 300 subjects were randomized and, as per the
> protocol-plan primary analysis, and as per FDA agreement, the first
> 229 subjects are included as the lead cohort through 24 weeks while
> safety data is included for all subjects.
>
> For our purposes today, all efficacy analyses presented by us will
> reflect the lead cohort. We, in the FDA, have subsequently analyzed
> the safety and efficacy on all patients through 24 weeks and it is
> these latter analyses that will be presented by the FDA today.
>
> \[Slide.\]
>
> Overall, the baseline characteristics for the subjects enrolled in
> this study were well balanced. About 20 percent of subjects were
> female. More than half were nonwhite. Approximately 28 percent of
> subjects had a prior AIDS-defining diagnosis.
>
> \[Slide.\]
>
> Patients in 043 did have a moderate amount of prior experience with
> antiretroviral agents. This included prior history of 140-week mean
> exposure to protease inhibitors, 180 weeks to nucs, and 85 weeks to
> non-nuc RT inhibitors.
>
> \[Slide.\]
>
> The patients prior PI exposure is reflected in this phenotypic
> sensitivity pattern. More than half the patients had decreased
> susceptibility to nelfinavir. The majority were fully susceptible to
> atazanavir and lopinavir, IC50 less than 2.5 times control.
>
> \[Slide.\]
>
> The HIV RNA mean change from baseline, expressed as a time-average
> difference, was a coprimary endpoint in the 043 study. Over the first
> few weeks, a very rapid RNA decline in both treatment arms of
> approximately 1.5 logs is noted. That decline then stabilizes for
> unboosted atazanavir while, in contrast, there is further RNA decline
> on the boosted lopinavir/ritonavir arm.
>
> The difference between these regimens, in terms of time-average
> difference, was approximately 0.31 logs through 24 weeks that favored
> lopinavir/ritonavir and was significant.
>
> It is not unexpected that the unboosted atazanavir regimen was less
> efficacious than the lopinavir/ritonavir boosted regimen. The
> reduction from baseline in HIV RNA was substantial for atazanavir. It
> is therefore important to determine the contribution of the atazanavir
> component of the regimen to the regimen\'s efficacy.
>
> This was estimated by retrospective comparison to results from studies
> evaluating dual-nuc regimens.
>
> \[Slide.\]
>
> Five historical controls were identified. They were conducted in
> treatment-experienced populations. They contained at least one
> treatment group with only dual-nuc therapy and that reported analyses
> of RNA at baseline and Week 24. Estimates of the Week 24 RNA change
> from baseline for dual-nuc treatment arms ranged from -0.25 to -0.89
> log.
>
> A combined estimate representing the dual-nuc treatment effect is
> -0.64 log with a tight 95 percent confidence interval seen in the top
> orange bar.
>
> In 043, the Week 24 mean RNA change from baseline for atazanavir
> combined with dual-nuc therapy was -1.73 log. Note that the atazanavir
> confidence interval, shown in green, does not overlap the confidence
> interval for the individual or combined estimates for dual nucs.
>
> We conclude that the atazanavir regimen has significantly greater RNA
> decline as compared with the dual-nuc therapy alone. Despite the
> inherent biases of historical and cross-study comparisons, the large
> difference observed between atazanavir with two nucs and two nucs
> alone overcomes many of these limitations. Therefore, atazanavir
> contributes to the efficacy in the treatment-experienced population
> beyond what would be expected with dual-nucs alone.
>
> \[Slide.\]
>
> Now let us compare the virologic responses for the unboosted
> atazanavir and the boosted lopinavir/ritonavir arms based upon the
> proportion of subjects below HIV RNA limit of quantitation which was a
> secondary endpoint. Through 24 weeks, antiviral efficacy was
> demonstrated for the boosted lopinavir/ritonavir regimen with 81
> percent below LOQ 400 and 52 percent below LOQ 50.
>
> Substantial efficacy was also demonstrated for the unboosted
> atazanavir regimen with 61 percent below 400 LOQ and 41 percent below
> LOQ 50. It is not surprising that the boosted PI performed better than
> a nonboosted PI. With efficacy of the atazanavir 400 having been
> demonstrated in the experienced-patient population, exploratory
> analyses were performed. While these exploratory analyses do not
> explain the differential efficacy observed between boosted and
> nonboosted PIs, they do suggest phenotypic and genotypic parameters at
> baseline that may be predictive of a good virologic response for
> atazanavir.
>
> \[Slide.\]
>
> Better virologic responses to atazanavir were determined for the
> following subgroups; subjects having no demonstrable phenotypic
> resistance to atazanavir\--i.e., less than 2.5 IC50 control\--and
> subjects having been exposed to only one prior PI regardless of
> baseline nuc mutations.
>
> As seen in this table, virologic response rates for atazanavir in
> these subgroups were enhanced up to 68 percent for LOQ 400. Therefore,
> a clinician may conclude that atazanavir, at 400 milligrams unboosted,
> would be most appropriate in experienced patients with minimal
> evidence of resistance, a patient profile that is commonly seen in
> early PI failures.
>
> \[Slide.\]
>
> With respect to immunologic response, significant improvement in CD4
> cell counts were seen and continued to rise over 24 weeks. The mean
> increase at Week 24 was 101 cells on the atazanavir-containing regimen
> and 121 cells on the lopinavir/ritonavir-containing regimen. The
> improved immunologic parameters support the efficacy contribution of
> atazanavir.
>
> \[Slide.\]
>
> It is important to note that the coprimary endpoint for the study was
> a comparison of the mean percent change in fasting LDL cholesterol
> from baseline between the two arms at 24 weeks. In this figure, we see
> a notable rise in LDL cholesterol on the lopinavir/ritonavir regimen
> with a decline on the atazanavir regimen that was significantly
> different per-protocol-defined objective.
>
> This is just one of multiple studies that confirm the unique lipid
> profile of atazanavir and which will be expanded upon later.
>
> \[Slide.\]
>
> Let\'s move on to safety assessments. Adverse events seen in the 043
> study are presented here and demonstrate the overall good safety and
> tolerability of atazanavir in this population. There was more diarrhea
> and nausea on lopinavir/ritonavir but more jaundice on atazanavir. The
> jaundice was not associated with hepatotoxicity and reflected benign
> elevations in unconjugated bilirubin and will be addressed in detail
> by Dr. Giordano.
>
> \[Slide.\]
>
> We conclude from the 043 study that atazanavir 400 has demonstrable
> safety and efficacy in the treatment-experienced population. The
> majority of patients are able to achieve LOQ 400 with the best
> responses seen in patients without evidence of phenotypic resistance
> to atazanavir having been exposed to only one prior PI, irrespective
> of baseline nuc mutations.
>
> A superior lipid profile was demonstrated for atazanavir relative to
> lopinavir/ritonavir. Therefore, atazanavir efficacy was associated
> with a substantial lipid benefit and thus represents an important
> treatment option for experienced patients.
>
> \[Slide.\]
>
> As we have previously stated, the experienced patient population is
> heterogeneous, while we have identified where atazanavir has
> substantial efficacy, we realize that the more highly
> treatment-experienced population might benefit from alternative dosing
> approaches.
>
> \[Slide.\]
>
> This group of patients is characterized by extensive use of prior PIs
> and nucs with associated geno- and phenotypic resistance. For these
> highly experienced patients, BMS has evaluated two different dosing
> strategies. One is the boosting of atazanavir with ritonavir in order
> to provide a more robust atazanavir PK profile.
>
> The second is combining atazanavir with another PI with nonoverlapping
> resistance, specifically saquinavir.
>
> \[Slide.\]
>
> We know patients with prior exposure to PIs may require higher drug
> levels to suppress virus because of decreased susceptibility to both
> the PI and nuc components of HAART. In this figure, the PK profile of
> atazanavir in healthy volunteers, given as a 300-milligram once-daily
> dose in combination with 100-milligram once-daily dose of ritonavir is
> shown in blue and, for illustrative purposes, it is compared to a
> typical concentration curve for atazanavir 400 once-daily, also in
> healthy volunteers, shown in green.
>
> In addition, we provide the estimated protein-adjusted EC90s for
> atazanavir as a cluster of dots determined from all subjects in the
> multiple-treatment-failure 045, Note the broad range of reduced
> susceptibilities. Ritonavir primarily slows the elimination phase of
> atazanavir. You see a substantial increase in exposure, two- to
> three-fold, and a trough on the order of 5- to 8-fold, with the
> boosted atazanavir.
>
> In addition, there is a decline in variability of drug concentrations
> in the presence of ritonavir. Furthermore, the Cmax which may be
> expected to drive certain adverse events of drug but not bilirubin
> elevations was very similar for atazanavir boosted and unboosted.
>
> In other PK studies, doses of atazanavir and ritonavir greater than
> 300 and 100, respectively, indicated a concern of increased adverse
> effects due to higher peaks and troughs. In fact, two studies in
> healthy volunteers have demonstrated that atazanavir 300 combined with
> ritonavir 100 once daily provide an optimal PK/PD and safety profile
> supporting its selection for a Phase III study in patients who failed
> multiple HAART regimens, Study 045.
>
> \[Slide.\]
>
> In Study 045, patients were enrolled who failed at least two HAART
> regimens that included an antiretroviral from each therapeutic class.
> These highly treatment-experienced patients were randomized among
> three arms. For the first two weeks, they maintained their nuc
> backbone and replaced their PI or NNRTI with one of the following;
> combination of atazanavir 300 with ritonavir 100 once daily on the
> left, combination of atazanavir 400 with saquinavir 1200 once daily in
> the middle, or lopinavir 400 with ritonavir 100 given BID on the
> right.
>
> From Week 2 onward, the NNRTI backbone was replaced with tenofovir 300
> once daily plus a nuc to which the patient demonstrated phenotypic
> susceptibility.
>
> The FDA has reviewed the interim analysis for efficacy that includes
> 106 of 358 subjects through Week 16 and for safety on all subjects
> through Week 16. However, we will briefly provide an updated analysis
> that includes the efficacy on all subjects through 24 weeks, an
> analysis you also find within the briefing document.
>
> For consistency, all future displays for Study 045 will include the
> 24-week unreviewed data. Of interest, 35 percent of the subjects in
> 045 had a prior AIDS diagnosis and these patients, indeed, were
> heavily treatment-experienced with about five-and-a-half years of
> prior antiretroviral use.
>
> The relative efficacy of the various dosing strategies is demonstrated
> on the next slide.
>
> \[Slide.\]
>
> The HIV RNA mean change from baseline expressed as a time-average
> difference is the primary endpoint. All three regimens show similar
> rapid declines in RNA of about 1.25 log over the first two weeks
> during which time only the PI was switched. Through Week 24, there is
> approximately 1.52 log RNA decline in the atazanavir/saquinavir arm,
> 1.86 log decline in the atazanavir 300 ritonavir-boosted arm, and 1.89
> log decline in the lopinavir/ritonavir-boosted arm.
>
> In terms of the time-average difference, there were no significant
> differences in efficacy between atazanavir/ritonavir and
> lopinavir/ritonavir regimens while lopinavir/ritonavir regimen was
> more efficacious than atazanavir/saquinavir.
>
> \[Slide.\]
>
> This table summarizes the virologic response as the proportion of
> subjects with HIV RNA below limit of quantitation either 400 or 50.
> For the treatment regimens at 24 weeks as intent-to-treat analyses,
> these data demonstrate that the atazanavir 300 ritonavir and
> lopinavir/ritonavir-containing regimens showed solid and comparable
> efficacy through 24 weeks, 64 percent and 62 percent, respectively for
> LOQ 400.
>
> This is in contrast to the atazanavir/saquinavir arm which had a
> substantial but lower response rate of 44 percent. In addition, the
> proportion of subjects with virologic response rates for LOQ 50 was
> comparable for atazanavir/ritonavir and lopinavir/ritonavir regimens.
>
> \[Slide.\]
>
> The longitudinal virologic response rates over 24 weeks for the two
> boosted regimens are displayed in this figure as well for both the LOQ
> 400 and LOQ 50. These data confirm the similarity of the
> atazanavir/ritonavir, shown in green and lopinavir/ritonavir shown in
> orange to these highly treatment-experienced subjects.
>
> With respect to immunologic response, we see substantial improvement
> in CD4 counts over the 24 weeks with a similar rise of 83 and 90 cells
> on atazanavir/ritonavir and lopinavir/ritonavir arms. These were
> somewhat higher than the cell-count rise on atazanavir/saquinavir.
>
> These increases are highly substantial for the treatment-experienced
> patient population and are of the magnitude known to confer clinical
> benefit. Safety assessments in 045 demonstrated that atazanavir has a
> safety and tolerability profile in these highly treatment-experienced
> patients that is similar to that seen in naive patients.
>
> \[Slide.\]
>
> Working across the columns, jaundice and scleral icterus were observed
> for 6 percent and 3 percent of subjects respectively on the
> atazanavir/ritonavir arm. Atazanavir/saquinavir subjects experienced
> more GI intolerance, nausea and vomiting, which contributed to the
> higher discontinuation rate relative to the two other arms.
>
> In contract, the lopinavir/ritonavir arm experienced predominantly
> diarrhea as an adverse event, 11 percent.
>
> \[Slide.\]
>
> We conclude from the 045 study in highly treatment-experienced
> patients that, through 24 weeks in unreviewed data, atazanavir 300
> boosted with ritonavir demonstrates efficacy that is comparable to
> lopinavir/ritonavir. Atazanavir/ritonavir provides a good safety and
> tolerability profile and the preference for a ritonavir boosting
> strategy for atazanavir in highly experienced patients is becoming
> clearer.
>
> \[Slide.\]
>
> We conclude from these pivotal and supporting clinical studies that
> the efficacy of atazanavir has been confirmed to be similar to both
> efavirenz and nelfinavir in treatment-naive patients at the
> 400-milligram once-daily dose. Extended studies in naive patients
> demonstrated durability of treatment effect to at least 108 weeks.
>
> We have also demonstrated the efficacy of the 400-milligram dose in
> treatment-experienced patients. Resistance develops infrequently in
> atazanavir-treated patients but, when atazanavir resistance does
> develop in naive and susceptible experienced patients, one sees a
> unique signature mutation, the I50L, which may preserve future
> treatment with PIs.
>
> We have demonstrated that atazanavir is safe and well tolerated at the
> 400-milligram once-daily dose in both treatment-naive and experienced
> patients.
>
> Two points will be discussed in upcoming presentations. First,
> hyperbilirubinemia and jaundice are dose-related adverse events that
> are manageable and are not associated with hepatotoxicity. Second,
> atazanavir has a consistent, durable lipid profile that may provide
> reduced cardiovascular risk.
>
> Drug-drug interactions have been well characterized including diverse
> antiretroviral combinations that have been shown to be safe and other
> concomitant drugs for which PK/PD impact have been assessed. These
> latter interactions will be further addressed by Dr. Lawrence.
> Finally, early data from 045 demonstrates the utility of ritonavir
> boosting of atazanavir for treatment-experienced patients. More data
> will be forthcoming from 045 and other studies to fully characterize
> atazanavir-boosting strategies.
>
> We will now turn to considerations that arose during the atazanavir
> development program. These include cardiac electrophysiology
> evaluations, hyperbilirubinemia and the very positive and unique lipid
> profile of atazanavir.
>
> Dr. Jack Lawrence will now present the cardiac-electrophysiology
> profile.
>
> **Cardiac Electrophysiology Evaluations**
>
> DR. LAWRENCE: Thank you, Steve.
>
> \[Slide.\]
>
> The development program for atazanavir included extensive assessments
> of the potential for atazanavir to affect cardiac electrophysiology.
>
> \[Slide.\]
>
> Our assessment included the following elements. Preclinical studies
> suggesting that atazanavir was comparable to other protease inhibitors
> with respect to potential to prolong the QTc interval, and assessments
> of QTc and PR intervals in human studies including 8 studies in 254
> healthy volunteers.
>
> There were also 5 clinical studies including 1,037 HIV-infected
> patients taking atazanavir and 629 patients taking comparator drugs.
>
> These studies demonstrated that atazanavir is comparable to other HIV
> drugs in terms of clinical cardiac electrophysiology.
>
> \[Slide.\]
>
> We have examined the electrophysiological effects of atazanavir in
> several in vitro and in vivo studies. We studied specific ion channels
> that play important roles in cardiac conduction and repolarization.
> HERG and Purkinje studies are important for identifying drugs with the
> potential to cause clinical effects on the QT interval.
>
> Atazanavir blocks sodium and HERG potassium channels with IC50s
> greater than 30 micromolar and blocks calcium channels with an IC50 of
> about 10 micromolar. To put these results into perspective, these
> effects are modest and all protease inhibitors we tested blocked HERG
> or prolonged action potential duration with in vitro potency similar
> to or greater than atazanavir.
>
> In a 9-month in vivo toxicology study in dogs, and up to 7-fold the
> human exposure by AUC, there were no electrocardiographic changes.
> Although we detected a weak in vitro signal, we saw no QT changes in
> dogs or subsequently in human studies.
>
> \[Slide.\]
>
> The 076 study was a double-blind, placebo-controlled, crossover study
> designed to evaluate the effects of atazanavir on the QTc and PR
> intervals. Seventy-two subjects received three treatments - placebo,
> 400 mg atazanavir and 800 mg atazanavir in a randomized sequence, each
> treatment for six days with at least a 14-day washout period between
> treatments.
>
> Serial electrocardiograms, 11 per 24 hours, were collected the day
> prior to dosing and at steady-state on Day 6 of each treatment period,
> along with PK samples on Day 6.
>
> The primary endpoints for this study were based on the QTc and PR
> intervals and their changes from baseline on Day 6.
>
> This study was the focus of our healthy volunteer assessment of QTc
> changes and included evaluations of heart rate and the PR interval.
>
> As described by Dr. Morganroth, the QT interval is a marker for drug
> effects on cardiac repolarization. Because the QT interval varies
> inversely with heart rate, a variety of heart rate correction formulas
> have been developed. Bazett\'s formula and Fridericia\'s formula are
> the most widely used.
>
> Consistent with the current FDA draft guidance on QTc, we were
> encouraged by the Antiviral Division to analyze our QT data using
> Fridericia\'s formula in addition to analyses we had initially
> submitted using Bazett\'s formula.
>
> In the 076 study, we observed a 3 beat per minute mean increase in
> heart rate at the 400 mg dose, and an 8 beat per minute mean increase
> in heart rate at the 800 mg dose. Changes of this magnitude especially
> at the 800 mg dose have the potential to result in overcorrection of
> QT intervals to prolonged values of QTc using Bazett\'s formula, but
> not using Fridericia\'s formula.
>
> Our assessment of QTc included the mean changes from baseline, the
> number of individual subjects with prolonged QTc, and the
> concentration dependence of QTc changes. We will review data using
> both Fridericia\'s and Bazett\'s formulas. Our initial analysis of the
> 076 study suggested a subclinical signal for Bazett-corrected QT
> prolongation.
>
> \[Slide.\]
>
> Using Bazett\'s formula, regression analyses suggested a small
> concentration-dependent effect of atazanavir on QTc. Looking at
> changes in QTc using the average value, the maximum value, or the
> value at Tmax, the changes in mean QTc at 400 mg were smaller than
> placebo, and at 800 mg, were greater than placebo. No subject had a
> QTc greater than 500 milliseconds.
>
> On placebo, one subject had a change in QTc greater than 60
> milliseconds, and on 800 mg, three subjects had a change greater than
> 60 milliseconds, a potentially clinically important level of change.
> All four of these subjects had time-matched increases in heart rate of
> 20 beats per minute or more, suggesting that the tendency for
> Bazett\'s formula to overcorrect at increased heart rates caused these
> to be false positive elevations.
>
> When we performed the same analyses using Fridericia\'s formula, which
> is a more appropriate correction formula in subjects with altered
> heart rates, we saw no effect of atazanavir on QTc.
>
> \[Slide.\]
>
> This is reflected in the scatterplot of QTc Fridericia versus the
> plasma concentration of atazanavir for which regression analyses
> showed no concentration-dependent effect on QTc. The placebo range of
> QTc at zero concentration encompassed all on-treatment values of QTc,
> further suggesting a lack of atazanavir effect.
>
> By the same measures of change in QTc described on the previous slide,
> mean changes in QTc at 400 mg and at 800 mg were less than placebo.
> Furthermore, no subject had a QTc greater than 500 milliseconds or a
> change greater than 60 milliseconds.
>
> We also measured QT intervals in four studies with active comparators.
>
> \[Slide.\]
>
> The comparators were nelfinavir, efavirenz, and lopinavir/ritonavir.
> These data demonstrated a low frequency of prolonged QTcF comparable
> for atazanavir and the comparators. There were no prolongations
> greater than 500 milliseconds, no effect on gender was apparent.
> Overall, atazanavir was comparable to other HIV drugs with respects to
> changes in QTc and had no clinically significant effects on cardiac
> repolarization.
>
> \[Slide.\]
>
> In summary, there was no concentration-dependent effect of atazanavir
> on QTcF. There were no individual subjects with outlier values of
> QTcF, and the frequencies of prolongation in QTc were comparable
> between atazanavir and comparators. Overall, the data demonstrate that
> atazanavir has no clinically significant effect on QTc.
>
> During the course of the evaluation of potential effect on
> repolarization, we did observe dose-dependent prolongation of the PR
> interval.
>
> \[Slide.\]
>
> The PR interval represents the conduction time from the atrium to the
> ventricle. An AV block is a delay or an interruption of conduction
> that can occur with different gradations.
>
> First-degree AV block, defined as an increase in the PR interval to
> greater than 200 milliseconds, is really just conduction delay without
> block. It is almost always asymptomatic and not accompanied by a
> change in heart rate.
>
> Second-degree and third-degree AV block represent gradations of actual
> block of conduction between the atrium and ventricle. The resulting
> symptoms are related to the slow beating rate of the ventricles.
>
> Our assessment of PR included mean changes from baseline, the number
> of individual subjects with first- degree AV block or higher, and the
> dose-dependence of PR changes. We found dose-dependent increases in
> the PR interval amounting to first-degree AV block.
>
> \[Slide.\]
>
> In the 076 study, there was a dose-dependent increase in the maximum
> PR interval recorded at any time post-dosing including a mean change
> of 24 milliseconds at the 400 mg dose, and a mean change of 60
> milliseconds at the 800 mg dose.
>
> The frequency of first-degree AV block was also dose dependent. At the
> 400 mg dose, PR prolongation was modest with 14 percent of subjects
> developing first-degree AV block. At the 800 mg dose, PR prolongation
> was more pronounced. More than half the subjects had first-degree AV
> block. There were no electrocardiograms with higher than first-degree
> AV block, and the electrocardiographic changes were asymptomatic.
>
> We also studied the PR interval in HIV-infected patients.
>
> \[Slide.\]
>
> In the clinical comparator studies involving nelfinavir, efavirenz,
> and lopinavir/ritonavir, the frequency and magnitude of PR
> prolongation was smaller than was observed in healthy volunteers, was
> not clinically significant, and was generally comparable for
> atazanavir and the comparators.
>
> Approximately 3 to 10 percent of subjects receiving each treatment had
> first-degree AV block. No subject had higher than first-degree AV
> block. One subject had overdosed on over 100 tablets of atazanavir,
> developed first-degree AV block with a bifascicular AV block that
> resolved over time.
>
> In addition to our experience in clinical trials, we also had safety
> experience in about 3,500 subjects in the early access program. We
> have recently seen junctional rhythms in two patients taking
> verapamil, a CYP3A4 substrate with concomitant atazanavir and other
> medications.
>
> One was on an additional 3A4 inhibitor delavirdine. The patient was
> hospitalized with shortness of breath and atazanavir and delavirdine
> were discontinued. Two days later, in the continued presence of
> verapamil, the patient suffered a cardiac arrest, was noted to have a
> slower junctional rhythm at 30 to 40 beats per minute, and did not
> survive.
>
> The other patient presented with syncope and a slow junctional rhythm
> approximately two weeks after started verapamil and atenolol for
> hypertension. Both of these drugs were discontinued with no
> interruption of atazanavir dosing, and the arrhythmia resolved.
>
> These two patients developed junctional rhythms likely as a
> consequence of CYP3A4 inhibition of verapamil metabolism.
>
> \[Slide.\]
>
> In summary, atazanavir had dose-dependent effects on the PR interval.
> Abnormalities in AV conduction were limited to first-degree AV block
> with rare exceptions. There has been no second-degree or third-degree
> AV block.
>
> The incidence of PR prolongations was comparable for atazanavir and
> comparators in the clinical studies. Class labeling for protease
> inhibitors recommends caution when using concomitant medications with
> a narrow therapeutic index that are metabolized by CYP3A4.
>
> Consistent with this language, caution should be taken when atazanavir
> is coadministered with drugs known to prolong the PR interval that are
> metabolized primarily by CYP3A4.
>
> \[Slide.\]
>
> Overall, to conclude, atazanavir has no effect on the QTc interval.
> Atazanavir has manageable effects on the PR interval that are
> comparable to several other HIV drugs.
>
> As with other protease inhibitors, caution is advised when atazanavir
> is administered with drugs known to prolong the QTc or PR interval
> that are metabolized by CYP3A4.
>
> Now, Dr. Giordano will continue with two other characteristics of
> atazanavir of special interest.
>
> **Characterization of Hyperbilirubinemia**
>
> DR. GIORDANO: Thank you.
>
> In the next two presentations, I will review data that relate to two
> special considerations, first, bilirubin, and then, second, the unique
> lipid and metabolic profile that is characteristic of atazanavir.
>
> Elevations in bilirubin were a laboratory abnormality observed early
> in the clinical development of atazanavir.
>
> \[Slide.\]
>
> Throughout the course of development, we learned that the elevations
> in bilirubin are principally unconjugated, they are predominantly mild
> in grade, they are reversible with drug interruption or with drug
> withdrawal.
>
> We also know from clinical trials that approximately 50 percent of
> patients may expect to experience a Grade 1 or a Grade 2 elevation in
> bilirubin and that approximately 5 percent may expect to experience
> Grade 4 elevation in their bilirubin. Again, these changes are
> reversible with drug withdrawal.
>
> \[Slide.\]
>
> In the next few minutes, we will review the physiologic mechanisms for
> bilirubin production and metabolism, and establish the mechanism for
> atazanavir-associated bilirubin elevations.
>
> Atazanavir, like the protease inhibitor indinavir, inhibits the enzyme
> uridine glucuronosyltransferase, UGT, and like the benign inherited
> condition, Gilbert\'s syndrome, leads to increases in unconjugated
> bilirubin without hepatotoxicity.
>
> I will then describe from a large number of treated patients from our
> clinical trial database the laboratory abnormalities and the clinical
> manifestations that relate to bilirubin. This description further
> dissociates bilirubin elevations from hepatotoxic processes.
>
> Finally, we will review the plans to manage clinically relevant
> elevations in bilirubin should they occur in the clinic.
>
> Increases in unconjugated bilirubin can be caused by disruption of any
> one of several steps in bilirubin production and bilirubin metabolism.
>
> \[Slide.\]
>
> The six principal ways in which this might occur are depicted in this
> schematic.
>
> First, there can be increases in bilirubin production through red cell
> hemolysis or ineffective hematopoiesis.
>
> Second, there could be impaired transport at the extracellular level
> as a result of alterations or interference in the binding of bilirubin
> to albumin.
>
> Third and fourth, there can be disruptions of bilirubin uptake by
> hepatocytes or disruption within the intrahepatic transport of
> bilirubin.
>
> Fifth, there can be inhibition of the intrahepatic glucuronidation
> step of bilirubin. This takes place prior to transport of bilirubin
> into the canaliculi.
>
> Sixth, there can be disruption or impairment of bilirubin export into
> the bile canaliculus.
>
> BMS is conducted in conducted in consultation with a number of experts
> in bilirubin metabolism, a series of preclinical experiments and
> clinical assessments that have established that inhibition of UGT 1A1
> is the mechanism for atazanavir\'s effect on bilirubin.
>
> Hyperbilirubinemia from increased bilirubin production or other
> mechanisms for elevations have been excluded.
>
> \[Slide.\]
>
> In addition, the gene responsible for regulation of UGT activity is
> known and is the gene responsible for the Gilbert\'s syndrome.
> Genotype analysis for this gene was conducted during a large Phase II
> program. This assessment established that bilirubin levels in patients
> varied directly with their genotype. The genotype reflecting the
> Gilbert\'s syndrome resulted in the highest bilirubin levels.
>
> The magnitude and extent of bilirubin elevations have also been
> extensively assessed and characterized, and allow bilirubin elevations
> to be further distinguished from hepatotoxic processes.
>
> \[Slide.\]
>
> This slide shows the total bilirubin and direct bilirubin levels for
> greater than 600 patients who have received 400 mg of atazanavir. The
> increases in total bilirubin are small and consist almost entirely of
> unconjugated or indirect bilirubin.
>
> As you can see, bilirubin elevations increase early, typically by the
> first study visit, and remain stable throughout the course of
> atazanavir treatment. Median total bilirubin levels remain mildly
> elevated to between 1.2 and 1.6 mg/dl over the course of treatment.
>
> As you can see, there are a large number of patients out to two years
> in this assessment and a fair number of patients out to almost three
> years.
>
> As is evident from this longitudinal graph, bilirubin levels remained
> stable with long-term atazanavir treatment.
>
> As described earlier by Dr. Schnittman, ritonavir-boosted atazanavir
> increases both the Cmin and the AUC.
>
> \[Slide.\]
>
> Total bilirubin and direct bilirubin levels from treatment-experienced
> patients who receive this regimen, that is, 300 mg of atazanavir
> boosted by ritonavir, indicate that the median total bilirubin
> increases are also small. The median total bilirubin increases ranged
> from 1.8 to 2.0 mg/dl.
>
> \[Slide.\]
>
> The potential clinical manifestations of elevated bilirubin has also
> been assessed. This assessment included the frequency of Grade 4
> bilirubin elevations, the potential clinical signs, and the frequency
> of treatment discontinuations.
>
> Note on this slide that in treatment-naive patients, 6 percent
> experienced bilirubin elevations that were greater than 5 times the
> upper limit of normal. Jaundice and scleral icterus occurred in
> approximately 11 percent of patients. The jaundice and scleral icterus
> was generally mild and rarely led to discontinuation of atazanavir.
>
> In clinical trials of naive patients, fewer than 1 percent of treated
> patients discontinued atazanavir for hyperbilirubinemia.
>
> Next, let\'s turn to ritonavir-boosted atazanavir in which the
> frequency of bilirubin elevations and the clinical manifestations,
> jaundice and icterus, were generally higher than those observed in
> naive patients who received unboosted atazanavir although overall, the
> frequency was less than anticipated.
>
> In clinical trials to date, no subjects in the ritonavir-boosted
> atazanavir regimen have discontinued treatment for hyperbilirubinemia.
>
> We also assessed concurrent Grade 3-4 elevations in transaminases and
> Grade 3-4 elevations in bilirubin. We found no association between
> hyperbilirubinemia and elevations in hepatic transaminases.
>
> \[Slide.\]
>
> This 2 by 2 table shows the frequency of Grade 3-4 elevations in ALT,
> and it was no different for subjects with or without Grade 3-4
> elevations in bilirubin. In both instances, the frequency of ALT
> elevations was 4 to 5 percent. This analysis reflects a conservative
> assessment in which any elevation of bilirubin or ALT throughout the
> course of the patient\'s treatment was considered.
>
> Similar assessments have been conducted in treatment-experienced
> patients receiving ritonavir-boosted atazanavir, and again dissociated
> Grade 3-4 elevations in transaminases from bilirubin elevations.
>
> Overall, in the atazanavir development program, the frequency of
> transaminase elevations were assessed and fall within the range
> observed with other marketed protease inhibitors.
>
> \[Slide.\]
>
> Hepatic transaminases were assessed for atazanavir in comparison to
> standard-of-care regimens in Phase III trials and are depicted here.
> In the 034 pivotal study in which atazanavir was compared to
> efavirenz, the rate of Grade 3-4 elevations in ALT was comparable
> between the regimens and ranged from 3 to 4 percent.
>
> In treatment-experienced patients receiving ritonavir-boosted
> atazanavir, or atazanavir with saquinavir, the rate of transaminase
> elevations were again 3 to 4 percent and comparable to
> lopinavir/ritonavir.
>
> In the 034 study, the 6 percent rate for atazanavir and the very low
> rate for lopinavir/ritonavir were outliers to the general experience.
>
> \[Slide.\]
>
> This development program included a large number of subjects
> co-infected with hepatitis B and C, ranging from 12 to 20 percent and
> generally reflective of what we are seeing in the HIV-infected
> population.
>
> Subject with co-infection did not experience bilirubin elevations more
> frequently than those who are not co-infected. In fact, in general,
> their bilirubin levels tended to be somewhat lower than those who were
> not co-infected.
>
> With regard to hepatic transaminases, in general and as expected,
> subjects had baseline and on-study ALT levels that were more
> frequently elevated if they were co-infected with hepatitis B or C,
> however, and importantly, among co-infected subject, the frequency of
> transaminase elevations was similar between atazanavir and all
> comparator regimens.
>
> \[Slide.\]
>
> The frequency and magnitude of bilirubin elevations have been
> thoroughly described and the overall hepatic safety of atazanavir has
> been established.
>
> The available data distinguished bilirubin elevations from
> hepatotoxicity based upon the biologic mechanism and based upon an
> absence of association between bilirubin and elevated hepatic
> transaminases.
>
> Bilirubin elevations are principally cosmetic in nature and are
> infrequently treatment limiting. There is no evidence for long-term
> sequelae. These results indicate that bilirubin elevations do not
> represent a significant safety concern for atazanavir.
>
> \[Slide.\]
>
> Nevertheless, BMS is committed to providing physicians and patients
> with a straightforward management plan which includes educational
> programs built upon the prior experience with the protease inhibitor
> indinavir.
>
> Liver function tests monitoring beyond what is done with standard of
> care is not necessary.
>
> Should elevations in bilirubin occur that are greater than 5 times the
> upper limit of normal, it is recommended that alternative
> antiretroviral therapy be considered.
>
> **Characterization of Lipid Profile**
>
> \[Slide.\]
>
> I will now move to a characterization of the potential treatment
> benefit of atazanavir\'s unique lipid and metabolic profile and
> discuss this in context of the lipid and metabolic issues that are
> commonly associated with other protease inhibitors and other
> antiretroviral agents.
>
> \[Slide.\]
>
> The metabolic profile and problems with current protease inhibitors
> are familiar ones. In the next few minutes, we will demonstrate
> atazanavir\'s unique serum lipid profile both within the PI class and
> against other comparators.
>
> In addition, we will observe that the favorable clinical impact of
> this profile is demonstrated as it reduces the need for lipid-lowering
> therapy when the accepted national cholesterol education program goals
> are applied.
>
> The data addressing the cardiovascular risk and event rate for
> individuals with HIV who are receiving HAART are still evolving,
> nevertheless, treatment experts recommend management of hyperlipidemia
> and hypertriglyceridemia among patients receiving HAART that is based
> upon the NCEP thresholds and risk assessment.
>
> We recognize that fat redistribution and lipodystrophy are important,
> but not ones that can be addressed currently by the atazanavir data.
> Its potential benefit will receive further attention when longer term
> data become available.
>
> Current protease inhibitor treatment often results in cholesterol,
> triglyceride, and other metabolic abnormalities.
>
> \[Slide.\]
>
> As seen here, a survey of the literature of the six currently
> prescribed protease inhibitors indicates that cholesterol is increased
> from baseline by roughly 30 percent and that triglycerides are
> increased by roughly 30 to 50 percent and sometimes higher.
>
> These increases are large and arguably important in and of themselves,
> but have also been confirmed by data that indicate that up to 30
> percent of U.S.-treated patients who received protease inhibitors also
> carry the diagnosis of hyperlipidemia.
>
> In addition, information from managed care databases indicate that a
> growing number of patients who receive protease inhibitors also
> receive statins, by the end of 2001, 18 percent.
>
> Atazanavir\'s lipid profile, as we will see shortly, differs
> considerably from this experience.
>
> \[Slide.\]
>
> We routinely compared a panel of cholesterol and triglyceride and
> other metabolic measurements, atazanavir and comparator regimens. This
> included comparators of the protease inhibitors nelfinavir,
> lopinavir/ritonavir, and efavirenz. The presentation will focus on the
> longitudinal comparisons of LDL cholesterol and triglycerides.
>
> LDL cholesterol from Study 034, depicted on this slide, patients
> treated with 400 mg of atazanavir in combination with zidovudine and
> 3TC showed no increase from baseline and LDL cholesterol.
>
> In contrast, the comparator efavirenz, which is not as lipogenic and
> some protease inhibitors, resulted in an 18 percent increase in LDL
> cholesterol from baseline.
>
> Similarly, when one looked at the comparative data for triglycerides,
> atazanavir demonstrates the same favorable profile. In Study 034,
> atazanavir resulted, in fact, in a 9 percent decrease from baseline in
> serum triglycerides. In contrast, efavirenz treatment resulted in
> elevations of triglycerides of 23 percent.
>
> In addition to these data from the 034 study, there are data from two
> comparative Phase II studies that showed similar cholesterol and
> triglyceride benefits for atazanavir over the protease inhibitor
> nelfinavir.
>
> \[Slide.\]
>
> Earlier, Dr. Schnittman showed the extended efficacy results for the
> 044 study in which atazanavir-treated subjects continued to receive
> atazanavir in combination with stavudine and lamivudine.
>
> The LDL cholesterol results from this study demonstrate the same
> long-term benefit, that is, over two years. LDL cholesterol ranged
> from 103 to 108 over this two-year period of time.
>
> \[Slide.\]
>
> The nelfinavir arm was truncated at Week 60 on the previous arm
> because on that study, patients on nelfinavir were allowed to switch
> to atazanavir. The results of this switch are discussed on this slide.
>
> As mentioned, large decreases in all cholesterol and triglyceride
> values were observed within four weeks and continued to 24 weeks after
> a switch from nelfinavir to atazanavir. The 24-week changes are
> depicted on this slide.
>
> These decreases in total cholesterol, LDL cholesterol, non-HDL
> cholesterol, and triglycerides reflected a return to baseline levels
> prior to institution or HAART therapy for this patient population.
>
> \[Slide.\]
>
> Atazanavir\'s potential for treatment benefit was further assessed by
> applying the NCEP treatment goals. NCEP provides specific management
> guidance for treatment of elevated cholesterol and triglycerides that
> is based upon cardiac risk factors and based upon the established LDL
> and non-HDL goals.
>
> Most antiretroviral-treated patients fit into one of two NCEP
> categories either by having two or more cardiac risk factors or by
> having zero to 1 cardiac risk factor. Therefore, we will use the
> cutoffs of 130 and 160 as the relevant thresholds for assessing the
> need for lipid lowering intervention.
>
> When NCEP goals are used, large differences in the need for
> lipid-lowering therapy are identified between atazanavir and other
> antiretroviral regimens.
>
> \[Slide.\]
>
> The extent to which naive patients met an NCEP treatment threshold on
> antiretroviral therapy are depicted for subjects treated with
> atazanavir and efavirenz on this slide.
>
> In the atazanavir arm prior to treatment, 12 percent of patients had
> an LDL cholesterol greater than 130, 2 percent had an LDL cholesterol
> greater than 160. On atazanavir treatment, there was no change in the
> percent of patients who met either of these NCEP goals.
>
> In contrast, there is roughly a doubling in the percent of
> efavirenz-treated patients who meet or exceed and NCEP treatment goal
> based upon the 130 and 160 threshold goals.
>
> \[Slide.\]
>
> The data for treatment-experienced patients who underwent a single
> substitution of atazanavir for nelfinavir are equally compelling. At
> study entry and after approximately 1.5 years of nelfinavir therapy,
> half overall had an LDL cholesterol greater than 130. Of these, 27
> percent had an LDL greater than 130, but less than 160, and 28 percent
> had an LDL cholesterol greater than 160.
>
> Twenty-four weeks after a switch to atazanavir, there was a 2- to
> 3-fold reduction in the percentage of patients who met either of these
> treatment thresholds.
>
> Similar assessment of patients meeting NCEP thresholds have been
> performed for treatment-experienced patients on the 043 study in which
> subjects switched from failing regimens to either atazanavir or
> lopinavir/ritonavir.
>
> First, look at the atazanavir-treated subjects. At baseline, 23
> percent had LDL cholesterols greater than 130, 6 percent had LDL
> cholesterols greater than 160. After 24 weeks of treatment with
> atazanavir, only 7 percent had LDL cholesterols greater than 130, and
> none had an LDL cholesterol greater than 160.
>
> In contrast, lopinavir/ritonavir treatment increased or did not change
> the percentage of patients who met the respective treatment
> thresholds.
>
> \[Slide.\]
>
> In summary, current clinical practice recognizes that achieving and
> maintaining favorable lipid and metabolic profiles for individuals who
> received protease inhibitors is important, but is also challenging.
> While hyperlipidemia may have been of secondary concern when
> individuals with HIV had very limited life expectancies, this is no
> longer true.
>
> In the U.S. and in many other places, long-term management of HIV is a
> reality and lifelong control is measured in decades, and not in months
> and years.
>
> In this regard, the management of hyperlipidemia with statins and
> other lipid-lowering agents is problematic for patients receiving
> HAART. Statins further complicate already complex regimens. They
> introduce the possibility of added toxicity and intolerance, and they
> complicate already complex drug-drug interactions.
>
> In addition, the data indicate that statins and other lipid-lowering
> drugs frequently to not result in achieving of the NCEP guidelines or
> thresholds when recipients are receiving protease inhibitors.
>
> \[Slide.\]
>
> The data are strong that atazanavir offers patients a potential
> treatment advantage. Lipid and triglyceride levels are not increased,
> cholesterol and triglyceride results are durable. This is true even
> when atazanavir is combined with a variety of nucleosides and with
> protease inhibitors despite the possibility that many of these agents
> may also contribute themselves to increases in lipids.
>
> In sum, atazanavir is a once-daily protease inhibitor with favorable
> lipids, offers patients unique treatment benefits. The need for
> lipid-lowering treatment is avoided in many atazanavir-treated naive
> patients. The need for lipid-lowering therapy is reduced when
> treatment-experienced patients are switched to atazanavir or when they
> institute atazanavir in lieu of other protease regimens.
>
> Finally, treatment with atazanavir may avoid an unnecessary increase
> in cardiovascular risk factors.
>
> Thank you.
>
> **Overall Risk/Benefit and Conclusions**
>
> DR. SIGAL: We can now briefly summarize atazanavir in the context of
> the issues that have been identified and the benefits that are
> established.
>
> \[Slide.\]
>
> The risks of treatment with atazanavir are well characterized. The
> majority of adverse events are mild to moderate and do not result in
> discontinuations. Hyperbilirubinemia, as you have heard, is well
> characterized, we believe manageable and similar to the benign
> condition that is common in Gilbert\'s syndrome, a genetic condition
> with inherently reduced UGT enzyme.
>
> Furthermore, atazanavir\'s mechanism for increasing bilirubin is
> similar to that of at least one other member of the protease inhibitor
> class that is in broad clinical use.
>
> Finally, you have seen today an example of extensive characterization
> of cardiac electrophysiology effects of a new chemical entity, and as
> I mentioned at the beginning, this is becoming the evolving norm and
> in our studies we have established no significant effect on QT
> interval for atazanavir.
>
> There is a well-characterized effect on the PR interval for which we
> believe there is appropriate management.
>
> \[Slide.\]
>
> Atazanavir is efficacious in the treatment of HIV infection for both
> treatment-naive and treatment-experienced patients. The effects, as
> you have seen, are durable, with controlled studies showing an
> efficacy past two years and patients showing benefit for three and a
> half years.
>
> The lipid profile supports long-term safety, reduces known
> cardiovascular risk factors, and the need for other medicines.
> Resistance is low in frequency and the I50L protease mutation may
> offer clinical utility.
>
> Lastly and importantly, atazanavir has once daily dosing.
>
> In conclusion, this is a novel protease inhibitor with advantages in
> managing the evolving viral resistance and comorbidity spectrum among
> HIV patients.
>
> I would like to thank you for your attention. Steve Schnittman and
> Michael Giordano will now join me to answer any clarifying questions
> that you may have.
>
> DR. GULICK: Thanks, Drs. Sigal, Schnittman, Lawrence, and Giordano.
>
> We are actually going to postpone the question and answer period until
> after the agency presents, and then we will do a combined Q and A for
> both groups.
>
> DR. SIGAL: Thank you.
>
> DR. GULICK: Which brings us to our break. It is 10 after 10:00 and we
> will reconvene at 10:25. Thanks.
>
> \[Break.\]
>
> DR. GULICK: So now let\'s proceed with the FDA presentation. You will
> first hear from Dr. Kendall Marcus.
>
> **FDA Presentation**
>
> DR. MARCUS: Good morning.
>
> \[Slide.\]
>
> In today\'s presentation by the FDA, I will first provide you with a
> brief review of clinical trials submitted in support of atazanavir.
>
> \[Slide.\]
>
> Dr. Tom Hammerstrom will present his review of the efficacy data for
> pivotal clinical trials. Dr. Lisa Naeger will then provide a summary
> of the clinical virology of atazanavir. Finally, I will discuss key
> safety issues and provide you with a brief summary of our conclusions
> regarding the safety and efficacy of atazanavir.
>
> \[Slide.\]
>
> NDA 21-567 for atazanavir sulfate was submitted to the FDA on December
> 20th, 2002. The proposed dosage is 400 mg, once daily, to be
> administered as two, 200 mg capsules with food. The proposed
> indication is for the treatment of HIV infection.
>
> \[Slide.\]
>
> This NDA package includes two, Phase II dose-finding studies. In Study
> 007, atazanavir at doses of 200, 400, and 500 mg were compared to
> nelfinavir given at 750 mg TID. Each were given with d4T and ddi.
>
> In Study 008, doses of 400 and 600 mg were compared to nelfinavir at a
> dose of 1,250 mg BID, each given with d4T and 3TC.
>
> In these studies, patients were blinded only to the dose of
> atazanavir.
>
> \[Slide.\]
>
> Phase III studies included Study 034, a randomized, double-blind,
> placebo-controlled, multicenter study comparing atazanavir to
> efavirenz, each with fixed dose Combivir in treatment-naive subjects.
>
> Study 043 is a randomized, open-label, multicenter study comparing
> atazanavir to Kaletra, each given with an optimized NRTI background in
> patients failing a PI-based regimen.
>
> \[Slide.\]
>
> Study 045 is an open-label study of highly treatment-experienced
> subjects who had failed at least two antiretroviral regimens
> containing drugs from all three classes.
>
> In this study, a ritonavir-boosted dose of atazanavir was compared to
> atazanavir given in combination with saquinavir and to Kaletra.
> Sixteen-week data on roughly 35 patients per treatment arm were
> submitted with the initial NDA. Sixteen-week data for all subjects was
> submitted as a safety update about two months into the review.
>
> As a result, efficacy data from this study will not be used to make a
> regulatory decision on this NDA.
>
> \[Slide.\]
>
> Other studies submitted with this NDA included rollover studies for
> subjects completing Phase II studies.
>
> Subjects completing Study 007 were enrolled into Study 041. Subjects
> who had received 200, 400, or 500 mg of atazanavir were all given 400
> mg of atazanavir in the rollover study, and subjects previously
> assigned to nelfinavir continued to receive it.
>
> Subjects completing Study 008 were enrolled into Study 044. In this
> study, patients continued to receive their previously assigned dose of
> atazanavir, however, nelfinavir-treated subjects were switched to
> atazanavir 400 mg.
>
> In addition to these studies, data was submitted from a pediatric
> protocol, an early access protocol, and several other smaller studies.
>
> At this time, I would like to turn the presentation over to Dr. Tom
> Hammerstrom.
>
> DR. HAMMERSTROM: The applicant has completed and submitted for FDA
> review two Phase III trials and two Phase II trials that are large
> enough to contain useful efficacy results.
>
> One of the Phase III trials, No. 34, and both Phase II trials, 7 and
> 8, involve ART-naive subjects. All three trials had percent with HIV
> RNA levels sustained below 400 copies/ml out to 48 weeks as primary
> endpoint, and TAD, the time average difference from baseline, also
> known as BAVG or AAUCMB of log HIV RNA as secondary endpoint.
>
> Trial 34 used efavirenz as control, Trials 7 and 8 used nelfinavir.
> All the arms in all three trials had two NRTIs as background regimen.
>
> \[Slide.\]
>
> One Phase III trial, No. 43, used ART-experienced patients,
> specifically those failing at least one prior PI regimen. This trial
> used Kaletra as a control with a background regimen of two NRTIs. The
> primary endpoint was TAD at Week 24 and the protocol specified
> secondary endpoint was percent with HIV RNA sustained below 400
> copies.
>
> \[Slide.\]
>
> First, I will go over the results from the three trials with ART-naive
> subjects.
>
> \[Slide.\]
>
> The primary findings on Trials 34, 7, and 8, on ART-native subjects,
> are summarized on this and succeeding slides. This slide shows the ITT
> results with dropouts as failures for the percent with HIV RNA
> sustained below 400 copies/ml.
>
> This is abbreviated frequently as TLVR, the time to loss of viral
> response, and you will notice that atazanavir is equal or better than
> efavirenz or nelfinavir in all three trials with the percent
> successful for the six arms all the range 60 to 69 percent at Week 48.
>
> At worst, the atazanavir arm was with 95 confidence no more than 1.5
> percent worse than efavirenz, no more than 5 percent worse than
> nelfinavir in one trial, and no more than 13.8 percent worse than
> nelfinavir in the other trial. This trial with the lowest confidence
> limit is the one with the smallest sample size, therefore, the widest
> confidence intervals.
>
> \[Slide.\]
>
> Now, I would like to go over in more detail, the result in the single
> trial with ART-experienced subjects.
>
> \[Slide.\]
>
> For Trial 43, the one reviewed trial with ART-experienced subjects, at
> Week 24, atazanavir was statistically significantly inferior to
> Kaletra with respect to both endpoints, there and there.
>
> It was, with 95 percent confidence, 8 to 30 percent worse with respect
> to percent of subjects with viral load less than 400. It was, with 95
> percent confidence, 0.078 to 0.4 log copies worse than Kaletra with
> respect to TAD.
>
> I should remark here that the FDA analysis used the full randomized
> dataset of 150 patients in each arm. The applicant has presented only
> the first 229 subjects because that was the originally intended sample
> size, however, by the time the computer files were made available to
> the FDA, all 300 subjects had completed 24 weeks of observation, so
> there is no reason not to include the last 71 patients in our
> analysis.
>
> I should also mention a difference in the calculation of percent below
> quantitation. The subjects whose first measurement showed a rebound to
> above 400 copies/ml at Week 24, and had not yet reached their Week 32
> visit, are counted as failures in our analysis, but they were counted
> as successes in the applicant\'s analysis.
>
> This change of handling applies to both arms, so it will have less
> effect on the difference between the arms when you compare this
> difference to the differences between the arms in the applicant\'s
> slide.
>
> The applicant attempted in their protocol to argue that 0.5 log copies
> was close enough to an active control regimen to constitute evidence
> of superiority to placebo. This is a problematic argument based on a
> generally recognized claim that the individual assay determinations at
> closely spaced times on the same subject have a standard deviation of
> about 0.5 log copies.
>
> This is, however, a measure of assay variability and should not be
> equated with minimum clinically relevant difference.
>
> \[Slide.\]
>
> There are at least two recognized methods for inferring differences
> between test drug and placebo in the absence of direct observation of
> such differences in a single randomized trial. Neither method
> naturally is quite as convincing as direct observation in a single
> trial.
>
> Method 1 is to add together differences from two or more clinical
> trials, each sharing a common comparator drug. For example, add the
> difference between atazanavir and Kaletra from one trial to the
> difference between Kaletra and placebo from a second trial.
>
> Method 2 is to collect results from a large number of representative
> clinical trials and to compare the observed endpoint and its
> confidence interval for the atazanavir plus 2 NRTI arms in Trial 43
> with the same observed endpoint for the two drug and three drug arms
> in all the other surveyed trials.
>
> We have already used these methods in a couple of previous NDAs, which
> were not presented to the committee, and we will probably expect these
> or other meta-analysis methods in future active control trials.
>
> \[Slide.\]
>
> This slide summarizes Method 1 for the endpoint of percent below 400
> copies at Week 24. From Trial 43, one directly observes that the
> atazanavir rate minus the Kaletra rate is -19 percent. That happens to
> be actually 46.6 percent minus 65.3 percent. The round-off is
> conducted after the subtraction. The standard error was 5.73 percent.
>
> From Trial 863, in the Kaletra NDA, one directly observes that the
> Kaletra rate minus the nelfinavir rate was 8 percent, 79 percent minus
> 71 percent, with a standard error of 3.36 percent.
>
> Finally, from Trial 511 in the nelfinavir NDA, one directly observes
> that the nelfinavir rate minus the placebo rate was 60 percent, 67
> percent minus 7 percent, with a standard error of 5.37 percent.
>
> Adding these three differences in the rates together, one infers that
> the atazanavir rate minus the placebo rate would have been -19 percent
> plus 8 percent, plus 60 percent, or 49 percent, with a standard error
> of 8.54 percent. Standard errors are not added directly, but I will
> skip the exact technical mathematics as to how one combines those
> three standard errors to get that.
>
> As mentioned above, this is not as convincing as direct comparison.
> Three stages are needed to reach placebo, each adding more uncertainty
> beyond that in the standard error. Trial 43, for example, used
> ART-experienced patients, the other two trials used patients who were
> either ART-naive or had limited experience.
>
> The two drug backgrounds among the three trials, as well, differed, as
> well as did the baseline levels of HIV RNA and CD4 count. Nonetheless,
> there is a sizable imputed difference showing superiority of
> atazanavir over placebo, 49 percent.
>
> \[Slide.\]
>
> This slide shows a similar computation but using Trial 888, the other
> trial in the Kaletra NDA. This analysis has the virtue of the Trial
> 888, also used ART-experienced patients, so it is more directly
> comparable to Trial 43 than is Trial 863.
>
> Again, the atazanavir rate minus the Kaletra rate is directly observed
> to be -19 percent. The directly observed difference between the
> Kaletra rate and the rate for an investigator-selected PI, not a
> placebo, was 24 percent, with a standard error of 5.69 percent.
>
> Adding these two differences together, one infers that the atazanavir
> rate minus the rate for a selected PI would be 5 percent, that is,
> superior imputed to atazanavir, but with a standard error of 8.07
> percent.
>
> This doesn\'t get one directly to the atazanavir rate minus placebo
> rate without reference to a large number of trials in the NDAs for all
> the selected PIs, so that step has been omitted in this computation.
>
> \[Slide.\]
>
> We can summarize the results from the two previous slides as follows.
> With respect to percent below 400 copies at Week 24, atazanavir is,
> with 95 percent confidence, directly observed to be between 7.9
> percent and 30 percent worse than Kaletra. It can be imputed to be
> between 10.8 percent worse and 21 percent better than in
> investigator-selected PI.
>
> Now, if one were to discount, to conduct a sensitivity analysis to
> reflect the added uncertainty due to pooling data across trials that
> are not directly comparable, one could do that by increasing the
> standard error by a factor of, say, 1.1, and discounting the estimated
> difference by a factor of 0.9.
>
> If one does that, one gets still an imputed superiority of atazanavir
> over selected PI of 4.5 percent and a 95 percent interval imputed to
> be between 12.3 percent worse than the selected PI and 23 percent
> better than the selected PI.
>
> Finally, one gets that atazanavir had an imputed 95 percent confidence
> interval of anywhere between 32 percent better and 66 percent better
> than placebo. No sensitivity analysis comparable to this slide was
> conducted for the placebo thing because it is clear that only a very
> extravagant discounting of this effect and inflation of the imputed
> standard error would make this lower bound equal to zero.
>
> \[Slide.\]
>
> This slide graphically presents the comparison of a number of trials
> in the current and previous NDAs for percent of subjects with viral
> load less than 400 or 500 copies while on either two-drug or
> three-drug regimens.
>
> For each arm, we have plotted the observed rate and the 95 percent
> confidence intervals. The rates are marked on the horizontal axis, and
> the vertical axis just shows the different trials.
>
> The orange interval at the top, marked with triangles, shows the rate
> for atazanavir in Trial 43. Working down the graph, the light blue
> intervals, marked with diamonds, correspond to three drug control arms
> from various NDAs.
>
> The beige intervals, marked by plus signs, correspond to two drug
> control arms from various NDAs. One will notice that all but one of
> these are lower than the atazanavir interval, and do not overlap it.
>
> The one exception, this one, corresponded to a trial with results
> collected at Week 16, not Week 24, and one might reasonably conjecture
> that had these subjects been followed an extra eight weeks, this
> interval would have shifted downward.
>
> The yellow intervals, marked by squares, down here, correspond to
> three drug arms with eventually approved test drugs. The atazanavir
> interval clearly allies with the three drug intervals and to the right
> in the superior direction than any of the two drug arms.
>
> \[Slide.\]
>
> The other endpoint used in this trial, and the one specified in the
> protocol was TAD, the time average difference from baseline in log HIV
> RNA. The FDA recommended against this endpoint at the protocol stage
> mainly because it suffers from more missing data problems than does
> percent BLQ.
>
> There is fairly convincing evidence that subjects quickly rebound to
> above quantitation once they discontinue ART use, so counting
> discontinued subjects as failures is a highly plausible solution to
> the missing data problem with percent BLQ.
>
> TAD does not lend itself to such easy solutions. Two possible
> solutions are to replace the missing data by LOCF, the last
> observation carried forward. This is an idea derived from outside the
> HIV research area. The other method is to replace missing data by
> baseline, a solution which is more supported by data from trials where
> subjects were followed beyond drug discontinuation without starting a
> new therapy.
>
> \[Slide.\]
>
> This slide shows the indirect estimation of atazanavir TAD minus
> placebo TAD using the same three trials as with percent below 400.
> From Trial 43, one directly observes that the atazanavir TAD minus the
> Kaletra TAD was 0.26 with a standard error of 0.093.
>
> I should also mention that in these computations, the FDA used missing
> data replaced by baseline.
>
> From Trial 863, in the Kaletra NDA, one directly observes that the
> Kaletra TAD minus the atazanavir TAD was 0.003 with a standard error
> of 0.057. From Trial 511 in the nelfinavir NDA, one directly observes
> that the nelfinavir TAD minus the placebo TAD was negative 0.37 with a
> standard error of 0.083.
>
> I need to remind you that with this endpoint, negative numbers are
> good and positive numbers are bad, so the 0.26 here, that is a
> superiority for Kaletra over atazanavir. The 0.003 is essentially a
> tie. The negative 0.37 is a superiority for nelfinavir over placebo.
>
> When one adds these three differences together, you get an observed
> imputed difference of negative 0.107, and that is an imputed
> superiority for atazanavir over placebo, but with an imputed standard
> error of 0.137.
>
> \[Slide.\]
>
> This slide presents a similar computation, but using Trial 888, the
> trial in the Kaletra NDA which used experienced patients. The
> computation begins as in the previous slide with atazanavir TAD minus
> Kaletra TAD equals 0.26. The directly observed difference between the
> Kaletra TAD and the TAD for an investigator-selected PI was negative
> 0.104\--that is a superiority for Kaletra\--with a directly observed
> standard error of 0.078.
>
> Adding these two differences together, one infers the atazanavir TAD
> minus the TAD for a selected PI to be 0.156. That is imputed
> superiority for the investigator-selected PI, with an imputed standard
> error of 0.121.
>
> In other words, since the Kaletra TAD was 0.2X log copies better than
> atazanavir, but only 0.104 log copies better than the selected PI, the
> imputation is that atazanavir had an inferior TAD by 0.156 log copies
> to the selected PI.
>
> \[Slide.\]
>
> We can summarize the results from TAD as follows. Atazanavir is, with
> 95 percent confidence, between 0.078 and 0.44 log copies worse than
> Kaletra. It can be imputed to be 0.156 log copies worse than a
> selected PI and with approximate 95 percent confidence between 0.081
> log copies better and 0.393 log copies worse than the selected PI. By
> the approximate in the 95 percent, I am referring to the added
> uncertainty due from pooling across different trials.
>
> It can be imputed to be 0.107 log copies better than placebo, but
> might credibly be anywhere between 0.376 log copies better and 0.162
> log copies worse than placebo.
>
> Even without performing a sensitivity analysis to widen the confidence
> intervals to adjust for the extra uncertainty of incomparable trial
> populations, one does not conclude that TAD showed atazanavir to be
> superior to placebo.
>
> \[Slide.\]
>
> This slide shows the results of Method 2, comparing the 95 percent
> confidence intervals for TAD of log HIV RNA for a number of two-drug
> and three-drug arms from other NDAs. There are fewer trials than the
> last time we saw a slide like this because this endpoint has been used
> less frequently than percent below quantitation.
>
> Again, for each arm we have the observed TAD and the 95 confidence
> intervals plotted on the horizontal axis, and the vertical axis just
> shows different trials.
>
> Again, the orange interval at the top, marked with triangles, shows
> the TAD for atazanavir in Trial 43. The light blue intervals, marked
> with diamonds, correspond to three drug control arms from various
> NDAs.
>
> The beige intervals, marked with plus signs, correspond to two drug
> control arms from various NDAs. The yellow intervals, marked by
> squares, correspond to three drug arms with eventually approved test
> drugs. Remember, with this endpoint, intervals further to the left,
> more negative, are better. This is where you want to be down here.
> This is bad up here.
>
> With respect to this endpoint, the atazanavir interval looks clearly
> inferior to most of the three drug intervals with two noticeable
> exceptions and comparable to at least half of the two drug arms.
>
> The two exceptions, however, this one and this one, are the three drug
> intervals, the control and Kaletra arms from Trial 888, which is a
> trial with experienced patients. These two results might be taken to
> suggest that TAD is closer to zero for experienced subjects.
>
> \[Slide.\]
>
> In summary, atazanavir, at the indicated dose, has been compared to
> active controls when added to a two drug background in three trials
> with ART-naive subjects. With respect to percent of subjects with HIV
> RNA less than 400 at Week 48, it was estimated to be equal or better
> than efavirenz or nelfinavir in all three trials, and with 95 percent
> confidence, no more than 5 percent worse than the controls in two out
> of three trials.
>
> One should note that we did, but did not present, the same kind of
> analyses performed for Trial 43 linking nelfinavir or efavirenz to
> placebo for these trials, and concluded that the narrow confidence
> intervals or the difference between atazanavir and nelfinavir or
> efavirenz translate into credible imputations of superiority of
> atazanavir to placebo.
>
> \[Slide.\]
>
> With respect to TAD of log HIV RNA at Week 48, although we didn\'t
> present these results in detail, it was better than or equal to
> efavirenz or nelfinavir in two out of three trials, and in all trials,
> it was with 95 confidence, no more than 0.28 log copies worse than the
> control.
>
> \[Slide.\]
>
> In one trial out to 24 weeks with ART-experienced patients, it was
> statistically significantly worse than Kaletra with respect to both
> percent below 400 and TAD. Indirect imputations of the difference
> between atazanavir and placebo gave results in which one endpoint,
> which the FDA regards as primary, percent below 400, appeared to
> demonstrate efficacy, and the second gave ambiguous results.
>
> \[Slide.\]
>
> With respect to percent below 400 at Week 24, which was the FDA
> recommended primary endpoint, it was indirectly inferred to be at
> least 33 percent better than placebo and no more than 10 to 12 percent
> worse than a physician-selected PI.
>
> Compared to other arms in other NDAs receiving two or three active
> drug, atazanavir, in this ART-experienced trial, looked to have a
> better rate than any two drug arm and a rate comparable to most other
> three drug arms.
>
> \[Slide.\]
>
> With respect to TAD, an endpoint with undesirable missing data
> problems and considered secondary by the FDA reviewer, one could
> indirectly infer no more than that atazanavir was 0.16 log copies was,
> at worst, no more than 0.16 log copies worse than placebo.
>
> Compared to other arms in other NDAs receiving two or three active
> drugs, atazanavir in this ART-experienced trial looked to have a rate
> comparable to many other two drug arms and inferior to most three drug
> arms with two important exceptions, which happen to have come from
> ART-experienced subjects.
>
> I will now turn the podium over to Dr. Naeger, who will give the
> resistance data.
>
> DR. NAEGER: Good morning.
>
> \[Slide.\]
>
> I will be discussing the atazanavir resistance development. The focus
> of this discussion is that there are different resistant pathways for
> atazanavir. Atazanavir has a unique pathway in treatment-naive
> patients with development of a key mutation, however, in
> treatment-experienced patients, atazanavir follows a common protease
> inhibitor resistance pathway with the development of mutations seen
> with other protease inhibitors.
>
> \[Slide.\]
>
> To assess the potential for atazanavir resistance development and to
> identify amino acids associated with atazanavir resistance, the
> applicant utilized in vitro selection.
>
> Three HIV strains were passaged at increasing concentrations of
> atazanavir, and resistant viruses were selected at four to five
> months. These resistant viruses exhibited 93- to 183-fold changes in
> atazanavir resistance, which is a change in the IC50 compared to
> reference strain.
>
> The key amino acid changes are highlighted for each of the three
> resistant viruses - a methionine at position 46, which changed to
> isoleucine or M46I. In addition, there was an A71V, I84V, N88S, and in
> another strain there was a unique mutation I50L, which is different
> from the amprenavir-associated mutation I50V.
>
> This demonstrates that there are different possible pathways for
> atazanavir resistance. One pathway contains and I84V mutation, which
> is associated with resistance to other protease inhibitors, and
> another pathway contains the unique mutation I50L.
>
> \[Slide.\]
>
> The applicant has provided evidence that atazanavir resistance
> corresponds to the I50L and A71V mutations by constructing recombinant
> viruses from eight clinical isolates. These viruses show 2- to 17-fold
> changes in IC50 for atazanavir compared to a reference strain.
>
> \[Slide.\]
>
> Importantly, recombinant viruses containing the I50L mutation either
> with or without the A71V mutation remains susceptible to other
> protease inhibitors. This suggests that treatment-naive patients that
> develop the I50L mutation in their virus would still have other
> treatment options.
>
> Another interesting finding is that the I50L mutation results in
> replication-impaired viruses. The addition of the A71V mutation
> restores some viability to the virus and suggests that this is a
> compensatory mutation.
>
> \[Slide.\]
>
> Now, turning to atazanavir clinical resistance, I will present the
> analyses in three parts starting with the mutations associated with
> atazanavir resistance from both treatment-naive studies 007, 008, and
> 034, and also treatment-experienced trial 009 and 043. Our analyses
> does not include Study 045.
>
> This is using evaluable clinical isolates from patients who were on
> atazanavir treatment and experienced virologic failure.
>
> Next, will be a baseline phenotypic and genotypic analyses, and then
> finally, an examination of cross-resistance with atazanavir and other
> protease inhibitors.
>
> \[Slide.\]
>
> There were 160 evaluable isolates from patients on atazanavir regimens
> who experienced virologic failure. Fifty isolates, or 31 percent, were
> atazanavir resistant, which is defined as greater than 2.5-fold change
> in the IC50 for atazanavir comparator reference.
>
> I would like to point out that four of these 50 isolates were from the
> rollover study 041 and 044, and developed the I50L mutation on
> atazanavir treatment.
>
> There were 93 evaluable isolates from the naive trials, 15 percent, or
> 14 isolates, were atazanavir resistant with a median fold change of
> 8.7. The percentage of atazanavir resistance goes up in
> treatment-experienced trials, whereas, 63 evaluable isolates from
> Trial 009 and 043, 51 percent were atazanavir resistant with a median
> 11-fold change in atazanavir resistance.
>
> \[Slide.\]
>
> As I said, there were 14 atazanavir-resistant clinical isolates from
> the treatment-naive studies. Eleven of these developed the I50L
> mutation, so almost 80 percent. They had a median 9-fold change in
> atazanavir resistance, and 7 of the 11 also developed the A71V
> mutation.
>
> The development of the I50L mutation ranged from 2 to 80 weeks,
> averaging 40 weeks.
>
> \[Slide.\]
>
> An examination of the clinical isolates that developed the I50L
> mutation shows an almost 11-fold change from baseline for atazanavir.
> The fold change from baseline for other protease inhibitors is less
> than 1, indicating increased susceptibility to other protease
> inhibitors. This suggests that the I50L mutation will remain
> susceptible to other protease inhibitors.
>
> \[Slide.\]
>
> There were 32 isolates that were atazanavir resistant and virologic
> failures from the treatment-experienced trials; 21 were on the 400 mg
> atazanavir treatment. The mutations that developed included an A71V or
> T, an I84V, and an N88S or D. As you recall, all these mutations were
> selected in the in vitro selection experiments.
>
> \[Slide.\]
>
> There were 11 clinical isolates on concomitant atazanavir/saquinavir
> treatment. Again, the mutations that developed include I84V, A71V or
> T, L90M, and M46I. These mutations were often seen in combination.
>
> It is not surprising that no I50L developed because of the concomitant
> saquinavir selection pressure here.
>
> \[Slide.\]
>
> These 32 atazanavir-resistant isolates that were virologic failures
> show a median 11-fold change in atazanavir susceptibility. The
> cross-resistance of these isolates show that 37 percent and 47 percent
> were also resistant to amprenavir and lopinavir respectively with
> median fold changes in atazanavir susceptibility of 1.7 and 2.0,
> however, over 80 percent of these isolates were resistant to
> saquinavir, ritonavir, indinavir, and 100 percent were resistant to
> nelfinavir with median fold changes in atazanavir susceptibility
> ranging from 5 to 28. So, these atazanavir-resistant isolates are
> cross-resistant.
>
> \[Slide.\]
>
> Now turning to baseline analysis.
>
> \[Slide.\]
>
> The baseline phenotypic analysis of the treatment-experienced trial
> 009 and 043 show that 56 percent of the isolates were resistant to at
> least protease inhibitor at baseline; 74 percent were resistant to at
> least one NRTI at baseline, and 20 percent resistant to at least one
> NRTI at baseline, so it is a fairly treatment-experienced patient
> population entering these two trials.
>
> \[Slide.\]
>
> Twenty-four percent of the isolates from these two trials showed
> atazanavir resistance at baseline.
>
> \[Slide.\]
>
> Examining the cross-resistance to other protease inhibitors at
> baseline, if the isolates were resistant to atazanavir at baseline,
> 100 percent were also resistant to nelfinavir. About 50 percent were
> resistant to indinavir and lopinavir, and greater than 50 percent were
> resistant to ritonavir and saquinavir.
>
> \[Slide.\]
>
> Now, looking at the response based on baseline genotype or the
> mutations that were present at baseline showed that if the isolates
> had an I84V mutation at baseline, over 90 percent failed if they were
> on atazanavir treatment compared to other comparative treatment.
>
> If they had an L90M at baseline, 74 percent failed compared to 43
> percent. With an A71V mutation at baseline, 62 percent failed on
> atazanavir treatment compared to 33 percent. With a change at N88, 56
> percent failed on atazanavir compared to 18 percent on other
> treatments, and with an M46I at baseline, 68 percent failed compared
> to 46 percent.
>
> This suggests that if the virus has any of the mutations at baseline,
> response to atazanavir treatment might not be as effective as other
> treatments.
>
> \[Slide.\]
>
> Turning to cross-resistance.
>
> \[Slide.\]
>
> First, cross-resistance by phenotype. Of the atazanavir-resistant
> isolates\--again, this is using baseline phenotypic data from all
> studies\--of the atazanavir-resistant isolates, 100 percent were
> resistant to nelfinavir, and there is a high cross-resistance to other
> protease inhibitors, with amprenavir having the lowest percent of 51
> percent.
>
> Isolates that were resistant to other protease inhibitors showed a
> high cross-resistance with atazanavir with 61 percent to 95 percent of
> the isolates resistant to atazanavir.
>
> \[Slide.\]
>
> Cross-resistance by genotype. In isolates that contained an I84V or
> G48V, greater than 90 percent were resistant to atazanavir. Around 60
> percent of the isolates that contained an L90M or V82 were resistant
> to atazanavir, and 38 percent with the D30N were resistant to
> atazanavir. Only 12 percent with the I50V were resistant to
> atazanavir.
>
> So, although the I50V confers resistance to amprenavir, you see here
> 100 percent, it generally does not confer resistance to atazanavir.
>
> Again, the I50L mutation confers resistance to atazanavir, but remains
> susceptible to all other PIs.
>
> \[Slide.\]
>
> Another way to look at cross-resistance is by the number of protease
> inhibitors that isolates are resistant to. Of the isolates that were
> resistant to one or two PIs, less than 20 percent were resistant to
> atazanavir, however, atazanavir loses effectiveness as isolates become
> resistant to three or more PIs, with greater than 80 percent of the
> isolates that are resistant to four or five other PIs are also
> resistant to atazanavir.
>
> \[Slide.\]
>
> This is shown in this slide also that the median fold change in
> atazanavir susceptibility increases as the number of PIs that isolates
> are resistant to goes up. This also gives you some idea of what a
> possible breakpoint for atazanavir might be somewhere between 2- to
> 6-fold.
>
> \[Slide.\]
>
> In summary, there are different resistant pathways for atazanavir. One
> pathway that appears to develop primarily in treatment-naive patients
> includes a unique mutation at I50L. The I50L mutation is specific for
> atazanavir resistance and is the predominant mutation developing in
> antiretroviral therapy-naive patients.
>
> In the studies that we analyzed, 80 percent of the
> atazanavir-resistant isolates developed the I50L.
>
> Importantly, viruses that develop the I50L mutation remain susceptible
> to other protease inhibitors. The other pathway occurring in
> treatment-experienced patients develops mutations associated with
> resistance to other protease inhibitors and confers cross-resistance.
>
> These mutations, such as L90M, I84V, a change at N88 or A71V or T,
> appear to confer atazanavir resistance and reduce the clinical
> response to atazanavir.
>
> So, the evidence suggests that if other PI mutations are present at
> baseline, atazanavir resistance develops through the latter pathway
> rather than the I50L pathway.
>
> Finally, if isolates are resistant to three or more protease
> inhibitors, they are more likely to be resistant to atazanavir.
>
> Now, I will turn it back over to Dr. Marcus.
>
> DR. MARCUS: Hyperbilirubinemia was the most common drug-related lab
> abnormality experienced by atazanavir-treated subjects. As discussed
> by the applicant, this appears to be due to inhibition of UDP-
> glucuronosyltransferase 1A1 or UGT1A1 by atazanavir.
>
> \[Slide.\]
>
> Grade 1-2 elevations in clinical trials were defined at 1.1 to 2.5
> times the upper limit of normal. A Grade 3 elevation of total
> bilirubin was defined as greater than 2.5 times the upper limit of
> normal, and Grade 4 elevations were defined as greater than 5 times
> the upper limit of normal.
>
> The upper limit of normal for total bilirubin varies slightly from lab
> to lab, but is generally defined as less than 1 to 1.5 mg/dl, and the
> upper limit of normal of direct bilirubin is generally defined as less
> than 0.2 to 0.5 mg/dl.
>
> \[Slide.\]
>
> The hyperbilirubinemia that was observed in dose-finding Phase II
> clinical trials was clearly dose dependent as can be seen in this
> chart. The incidence of Grade 3-4 elevations in total bilirubin ranged
> from 20 percent for subjects receiving the 200 mg dose of atazanavir
> to 50 percent for patients receiving 600 mg.
>
> A management strategy of dose reduction for severe hyperbilirubinemia
> was utilized in clinical trials of atazanavir. Patients with confirmed
> Grade 4 elevations of total bilirubin underwent dose reduction.
> Subjects receiving the 400 mg dose of atazanavir were dose reduced to
> 200 mg. If Grade 4 hyperbilirubinemia persisted or recurred, these
> patients were discontinued from treatment.
>
> Insufficient data regarding the efficacy of a reduced dose of
> atazanavir was provided with this NDA and as a result, will not be
> recommended for general clinical practice.
>
> \[Slide.\]
>
> The incidence of any grade elevation of total bilirubin was common in
> clinical trials and ranged from 74 percent in treatment-experienced
> study 043 to over 90 percent in dose-finding studies 007 and 008.
>
> Grade 3-4 elevations ranged from 20 to 40 percent across these
> studies. The mean total bilirubin was 1.7 mg/dl for treatment-naive
> subjects in Study 034, 1.4 mg/dl for treatment-experienced subjects in
> 043, and 1.3 mg/dl in highly treatment-experienced subjects receiving
> atazanavir 400 mg in combination with saquinavir in Study 045.
>
> \[Slide.\]
>
> Jaundice and/or scleral icterus was reported in 15 to 21 percent of
> patients receiving the 400 mg dose of atazanavir. Despite this,
> treatment discontinuation due to either event was uncommon. This may
> have been due in part to dose reduction as the management strategy for
> Grade 4 hyperbilirubinemia, which I will discuss further in a moment.
> It may be postulated that treatment discontinuation for these adverse
> events may be more common in clinical practice.
>
> \[Slide.\]
>
> Five percent of subjects in Study 034 underwent dose reduction for
> confirmed Grade 4 hyperbilirubinemia and 1 percent of subjects in
> Study 043. This led to the need for treatment discontinuation for
> Grade 4 hyperbilirubinemia for only one subject in Study 034.
>
> The applicant is currently proposing that patients discontinue
> treatment with atazanavir for confirmed elevations of bilirubin
> greater than 5 times the upper limit of normal. As a result, one can
> reasonably expect that about 5 percent of treatment-naive subjects and
> about 1 percent of treatment-experienced subjects will discontinue
> treatment for hyperbilirubinemia.
>
> \[Slide.\]
>
> This graph might be a little confusing. It shows mean total and direct
> bilirubin as grouped by category of total bilirubin - the categories
> being less than 2.5 mg/dl, 2.5 to 5.0 mg/dl, and greater than 5.0
> mg/dl.
>
> I have taken all of the bilirubins reported in Study 034 and grouped
> them by these categories and calculated the means. The mean direct
> bilirubin reported with each category of total bilirubin then
> represents the mean direct bilirubins that corresponded to the total
> bilirubin values.
>
> The mean direct bilirubin was minimally elevated across all categories
> of total bilirubin, supporting inhibition of UGT 1A1 as the mechanism
> of hyperbilirubinemia.
>
> \[Slide.\]
>
> Severe elevations of total bilirubin, which I have defined here as
> greater that 10 mg/dl, were uncommon and occurred in only 10 patients
> across clinical trials. The highest total bilirubin reported in
> clinical trials was 12.1 mg/dl. In these patients, elevations of
> direct bilirubin and other LFTs were more common.
>
> Four out of the five patients who had other indices of hepatic injury
> or inflammation were co-infected with the hepatitis virus, and the
> remaining subject appeared to have a resolving hepatitis at the time
> of study enrollment.
>
> \[Slide.\]
>
> In Study 007, all grades of LFT abnormalities were more common in
> atazanavir-treated subjects as compared to nelfinavir. In this study,
> Grade 3-4 LFT abnormalities were more common in atazanavir-treated
> subjects than in nelfinavir-treated subjects.
>
> In Study 008, all grades of LFT abnormalities were also more common in
> atazanavir-treated subjects, however, Grade 3-4 LFT abnormalities were
> slightly more common in nelfinavir-treated subjects.
>
> Discontinuations for LFT abnormalities were similar between atazanavir
> and nelfinavir-treated subjects when treatment arms for these two
> studies were combined.
>
> \[Slide.\]
>
> In Study 034, all grades of LFT abnormalities with the exception of
> total bilirubin were slightly more common in efavirenz subjects as
> compared to atazanavir. However, the incidence of Grade 4
> abnormalities was similar.
>
> \[Slide.\]
>
> Discontinuations for abnormal elevations of LFTs excluding isolated
> hyperbilirubinemia appeared to occur with similar frequency in
> atazanavir-treated subjects relative to comparators. The majority of
> these subjects were co-infected with hepatitis B or C.
>
> Three subjects receiving atazanavir and one subject receiving
> ritonavir/saquinavir had no apparent risk factors for hepatic
> inflammation or injury.
>
> \[Slide.\]
>
> In summary, inhibition of UGT 1A1 by atazanavir appears to result in a
> predominantly unconjugated hyperbilirubinemia that is reversible upon
> discontinuation of treatment. The risk of hepatic toxicity seen with
> atazanavir use appears to fall within the range of that seen with
> other currently marketed antiretroviral agents.
>
> \[Slide.\]
>
> It was first observed in Phase II dose-finding studies that use of
> atazanavir resulted in minimal changes in lipid profiles as compared
> to nelfinavir. Use of nelfinavir was associated with significant
> increases in total and LDL cholesterol and fasting triglycerides.
>
> These dose-finding studies were not specifically designed to collect
> this data, so fasting lipid profiles were available for only one-half
> to three-fourths of patients. However, these findings were confirmed
> in Phase III studies.
>
> \[Slide.\]
>
> At Week 48, in Study 034, minimal changes in fasting total and LDL
> cholesterol were observed in atazanavir-treated patients while
> significant increases in these parameters were seen in
> efavirenz-treated patients.
>
> Atazanavir use was associated with a modest decrease in fasting
> triglycerides while efavirenz use was associated with a significant
> increase. HDL levels increased significantly in both treatment arms,
> however, the increase in HDL was greater in efavirenz-treated
> subjects.
>
> \[Slide.\]
>
> Categorical analysis of lipid profiles revealed that more patients
> receiving efavirenz as compared to atazanavir experienced significant
> elevations in total and LDL cholesterol and fasting triglycerides that
> might require dietary modification or medical management.
>
> \[Slide.\]
>
> At Week 24, in Study 043, atazanavir-treated subjects experienced
> minimal decreases in fasting total and LDL cholesterol and in fasting
> triglycerides while Kaletra-treated subjects experienced elevations in
> all of these lipid parameters.
>
> Differences in lipid profiles between treatment arms were
> statistically significant. Patients in both treatment arms experienced
> increases in fasting HDL.
>
> \[Slide.\]
>
> More patients in this treatment-experienced study had elevated lipids
> at baseline as compared to those in treatment-naive study 034. In this
> study, 5 to 12 percent of patients had significant elevations of total
> or LDL cholesterol or fasting triglycerides at baseline as compared to
> 2 to 4 percent of patients in Study 034.
>
> At Week 24 of treatment, fewer atazanavir-treated subjects had
> elevated total or LDL cholesterol than at baseline while increases
> were observed in Kaletra-treated patients. No significant change was
> seen in the percentage of atazanavir-treated subjects with elevated
> triglycerides.
>
> \[Slide.\]
>
> This slide shows the mean change in fasting triglycerides over time in
> the dose-finding studies 007 and 008. The yellow lines represent
> atazanavir-treated subjects and the white lines represent
> nelfinavir-treated subjects.
>
> Nelfinavir-treated subjects experienced a rapid increase in fasting
> triglycerides that was sustained throughout treatment.
> Atazanavir-treated subjects initially appeared to have modest
> decreases in fasting triglycerides, however, the levels appeared to
> increase slightly over time. This may suggest that other factors may
> also contribute to changes in fasting triglycerides.
>
> \[Slide.\]
>
> Use of atazanavir did not appear to result in a lower incidence of
> patient- and investigator-reported lipodystrophy events through one to
> two years of treatment.
>
> \[Slide.\]
>
> Significant cardiovascular events were rare in atazanavir clinical
> trials and the duration of follow-up too short to reach any
> conclusions regarding the reduction of cardiovascular risk with the
> use of atazanavir as compared to other protease inhibitors or to
> efavirenz.
>
> \[Slide.\]
>
> In conclusion, the favorable lipid profiles associated with atazanavir
> use appeared to persist through two years of treatment although data
> from Phase II trials is limited by study design.
>
> Benefits for treatment-experienced patients are less well defined as
> factors other than current protease inhibitor use appear to contribute
> at least to hypertriglyceridemia. Lipid effects do not appear to be
> associated with a reduced incidence of lipodystrophy through two years
> of treatment, and cardiovascular benefit at this time remains unclear.
>
> \[Slide.\]
>
> Preclinical evaluation of atazanavir for potential effects on cardiac
> conductivity were remarkable for modest inhibition of HERG channels at
> high concentrations. In Purkinje fiber studies, it was also noted to
> produce a dose-dependent increase in the mean action potential
> duration.
>
> As a result of these findings, studies were undertaken by the
> applicant to examine potential effects of atazanavir on the QT
> interval.
>
> \[Slide.\]
>
> As mentioned previously by the applicant, Study 076 was a
> three-treatment, three-period crossover study where subjects were
> assigned to receive placebo 400 mg or 800 mg of atazanavir in six
> different sequences. Each treatment period was separated by a washout
> period of at least 14 days. Twelve EKGs were obtained over a 24-hour
> period at baseline and on Day 6 of each treatment period.
>
> \[Slide.\]
>
> In this study, unlike previous studies designed to evaluate EKG
> changes with atazanavir use, a dose-dependent increase in the heart
> rate was noted. This effect was detected in this study possibly due to
> larger number of enrolled subjects as compared to previous studies and
> due to the 14-day washout period between treatment arms.
>
> \[Slide.\]
>
> I have two graphs here plotting heart rate against corrected QT
> intervals obtained from Study 076 in the placebo treatment arm. The
> graph on the left shows the QT intervals calculated by Bazett\'s
> correction and the graph on the right shows QT intervals calculated
> using Fridericia\'s correction.
>
> As you can see from these graphs, Bazett\'s correction appears to
> overcorrect the QT interval as the heart rate increases. Fridericia\'s
> correction formula appears to provide a more consistent correction
> over a range of heart rates.
>
> The placebo-corrected mean change in the QT interval, as measured as
> Tmax, from baseline to the 800 mg dose is 7.9 milliseconds when
> calculated using Bazett\'s correction.
>
> The mean change when calculated using Fridericia\'s formula is -1.6
> milliseconds. The 95 percent confidence interval for the mean change
> using Fridericia\'s correction include zero.
>
> \[Slide.\]
>
> In Studies 034 and 043, no significant differences in the incidence of
> prolonged QT intervals was observed between atazanavir and
> comparators.
>
> \[Slide.\]
>
> All events, cardiovascular events potentially related to arrhythmia
> were reviewed. No events related to atazanavir use and prolongation of
> the QT interval were identified.
>
> \[Slide.\]
>
> Although data from placebo-controlled study 076 is limited by the lack
> of a positive control, this study may indicate that atazanavir has
> little or no effect on the QT interval, however, the overall risk is
> unknown.
>
> No signal for any significant risk or an increased risk relative to
> comparators was identified in clinical trials.
>
> \[Slide.\]
>
> My next topic will be the effects of atazanavir on the PR interval.
>
> \[Slide.\]
>
> Multiple mechanisms can lead to prolongation of the PR interval and
> varying degrees of AV block. Medications can cause PR interval
> prolongation through direct effects on the AV node, through calcium
> channel blockade or through other mechanisms.
>
> Medical conditions, such as fibrosis of the conduction system,
> ischemic heart disease cardiomyopathy, and myocarditis can also cause
> PR interval prolongation and AV block.
>
> In pharmacokinetic studies undertaken to evaluate effects on the QT
> interval, atazanavir caused a dose-dependent prolongation of the PR
> interval. In vitro studies also indicated that it was a moderate
> calcium channel inhibitor, and this is the likely mechanism for PR
> interval prolongation.
>
> \[Slide.\]
>
> The most common abnormality observed in EKG in clinical trials was
> first-degree AV block. While first-degree AV block appears to be
> largely asymptomatic, there may be clinical scenarios where
> significant prolongation of the PR interval may impact upon patient
> stability.
>
> According to the ACC 2002 guidelines on pacemaker placement, PR
> intervals greater than 300 milliseconds may lead to worsening to
> symptoms of CHF in patients with LV dysfunction. Expert consensus is
> the primary basis for recommendation for pacemaker placement in these
> patients.
>
> \[Slide.\]
>
> This graph shows the mean PR intervals of subjects taking the placebo
> 400 mg and 800 mg doses of atazanavir in Study 076. As mentioned
> previously, 60 percent of patients receiving the 800 mg dose of
> atazanavir were observed to have first-degree AV block.
>
> The highest PR interval recorded in this study was 324 milliseconds in
> a patient receiving the 300 mg dose.
>
> \[Slide.\]
>
> In clinical trials, EKGs were collected at three time points - at
> baseline or trough prior to dosing, at two to three hours after
> dosing, and at six to 12 hours after dosing.
>
> The mean PR intervals that I am presenting here were recorded at the
> time corresponding to maximum atazanavir concentration, two to three
> hours post-dose. Although the mean intervals seen at this time point
> were not significantly different than those seen at other time points.
>
> \[Slide.\]
>
> In Study 034, the mean PR interval for efavirenz at two to three hours
> post-dose was 153 milliseconds. The mean PR interval for atazanavir
> was 7 milliseconds longer. Maximum recorded PR intervals for
> atazanavir-treated patients in this trial ranged from 265 to 307
> milliseconds.
>
> \[Slide.\]
>
> First-degree AV block was slightly more common in atazanavir-treated
> subjects as compared to the efavirenz-treated subjects in Study 034.
>
> \[Slide.\]
>
> The mean PR interval for atazanavir-treated subjects was 6
> milliseconds longer than the mean PR interval for nelfinavir-treated
> subjects in rollover study 041, however, this difference was not
> statistically significant.
>
> \[Slide.\]
>
> The incidence of first-degree AV block in nelfinavir-treated patients
> appeared to be similar to that seen in atazanavir subjects
> participating in the rollover studies.
>
> \[Slide.\]
>
> Finally, the mean PR intervals of atazanavir and Kaletra-treated
> subjects were similar at all time points.
>
> \[Slide.\]
>
> The incidence of first-degree AV block also appeared to be similar
> between atazanavir and Kaletra-treated patients.
>
> \[Slide.\]
>
> I would like to just briefly mention two cases where use of atazanavir
> may have been associated with more serious conduction abnormalities.
>
> In this case, a 43-year-old male ingested a large number of
> atazanavir, 3TC, and d4T pills in an apparent suicide attempt. The
> patient was noted to have a severely prolonged PR interval with
> bifascicular block. These abnormalities resolved five days after drugs
> were withheld.
>
> \[Slide.\]
>
> In this case, a 50-year-old male was hospitalized on Day 11 of
> treatment with atazanavir, delavirdine, 3TC, and tenofovir for angina
> and shortness of breath. He was also receiving verapamil for
> hypertension.
>
> EKG on admission was remarkable for a junctional rhythm.
> Antiretroviral medications were held, however, the patient continued
> to receive verapamil. One day following admission, an EKG showed
> persistence of the junctional rhythm, and the next day the patient was
> found unresponsive with an idioventricular rhythm.
>
> \[Slide.\]
>
> In conclusion, atazanavir appears to cause a dose-dependent
> prolongation of the PR interval. The incidence of first-degree block
> seen in atazanavir-treated patients appears to be similar in incidence
> observed in patients treated with comparators.
>
> Severe PR prolongation or more serious events appear to be rare.
>
> \[Slide.\]
>
> I just wanted to briefly mention the pediatric ACTG protocol that
> continues to enroll patients in order to evaluate safety and
> pharmacokinetics of atazanavir in infants greater than 3 months of
> age, children, and adolescents.
>
> Adverse events in children appear to be generally similar to those
> seen in adults with hyperbilirubinemia being the most common adverse
> event reported. Unfortunately, due to wide variability of PK data, a
> dose has not yet been defined for any of the age groups.
>
> \[Slide.\]
>
> I also just wanted to briefly highlight drug-drug interactions.
>
> \[Slide.\]
>
> Drugs that fall into the following categories can potentially have
> significant interactions with atazanavir. Those that are CYP3A
> inhibitors, inducers, or substrates, drugs that increase pH, drugs
> that cause PR prolongation, and 2C9 or 1A2 substrates.
>
> \[Slide.\]
>
> Diltiazem is a CYP3A4 substrate and also prolongs the PR interval.
> Atazanavir, when coadministered with diltiazem, raised the Cmax and
> area under the curve of diltiazem by 100 percent. More subjects
> experienced first-degree AV block when receiving the combination of
> atazanavir and diltiazem than when either drug was administered alone.
>
> The longest PR interval observed in this study was 302 milliseconds in
> one subject receiving the combination of atazanavir and diltiazem.
>
> \[Slide.\]
>
> Ethinyl estradiol and norethindrone are both CYP3A4 substrates, and
> ethinyl estradiol is also a UGT 1A1 substrate. Because of this,
> concomitant use of oral contraceptives and atazanavir was examined for
> potential drug interactions.
>
> When coadministered with Ortho-Novum 7/7/7, atazanavir increased the
> Cmax and area under the curve of both ethinyl estradiol and
> norethindrone. This should not have an impact on the efficacy, but may
> impact safety.
>
> As a result of these findings, it may be recommended that physicians
> prescribing oral contraceptives should attempt to use the lowest
> effective dose.
>
> \[Slide.\]
>
> In conclusion, atazanavir appears to have antiviral activity similar
> to efavirenz or nelfinavir in treatment-naive patients. It was
> inferior to Kaletra in treatment-experienced patients.
>
> Potential treatment advantages include a low pill burden and a unique
> resistance profile in treatment-naive subjects.
>
> \[Slide.\]
>
> The hyperbilirubinemia associated with the use of atazanavir appears
> to be due to inhibition of UGT 1A1 and is reversible with treatment
> discontinuation.
>
> The risk for hepatotoxicity appears to fall within the range of that
> seen with other antiretroviral medications.
>
> \[Slide.\]
>
> Atazanavir causes a dose-dependent prolongation of the PR interval.
> Clinically significant events due to this effect appear to be rare.
> Effects of atazanavir on the QT interval appear to be minimal.
>
> \[Slide.\]
>
> One other potential treatment advantage for atazanavir appears to be
> its lack of effect on lipid profiles. Despite this, patient and
> investigator reported lipodystrophy events appeared similar between
> atazanavir and comparators at least through two years of treatment.
>
> Finally, the impact on cardiovascular events is unknown at this time.
>
> DR. GULICK: Thanks, Drs. Marcus, Naeger, and Hammerstrom.
>
> We are now ready go into the question and answer period for both the
> sponsor and the agency. Just to remind the committee we have plenty of
> time for discussion in the afternoon, so let\'s try to stick to
> questions of clarification or information at this time.
>
> Dr. Morganroth would like to start us off.
>
> **Questions from the Committee**
>
> DR. MORGANROTH: I have a question for the sponsor. On the 076 study,
> can you tell us what percentage of the subjects were female and what
> the results of the central tendency and outlier analysis was in the
> females compared to men? Then, I have a follow-up question after that.
>
> DR. LAWRENCE: In the 076 study, approximately 25 percent of the
> subjects were females. At the 400 mg dose in that study, as well as in
> our clinical program, there was no gender difference with respect to
> PR change or QT change.
>
> DR. MORGANROTH: If you interpret that study as using Fridericia\'s as
> a negative trial and you saw no events in QT analysis in the Phase
> II/III program and no signals, and you weren\'t even able to reach an
> IC50 in HERG preclinically, why is it that you are recommending that
> prescribers not use concomitant QT-prolonging drugs with your drug?
>
> DR. LAWRENCE: Our specific recommendation is caution when the
> concomitant drug that prolongs QT interval is metabolized by 3A4, so
> we are advising caution in the setting of a potential PK interaction,
> but our drug intrinsically doesn\'t appear to affect QT.
>
> DR. MORGANROTH: Thank you.
>
> DR. GULICK: Dr. Fletcher.
>
> DR. FLETCHER: Also on the 076, you found the dose effect on the PR
> interval of atazanavir, doses of 400 and 800. My question is what
> about the boosted 300, 100, atazanavir/ritonavir, and that it would
> produce exposures above what 800 mg of atazanavir would?
>
> DR. SCHNITTMAN: In fact, we have looked at exposures of 300 and 100,
> and they are less than what is seen for 800 mg. The primary effect of
> the ritonavir is to delay the elimination. There is actually a very
> small increase in Cmax of about 20 percent relative to a 400 mg dose
> by itself.
>
> DR. FLETCHER: But what about at Cmin?
>
> DR. SCHNITTMAN: The Cmin of the 800 is higher, but still higher than
> even the 5- to 8-fold increase that we see with the 800 mg, as well.
>
> DR. GULICK: Dr. Kumar and then Dr. Wood.
>
> DR. KUMAR: Can you comment on what happened to the lipid profile when
> the drug was combined with ritonavir in 045, similar to the slide you
> have, your slide 90?
>
> DR. GIORDANO: We did look at the lipid values, LDL cholesterol and
> triglycerides on the 045 study, and similar to what we have described
> in other studies, there were significant differences between
> lopinavir/ritonavir and atazanavir/ritonavir with regard to LDL
> cholesterol and triglycerides.
>
> DR. GULICK: You wanted to see the data?
>
> DR. GIORDANO: Did you want to see the data?
>
> DR. KUMAR: Yes, that would be great.
>
> DR. GIORDANO: I would be happy to pull up the slide of the 045 study.
>
> \[Slide.\]
>
> DR. GIORDANO: These are the LDL cholesterols over time, 16 weeks. In
> green and in blue are the two atazanavir treatments, one with
> ritonavir in green, in orange is the lopinavir/ritonavir. Remember
> that this reflects a direct switch from previous therapy to the new
> therapy without a washout period.
>
> We have a similar slide for triglycerides.
>
> \[Slide.\]
>
> DR. GIORDANO: 6J8. Again, we see that there is somewhat of a decrease
> in triglycerides over 16 weeks, and a further increase in
> triglycerides on the lopinavir/ritonavir treatment.
>
> DR. GULICK: Dr. Wood.
>
> DR. WOOD: My question again relates to the QT and the PR intervals. My
> understanding is from the 076 studies, that the EKGs were done over a
> 24-hour period. Do you all have any data regarding QT and PR intervals
> after individuals have been dosed chronically with atazanavir after
> weeks or months of exposure?
>
> DR. SCHNITTMAN: The chronic data comes from the clinical trials. In
> 043, 034, 045, we had multiple ECGs, number one, that were done on a
> given day, three that were done on a given day, and then done at least
> four to eight times more, three times, as well, that confirm those
> responses.
>
> DR. WOOD: A second related to the PR interval is that first-degree AV
> block is very common in clinical practice, and did you all do any
> substudy analysis of individuals who may have had pre-existing
> first-degree AV block in terms of PR prolongation and whether or not
> there was a greater percentage of prolongation in those individuals?
>
> DR. LAWRENCE: We couldn\'t look precisely to answer that question, in
> part because for the latter studies, protease inhibitor therapy
> wasn\'t interrupted before study drug was initiated, so the baseline
> is a little bit complicated, but where we could look at it, it seems
> that about 2 percent of subjects came in with a PR that was modestly
> prolonged, and it was infrequent that it got significantly further
> prolonged on study drug.
>
> DR. GULICK: Dr. Tephly and then Dr. Fish.
>
> DR. TEPHLY: Yes, I have about four or five questions.
>
> The first one, what is the distribution of this drug?
>
> DR. SCHNITTMAN: It is distributed widely and to give a further
> description of that, I want to turn to our PK person. While he is
> walking up here, there is penetration into the CNS, but it is of a low
> order similar to other protease inhibitors.
>
> DR. TEPHLY: That was my next question actually.
>
> DR. SCHNITTMAN: And it penetrates also into the semen.
>
> DR. TEPHLY: While he is walking up, you might answer this one then. Is
> morphine used to any extent in AIDS patients?
>
> DR. SCHNITTMAN: Excuse me?
>
> DR. TEPHLY: Is morphine used in AIDS patients?
>
> DR. SCHNITTMAN: In terminal cases.
>
> DR. TEPHLY: I think the answer is yes.
>
> DR. SCHNITTMAN: Yes.
>
> DR. TEPHLY: The question I have is do you realize that morphine also
> is a CYP3A4 substrate, and I didn\'t see any opioids tested in terms
> of drug-drug interactions. Is that true?
>
> DR. SCHNITTMAN: To date, yes. A methadone study is currently ongoing
> now, because we realized it is an important drug interaction
> consideration. That is currently ongoing.
>
> Dennis, do you want to address the other question?
>
> DR. GULICK: Can you introduce yourself, as well.
>
> DR. GRASELA: Dennis Grasela, Bristol-Myers Squibb.
>
> I don\'t really have anything further to add to what Dr. Schnittman
> has said. The drug is distributed in the body and does hit some of the
> reservoir sites.
>
> DR. TEPHLY: Well, what is the mechanism of lipid lowering for this
> chemical?
>
> DR. GIORDANO: We have looked at a number of preclinical experiments
> trying to ascertain and elucidate the mechanism by which atazanavir
> has a different effect on lipids from other protease inhibitors.
>
> Compared to other protease inhibitors, atazanavir is less likely to
> induce lipogenesis in adipocytes and in hepatocytes. It also has
> differential effects on glut \[?\] 4, but those are relative to other
> protease inhibitors.
>
> DR. TEPHLY: But there is no effect on the reductase, HMG CoA
> reductase?
>
> DR. GIORDANO: I am not sure of the answer to that question. Does it
> have no effect on HMG CoA reductase, is that the question?
>
> DR. TEPHLY: Yes.
>
> DR. GIORDANO: Dr. Parker, who is in our group, conducted most of the
> preclinical work, will be able to help us out on that.
>
> DR. GULICK: Please introduce yourself.
>
> DR. PARKER: Rex Parker from Bristol-Myers Squibb Preclinical.
>
> While we haven\'t specifically addressed HMG CoA-reductase, we have
> done a number of studies that have surveyed potential areas of
> interaction of atazanavir in comparative studies with other PIs.
>
> You see on the slide, areas for molecular and cellular interactions
> with transport hepatocyte lipogenesis at the site differentiation, and
> importantly, gene expression profiles in both adipocytes and
> hepatocyte models, and all of these studies converge on the finding
> that we reproduce what other labs have shown with several other PIs as
> comparators, but that atazanavir is relatively devoid of activities on
> each of these pathways or molecular points of intervention, and
> specifically does not have any effect on cholesterol synthesis rate,
> on triglyceride synthesis rate, which would address your question
> about the reductase.
>
> DR. TEPHLY: So, there would be no effect on the jerenial \[?\] system?
>
> DR. PARKER: No effect as we know it with current studies.
>
> DR. TEPHLY: Is there any effect on absorption from the gut, other
> substances such as vitamin B?
>
> DR. GRASELA: At this point, we have no data to address that question.
>
> DR. TEPHLY: I see that that kind of information was sort of missing
> from the compilation of information we got, but it is of some concern
> if there is an effect on lipid transport across the GI tract, either
> direction.
>
> It would be interesting, and I doubt that there would be a problem,
> but it is something that might be addressed.
>
> I do have a couple more questions, and that is, the patients who
> showed hyperbilirubinemia, were they tested for Gilbert\'s before the
> study began? I may have missed that.
>
> DR. GIORDANO: Routine genotyping for Gilbert\'s was not conducted on
> all patients on all studies. We do have data from select Phase II
> studies to look at Gilbert\'s genotype with regard to the 7/7
> genotype.
>
> DR. TEPHLY: Because it is fairly common. It is 40 percent of the
> population, and I noticed that 40 percent of your 400 mg dose, at
> least at first, I think was affected. So, I was just wondering whether
> you just perturbed patients who had Gilbert\'s to begin with.
>
> DR. GIORDANO: Undoubtedly. We know that we included patients with the
> Gilbert\'s syndrome in our clinical program. The number that we came
> up with, with regard to the frequency, was closer to 10 percent of our
> patients on clinical study, which appears to be reflective of the
> general number in the population, so they were not excluded.
>
> DR. TEPHLY: Is that 10 percent homozygotes?
>
> DR. GIORDANO: Yes, 10 percent 7/7s.
>
> DR. TEPHLY: You didn\'t look at any other?
>
> DR. GIORDANO: We also looked at 6/7s, 7/8s, 6/6s on our Phase II
> program. We conducted a cross-sectional study through one, Phase II
> study. Most of those samples came from the U.S. because of the
> availability of testing, so I can\'t speak to the entire assessment
> across various genetic and racial profiles.
>
> DR. GULICK: Dr. Fish.
>
> DR. FISH: It was mentioned in the presentation that coadministration
> of didanosine and atazanavir should be separated in time. Is it just a
> coadministration buffering issue, because in the information that we
> were given, it looks like the impact on atazanavir levels is
> substantial and that the PK data, when they are given in the same
> patient, although separated in time, and how much time is necessary
> since they are both once-a-day drug deliveries?
>
> DR. SCHNITTMAN: The effect is purely an antacid effect, buffering
> effect, and with a two-hour separation, there is no decline in
> concentration.
>
> DR. GULICK: Mr. Sharp.
>
> MR. SHARP: I was wondering about adherence studies. I mean this is a
> once-a-day drug, but I think we need to look at adherence. I wonder
> what you have done.
>
> DR. SCHNITTMAN: Adherence, as you say, is a critical question. The
> problem with the blinded pivotal trials is that we have dummy pills,
> placebo pills, et cetera, so that, in effect, for those studies, one
> has the same number, and one cannot evaluate adherence per se on that.
>
> We do, though, now in our experienced patient studies and future
> studies where we don\'t have the blinded situation, actively
> controlling, capturing that information for adherence and compliance.
>
> MR. SHARP: Are you going to be doing interaction studies with
> tenofovir and nevirapine?
>
> DR. GIORDANO: The tenofovir one, in fact, we have recently completed,
> but that data is currently under FDA review, and nevirapine is a
> planned study that will occur very soon.
>
> MR. SHARP: When will the methadone studies be completed?
>
> DR. GIORDANO: As I said, it is currently underway. I suspect that we
> should have some preliminary information hopefully by the end of this
> year.
>
> DR. GULICK: Dr. Kowey.
>
> DR. KOWEY: I have two questions actually. One has to do with clinical,
> and one preclinical.
>
> Obviously, in the 076 study, we are used to seeing doses of drug given
> which are much higher than the doses that are recommended for clinical
> use, and I suspect that the reason you didn\'t do that, at least in
> the repetitive dosing scheme, was because of the fear of inducing
> hyperbilirubinemia in a normal volunteer population.
>
> But if it\'s true that the metabolite doesn\'t have much of an effect
> on HERG, and if it is true that the metabolites are not important, why
> not do a large dose, single study in QT looking at values in Cmax?
>
> DR. LAWRENCE: I think a partial answer to that is that although the
> 800 mg dose is twice the 400 recommended dose, the exposures are more
> than twice, so we at least achieved exposure levels that are unlikely
> to be encountered by the 400 mg dose or the boosted dose.
>
> Now, as far as the safety margin, that study maybe doesn\'t provide
> the 5- or 10-fold margin that you would like, but I think looking at
> the data in toto, I think it is reasonable to conclude that the effect
> is negligible on QT.
>
> DR. KOWEY: Well, I don\'t want to get in an argument with you now,
> because we will do this later, but I think that last statement we need
> to flag.
>
> The second question has to do with the preclinical models. If I read
> the documents correctly, you looked at action potential duration in a
> Purkinje preparation and you looked at HERG, and you looked at IKs,
> and that\'s it, that was your preclinical package? Is there anything
> else that I missed?
>
> DR. LAWRENCE: As far as screening for QT effect, that\'s right. Our
> standard paradigm is to screen for those assays to see if a signal is
> present to do a dog study, to also look for a signal, and if any of
> those studies, a signal is present, then, we do the extensive sort of
> ECG evaluation that was done in 076.
>
> DR. KOWEY: But you don\'t do any other preclinical work?
>
> DR. LAWRENCE: Generally not.
>
> DR. KOWEY: We will get to that later.
>
> DR. GULICK: Just to let the committee know, I am going to let people
> who haven\'t had a chance to ask questions first before I go back to
> people a second time.
>
> Dr. Illingworth and then Dr. Sherman.
>
> DR. ILLINGWORTH: A couple of questions. One is the 10 patients who had
> values over 10, did they all have Gilbert\'s syndrome underlying?
>
> DR. GIORDANO: They were not specifically tested for their genotype.
> Most of those patients had other concurrent events, such as
> intercurrent hepatitis, either A or C, but they were not genotyped, so
> I don\'t know the answer to that question.
>
> DR. ILLINGWORTH: You haven\'t done any testing in normal volunteers
> with Gilbert\'s syndrome to see whether they had a much bigger rise in
> bilirubin?
>
> DR. GIORDANO: We have done genotyping in our Phase I program and our
> Phase II program, and as a general rule, patients who have the
> genotype which is consistent with Gilbert\'s will experience average
> higher bilirubin levels than those who do not.
>
> DR. ILLINGWORTH: My second question concerns the lipid modifying
> effects. Have you looked at other markers of vascular disease, such as
> high sensitivity C-reactive protein to see whether this drug does not
> raise CRP where others do?
>
> DR. GIORDANO: In the program to date, we have not looked at high
> sensitivity C-reactive protein. We have assessments such as those
> planned in some of our specialty studies that are ongoing in the III-B
> and Phase IV program.
>
> DR. GULICK: Dr. Sherman.
>
> DR. SHERMAN: Thank you. The first question actually follows nicely on
> that one related to the EGT polymorphisms. Do you have any data where
> you can show the comparative levels of those patients that you sampled
> of bilirubin elevation?
>
> DR. GIORDANO: Yes. The question was do I have data on bilirubin levels
> as related to genotyping, and I think slide 4N1 gives us some data.
>
> \[Slide.\]
>
> DR. GIORDANO: This is an illustration of the bilirubin level by
> concentration and then the 6/6, 6/7, and 7/7 with the 7/7 reflecting
> the Gilbert\'s genotype. You can see the trends where there is higher
> bilirubin levels at any given Cmin as the patient has two genes, the
> 7/7, which is the Gilbert\'s.
>
> DR. SHERMAN: So, there was little effect on the 6/6s.
>
> DR. GIORDANO: There is much less effect on the 6/6s, yes, 6/6s
> representing, as you know, what most of the population has.
>
> DR. SHERMAN: You mentioned antacids affecting presumably absorption.
> Do you have any data on that?
>
> DR. SCHNITTMAN: The absorption of atazanavir is very dependent on low
> pH, so antacids could have an impact. At this point, we did do
> analyses to look at the patients who may have been taking antacids in
> the program, demonstrate neither a safety nor efficacy difference in
> those, and we do recommend that there is separation, just as there
> would be with didanosine of approximately two hours for antacids.
>
> DR. SHERMAN: What about PPIs\>
>
> DR. SCHNITTMAN: PPIs and H2 blockers have more prolonged effects. We
> have not yet studied that, and that is an important drug interaction
> study that we need to do, and we will do.
>
> DR. SHERMAN: I will ask one last one. This one actually is for the
> agency reviewer.
>
> DR. GULICK: Can you speak up, Ken?
>
> DR. SHERMAN: This question is for the agency reviewer related to the
> ALT abnormalities. I saw one slide that suggested that although there
> was not an increase in Grade 3/Grade 4 ALT abnormalities, compared to
> nelfinavir, it appeared there was overall an increase in all ALT
> abnormalities, Grades 1 through 4.
>
> Is that correct and was that statistically significant?
>
> DR. MARCUS: Yes, that\'s correct. I believe that it reached
> statistical significance, but I would have to check and get back to
> you with that.
>
> DR. SHERMAN: The follow-up to that would be is it attributable based
> upon known associations with underlying viral infection or is it
> thought to be primarily drug related?
>
> DR. MARCUS: It is not associated with underlying viral, if you are
> referring to hepatitis B or C co-infection, the incidence of hepatitis
> B and C co-infection were similar between atazanavir and nelfinavir.
> Whether it is related to atazanavir or not, I would say that one might
> reasonably that it is a drug-related effect, however, it did not
> appear to result in an increased incidence of severe elevations or
> discontinuations.
>
> DR. SHERMAN: I think that is also something that perhaps needs to be
> discussed later because lower levels may still contribute to
> significant long-term toxicity.
>
> DR. GULICK: Dr. DeGruttola.
>
> DR. DeGRUTTOLA: I had a question on the calculation of the mean
> difference, mean change in viral load from baseline. How are assays
> that went below limits of detection handled in those comparisons?
>
> DR. LaBRIOLA: Dominic LaBriola, Biostatistics, BMS.
>
> We actually imputed a value of one less than the lower limit of
> quantification in the calculations. So, if the limit of quantification
> was 400, we would impute a value of 399 for calculating means.
>
> DR. DeGRUTTOLA: So, you didn\'t use any censored data methods for
> those?
>
> DR. LaBRIOLA: No.
>
> DR. DeGRUTTOLA: I had a question about the ALT elevations that
> appeared to be more common in the atazanavir in one study, the 043
> study, but not in two other studies. It was mentioned during the
> presentation that that 043 study was an outlier. I was wondering if
> that was based on some statistical evaluation of heterogeneity across
> studies, and I was also interested in whether that comparison of
> atazanavir to lopinavir/ritonavir was significant for the ALT
> elevations in 043.
>
> DR. GIORDANO: I was using the word outlier in the generic sense in
> that the frequency for lopinavir/ritonavir was much lower than we had
> seen in any of our other comparator trials in our program, and the 6
> percent for atazanavir, we looked very closely at those cases, and 6
> of the 8 were associated with other events, and it resolved to normal
> while continuing to take atazanavir, so do not think that that
> reflected a potential hepatic signal.
>
> With regard to the statistical question, we did not routinely perform
> statistical tests on percent ALTs.
>
> DR. DeGRUTTOLA: One final question. for all of the virological
> response analyses where you are looking at percent below 400 or below
> 50, were all of those done with non-completers equal failure?
>
> DR. SCHNITTMAN: The intent-to-treat analysis were all non-completer
> equals failure, correct.
>
> DR. GULICK: Dr. Mathews.
>
> DR. MATHEWS: Two brief questions. You showed us some data that
> suggested that the lipid effect of PK-boosted atazanavir was more
> favorable than the Kaletra arm, but do you have any direct comparison
> of atazanavir unboosted to boosted in terms of whether the effects
> that were seen unboosted are attenuated at all when combined with
> ritonavir?
>
> DR. GIORDANO: We don\'t have any direct head-to-head data in which a
> naive patient population was treated with either atazanavir or a
> boosted atazanavir with ritonavir to make that direct assessment, only
> the comparative data from 043.
>
> DR. MATHEWS: How about across your studies in terms of the magnitude
> of the changes in LDL?
>
> DR. GIORDANO: We have not conducted those assessments again because
> the studies reflect very different patient populations. There were
> experienced patients who came from perhaps five or six different
> regimens, went on to then five or six different regimens on the 045
> and similar things on 043.
>
> DR. MATHEWS: That is obviously a big question for the
> treatment-experienced patients once this drug is approved.
>
> The other issue relates to exclusions from the registrational trials
> for liver dysfunction. What was the ALT cutoff for exclusion?
>
> DR. GIORDANO: Greater than 3-fold upper limit of normal.
>
> DR. GULICK: Can you repeat the question? I am not sure everybody
> heard.
>
> DR. MATHEWS: The level of exclusion for ALT from the registrational
> trials, you said was greater than 3-fold. The question is what
> experience is there with patients who have more severe liver injury,
> and do we know anything about what their risk of further
> hepatotoxicity might be in groups that were excluded from the
> registrational trials, perhaps from the expanded access program?
>
> DR. GIORDANO: We don\'t have large additional experience with patients
> who entered studies with ALTs or ASTs greater than 3-fold upper limit
> of normal to address that question. The expanded access program has
> more liberal entry criteria, but we don\'t yet have sufficient data to
> make any strong assessments.
>
> I can parenthetically add that we have not identified any problems,
> but I think the experience needs to be extended.
>
> DR. MATHEWS: The reason I asked that question besides the obvious one
> that they were not studied as much related to this phenomenon which is
> fairly common and not something that I would anticipate would be a
> bigger problem with atazanavir, but the flare of liver injury that is
> often seen in patients who initiate combination therapy with a
> protease inhibitor in the setting of active hepatitis C or other liver
> disease.
>
> The clinical problem, of course, always is how do you know what that
> flare is due to, is it due to hepatotoxicity of the drug, one of the
> drugs, is it due to immune restoration. I am not saying that this a
> problem specifically for this drug, but it points out a generic
> problem in the setting of elevated bilirubins, which most of these
> patients may have.
>
> DR. GIORDANO: I would like to say one or two things and then perhaps
> Dr. Sulkowski can add a few comments.
>
> One is overall, the frequency of transaminase elevations in the
> program was no different from comparators, and our population was
> quite rich for hepatitis C co-infected patients, 12 to 20 percent.
>
> Your point is one which I would also ask Dr. Sulkowski to comment on
> with regard to how one might differentiate the two groups.
>
> DR. SULKOWSKI: Mark Sulkowski, Johns Hopkins University.
>
> I think you have raised a very good point and one that we have been
> keenly interested in, in the Johns Hopkins HIV cohort. That is the
> fact that in clinical trials, patients are generally selected, and
> that is not necessarily true just of atazanavir, but other PIs, as you
> point out.
>
> In looking at our clinical experience, in a large cohort of patients
> enriched with hepatitis C, as well as other liver problems, such as
> alcohol use, we have, in general, noticed higher rates of Grade 3/4
> liver injury.
>
> I would not anticipate based on the data obtained in these
> registrational trials that that experience would be any different with
> respect to atazanavir compared to the other PIs we have looked like in
> our experience.
>
> I think the second point you raise, which is how do you determine what
> is the etiology of event, remains a very vexing one, and one that is
> difficult in clinical practice to often attribute the etiology.
>
> Sometimes we find that there are other explanations, such as hepatitis
> A or B. Sometimes there are issues related to nucleoside analogs such
> a mitochondrial injury, and sometimes we can attribute it directly to
> the PI, but it is a difficult situation which requires clinical input.
>
> DR. GULICK: I have Dr. Sun, then Dr. Washburn, then Dr. Remmel.
>
> DR. SUN: I have two questions. The first relates to predictability of
> response particularly in treatment-experienced patients, because
> clinicians are using the available resistance tests more and more, and
> the question is, have you analyzed the response particularly in Study
> 043 versus genotype and phenotype, and how do you respond to the
> FDA\'s suggestion that a breakpoint might be in the 2- to 6-fold range
> for phenotypic fold change.
>
> Another way to ask the question, I guess is, how would you expect
> resistance data to be reported out in some of the commercial tests
> that are currently available? That was one question.
>
> DR. GULICK: Do you want to take one at a time?
>
> DR. SCHNITTMAN: The first question deals with predictors of response
> in the treatment-experienced patients. I would like to put up a slide
> 2J2 for you to see.
>
> \[Slide.\]
>
> DR. SCHNITTMAN: This is from the 043 study. We are looking here at
> Week 24 response rates by patients done in both overall and by
> different resistant subgroups. The resistant subgroups include PI
> sensitivity, whether or not there was one or more prior PIs, and
> whether or not there was nuc mutations present.
>
> As you can see in the 043 data, that atazanavir has an enhanced
> response rate when the PI phenotype is less than 2.5 times control
> EC50, also when there is one prior PI, it is enhanced, but it does not
> appear to be a significant effect on prior nuc mutations.
>
> Let\'s now look also to extend this, what we have done on 045 to try
> to understand this, as well, and this will be slide 2K2.
>
> \[Slide.\]
>
> DR. SCHNITTMAN: Here, we are looking at the same proportions in
> response, and we are looking again here at effect of PI and nuc
> mutations and PI sensitivity. Here, we have three arms just to remind
> you again.
>
> In green is the atazanavir/ritonavir arm. In blue is
> atazanavir/saquinavir, and in orange is lopinavir/ritonavir. As you
> can see on the left is the overall responses that are equivalent for
> atazanavir, ritonavir, and lopinavir/ritonavir.
>
> We see an enhancement of response by PI phenotype less than 2.5, by
> having fewer than 4 PI mutations, and really no significant effect
> with nuc mutations. You can also see that the curves are pretty much
> the same for the two boosted regimens.
>
> I do want to take this opportunity to have Rich Collono describe some
> of the genotypic changes that we see.
>
> DR. COLLONO: Good morning. Rich Collono, BMS Virology.
>
> What I would like to show you is just an analysis that we have done
> previously in analyzing 952 clinical isolates that were both
> susceptible and resistant to other PIs to try to understand if we can
> predict where atazanavir could be placed in terms of susceptibility.
>
> \[Slide.\]
>
> DR. COLLONO: In this slide again, just a very simple analogy which one
> would expect to see for most PIs, but again holds true also for
> atazanavir, that as you become resistant to more PIs, you start to
> lose susceptibility to atazanavir.
>
> So, if an isolate is resistant to one to two PIs regardless of the PI,
> the specific PI, we retain approximately 86 percent of those isolates
> will still maintain susceptibility to atazanavir. That goes down as
> you become more cross-resistant, such that when you are resistant to
> three or four PIs, you have approximately 25 percent of those isolates
> still being susceptible.
>
> Let\'s go to A16.
>
> \[Slide.l
>
> DR. COLLONO: We have done a genotypic analysis of those 950 or so
> isolates trying again to understand correlations of the presence of an
> amino acid substitution with susceptibility to atazanavir, and the
> mutations that Steve has spoken about, PI mutations, we are referring
> to 14 amino acids that we have identified that correlate strongly with
> loss of susceptibility to atazanavir.
>
> Now, we have gone through this analysis and found that no single amino
> acid substitution is predictive of lost susceptibility, nor do we find
> combinations of one or two that are susceptible, but if you get an
> accumulation of any five of those or more, that correlates fairly
> strongly with loss of susceptibility to atazanavir.
>
> That is demonstrated on A18, the final slide that I will show you, the
> correlation with number and loss of susceptibility.
>
> \[Slide.\]
>
> DR. COLLONO: In this bubble chart, the size of the bubble is
> reflective of how many data points are at that particular spot, so the
> bigger the bubble, the more data points there versus a small bubble.
>
> As you can see, along the bottom, on the y axis, we have number of Q
> mutations, number of these 14 Q mutations. In yellow, right along that
> axis, we have the mean EC50s that we obtained for that population of
> isolates, but as you can see, a gradual increase in resistance levels
> to atazanavir as you accumulate those mutations, and depending if you
> use a cutoff of 2.5 or 3.0, it looks like the breakpoint is
> approximately having 4 or so of those mutations present.
>
> DR. SCHNITTMAN: We see the importance of genotypic and phenotypic
> mutations now in allowing the clinician to make better decisions about
> which patients to treat and how to treat them is quite clear.
>
> As a final comment, I would like to ask Dr. D\'Aquila to make a
> comment on his impressions of this particularly as these are becoming
> more and more incorporated into the IAS and PHS treatment guidelines.
>
> Rich.
>
> DR. D\'AQUILA: I am Richard D\'Aquila from Vanderbilt.
>
> I think the standard of care now does include antiretroviral
> resistance testing whenever a regimen is failing. This has been
> promulgated by the IAS-USA guidelines from 2000, as well as the DHHS
> guidelines.
>
> There are new revisions to the IAS-USA guidelines that are in press
> that will further suggest additional situations where genotyping might
> be useful including screening before a first regimen in many cases.
>
> I think because this is standard of practice, we will be able to
> choose patients for whom atazanavir would be likely to succeed.
>
> I would expand my answer a little bit to address what Dr. Sun asked. I
> think some of the genotypic criteria can be suggested from these data,
> and I am sure as we have seen with other protease inhibitors, we will
> continue to evolve those criteria.
>
> I think the genotypic criteria will improve with increasing use
> starting with what we heard today. I think the phenotypic resistance
> cut point at present is probably going to be something around
> 2.5-fold, but again, I think further data would be helpful to see
> whether particularly if the drug is ever used with ritonavir boosting,
> that cut point might go up.
>
> DR. GULICK: Dr. Sun, you had another question I think.
>
> DR. SUN: The second question is related, which is in your analysis of
> the virologic failures from your various clinical trials, have you
> analyzed the pharmacokinetics in those patients especially given the
> fact that there is a fairly large variability in PK, particularly in
> HIV subjects, particularly around Cmin, and that might account for a
> substantial part of the failures that you can\'t attribute just to
> phenotypic analysis.
>
> DR. SCHNITTMAN: We have not selectively analyzed the pharmacokinetic
> parameters in those subjects who have failed. In fact, when one goes
> back and looks at these patients, many of the reasons for failure have
> to do with adherence compliance or other issues that really have no
> bearing on what the actual absorption of drug is.
>
> It is really a complex multifactorial process that leads to failure of
> patients in these trials, but it is certainly a good point.
>
> DR. GULICK: Dr. Washburn and then Dr. Remmel.
>
> DR. WASHBURN: My question is about the hyperbilirubinemia. If I am
> remembering correctly, I think trimethoprim sulfamethoxazole is
> occasionally capable of causing hyperbilirubinemia, and I was
> wondering if any effort has been made to look to see whether
> concomitant trimethoprim sulfamethoxazole use may have played into the
> degree of hyperbilirubinemia seen in these studies.
>
> DR. GIORDANO: As you can imagine, a very large percentage of the
> patients may have been and were taking trimethoprim sulfamethoxazole
> in our studies, but we don\'t have any data to indicate that they had
> higher bilirubin levels compared to those not taking it. We didn\'t
> conduct a specific analysis of that question.
>
> DR. GULICK: Dr. Remmel.
>
> DR. REMMEL: I wanted to follow up a little bit on concentration
> relationships which you have got a drug with an AUC variability of
> 20-fold at the 400 mg dose, and did you do any studies looking at
> concentration relationships with bilirubin levels other than you
> presented something with Cmin, but perhaps Cmax or the average
> steady-state concentration might be better tools in that sense.
>
> DR. GIORDANO: In addition to the work done with phenotyping, which is
> obviously a host factor, we have looked at AUC and Cmin and a variety
> of pharmacologic parameters, and in general, higher concentrations are
> associated with higher bilirubin levels, not just the Cmin, but also
> the AUC as you indicate.
>
> DR. REMMEL: My second question was about the metabolism, which is a
> little bit sketchy in the report that we received. There wasn\'t even,
> you know, structures, and that sort of thing. Could you fill us in on
> what are the metabolites, what are the percent of metabolite formed,
> and what are the enzymes responsible for the metabolism?
>
> DR. SCHNITTMAN: Dr. Grasela will come forward to review the
> metabolites and their properties. As he is coming up, I will just
> mention that the three major metabolites there, which are all under 20
> percent, none, by the way have anti-HIV activity, and Dr. Grasela will
> review for you what the specific CYP pathways are.
>
> DR. GRASELA: Can you show slide 13D1, please.
>
> \[Slide.\]
>
> DR. GRASELA: This is a complicated slide that I will walk you through.
> In the circulation, atazanavir, approximately 54 percent of the
> components in plasma are atazanavir. There have been 16 metabolites
> that have been identified in humans and in animal species studied, 8
> of those are in plasma.
>
> Of those in plasma, only 3 metabolites are greater than 3 percent of
> total plasma radioactivity, and those metabolites are shown on this
> slide.
>
> The metabolites are generated by a series of oxidative processes. The
> specific PE for 50 enzymes that may be associated with those have not
> been completely worked out. The first metabolite is BMS-419, the
> structure is shown here. It represents between 14 and 20 percent of
> plasma radioactivity. The Cmax value is 0.27 micromolar. It represents
> about 14 percent on an AUC basis.
>
> The second metabolite is 160, the structure is shown here. It is 12 to
> 18 percent of plasma radioactivity, Cmax is 0.54 micromolar with
> steady-state AUC ratio of metabolite to parent of about 29 percent.
>
> The third metabolite, this is a postulated structure for that
> metabolite, is about 14 percent of plasma radioactivity.
>
> As Dr. Schnittman had indicated, these are not active against HIV. 419
> has not been shown to inhibit any of p450 enzymes. 160 has not been
> shown to inhibit any of the p450 enzymes either. 2C19 has an IC50
> value of 4.9 micromolar, which is 10-fold that of the Cmax value.
>
> DR. REMMEL: There was also mention of a glucuronidation as a potential
> pathway, and is that catalyzed by UGT 1A1, or is the compound a
> substrate for UGT 1A1?
>
> DR. GRASELA: Atazanavir is not a substrate of UGT 1A1. There are some
> glucuronide components in the urine, and they have been associated
> with these metabolites.
>
> DR. GULICK: Anyone who hasn\'t had a chance to ask a question on the
> committee? Okay. I have a few and then I am going to go back to the
> people who would like to ask one more question.
>
> The first is virologic response on 034. While it is difficult to
> compare responses across studies, the percentages less than 50 really
> are quite different from other studies that we have seen, particularly
> for the efavirenz control arm.
>
> Could you comment on those results?
>
> DR. SCHNITTMAN: You are right, it is difficult to compare across
> studies. Clearly, for the less than 400 copies per ml, the response
> rates that we are seeing here were comparable to that seen in the
> DMP-06 study, which is in the efavirenz label.
>
> Regarding the less than 50, we have done extensive analysis looking at
> what are some of the possible contributing factors to the lower
> response rates that we are seeing there. These included several.
>
> One was study conduct. As I mentioned earlier, patients that switched
> nucleosides were counted as failures, which impacted significantly. In
> addition, we utilized a growing amount in many of the countries of 1.5
> assay for the amplicore versus the 1.0. For those who may be aware of
> it, the 1.5 is a much more sensitive assay, picking up non-clade B\'s,
> but even for clade B\'s, it raises the RNA approximately 0.3 log,
> which can lead to higher RNA values than people would have measured in
> previous studies.
>
> In addition, we utilized PPT tubes, since this was a multi-national
> study, that we wished to limit risk to people working with the
> specimens, but we used these tubes, so they didn\'t have to open them.
> They shipped these as gel separator tubes after they were spun down
> frozen in situ.
>
> What happens using the PPT tubes, there is sometimes greater release
> of RNA from the cellular elements that could raise the level of RNA.
>
> So, we can\'t give a specific contribution to each of these things,
> but we think together they may have contributed.
>
> Can we now show slide 2A2.
>
> \[Slide.\]
>
> DR. SCHNITTMAN: We did look at the question, though about the
> variability around the 50 copy per ml cutoff. As I know many of you
> are aware, this is a thing that has been looked at and examined by the
> ACTG and other investigators in terms of the variability around that
> 50 cut point.
>
> We looked at response rates on the TLVR analysis for 400, 200, and 50.
> As you see, the 400 and 200 response rates are very close to each
> other, meaning that most of the failures are occurring in the 200 to
> 50 range.
>
> The next slide.
>
> \[Slide.\]
>
> DR. SCHNITTMAN: On the histogram, this shows you quite specifically
> that most of the RNA values that are occurring here are between the 50
> and 200 range, but very importantly, notice that the pattern is the
> same for both atazanavir and efavirenz, so the effect is really not
> treatment specific.
>
> DR. GULICK: Thanks. Regarding Study 043 in experienced patients, can
> you review again what the entry criteria was? Specifically, it is
> failing one PI, but what was the definition of failure?
>
> DR. SCHNITTMAN: They need to have at least 12 weeks experience with a
> rebound of at least a log above their baseline to enter, as well. They
> could also have had \--we did not exclude people who also had a
> non-nuc failure, so they could have had PI plus a non-nuc.
>
> DR. GULICK: Did I correctly pick up that only 56 percent of the
> patients at baseline had any PI resistance on that study?
>
> DR. SCHNITTMAN: About half the subjects had nelfinavir resistance
> looked at alone.
>
> DR. GULICK: And that follows up to my next question. So, if people
> failed one PI, but they could have taken other PIs prior to that, is
> that right?
>
> DR. SCHNITTMAN: That is correct. They could have taken it and come off
> of it for intolerance or other reasons, and we had no way of
> controlling to what extent they took it and for what reasons, but
> theoretically, the intent of it was just to have a single failure of
> PI, but they could have taken more than one.
>
> DR. GULICK: Do you have a listing of what the protease inhibitors were
> that people took?
>
> DR. SCHNITTMAN: We will dig that up. This is the prior PI usage in
> 043.
>
> Nelfinavir was the one, by the way, of greatest usage, not
> surprisingly.
>
> DR. GULICK: That is what I was interested in, and the percentage on
> nelfinavir roughly?
>
> DR. SCHNITTMAN: It was probably three-quarters, I think it was close
> to three-quarters of the patients with indinavir then coming behind
> that.
>
> DR. GULICK: A last question about the 043 study. Maybe I missed it,
> but did we see the resistance patterns for people who failed in terms
> of nucleoside resistance?
>
> DR. SCHNITTMAN: What I showed there earlier was in terms of number of
> nuc mutations, what it looked like, and the presence or absence did
> not really predict whether those patients were going to be responders.
>
> DR. GULICK: Maybe I am not being clear. At failure, we heard a lot
> about what the PI resistance looked like, but unless I missed it, we
> didn\'t see what the nucleoside resistance was in people that
> experienced failure.
>
> DR. SCHNITTMAN: I am not sure if we have the distribution of the
> nucleoside resistance.
>
> DR. GULICK: I am interested because you would expect to see lots of
> 3TC resistance, but clearly, other studies have shown differences
> among arms in terms of the amount of 3TC resistance.
>
> DR. COLLONO: This looks at all the resistant isolates again, at
> atazanavir-resistant isolates, and what happened in terms of the nucs.
> I hope this is what you are asking.
>
> In the naive patients, again, for 007 and 041, you had 12 that failed
> on atazanavir, we had one that also failed on the nucs, which happened
> to be this case, BDDI-D14, and then 3 out of the 4, 6 out of the 7 in
> naives, and in the experienced populations, again, you can see the
> numbers.
>
> The interesting thing in the experienced populations that many of
> those failures actually started on baseline resistance to start with,
> so you can account for a number of the atazanavir resistance by the
> fact that they are already resistant.
>
> DR. GULICK: Thanks. My last question is for both the sponsor and the
> agency, and it\'s about lipodystrophy. We heard it stated that there
> is no effect of these lowered lipid levels on the occurrence of
> lipodystrophy, but I would like to ask what definition was used and
> how is that assessed by the investigators?
>
> DR. GIORDANO: I can start if you would like. Lipodystrophy was
> collected passively on case report forms without specific criteria for
> diagnosis. We did use the ACTG guidelines for how one may assess
> lipodystrophy as a tool which investigators could use, but there was
> no specific criteria by which a lipodystrophy diagnosis could be made.
>
> That said, we included broadly any term that might be reasonably
> thought to represent lipodystrophy, so fat redistribution, fat lumps,
> sometimes weight gain, weight loss, et cetera.
>
> DR. GULICK: It\'s 12:30. Three other people have asked to have brief
> questions, so we will allow those.
>
> Dr. Kumar, then Dr. Wood, and then Mr. Sharp.
>
> DR. KUMAR: I wanted to ask the effect of unconjugated bilirubinemia in
> pregnancy, specifically, whether you could postulate whether there
> could be any of the clinic \[?\] tests done for the unborn child?
>
> DR. GIORDANO: I am sorry. Could you say that one more time?
>
> DR. KUMAR: I am interested to see whether you have any information or
> whether you could help me understand the effect of the elevated
> unconjugated bilirubin in pregnancy, specifically, whether there may
> be a risk, a chronic risk to the child.
>
> DR. GIORDANO: There were patients who were pregnant on atazanavir
> trials, not very many pregnancies continued on atazanavir through
> delivery, however, based upon the biology of elevations in bilirubin
> observed on atazanavir, one would not expect that those levels of
> bilirubin would pose any difficulty for the fetus.
>
> I would like one of our consultants, Dr. Wolkoff, who is here, and who
> is a bilirubin expert, to give us some comment, as well.
>
> DR. WOLKOFF: Hi. I am Allan Wolkoff from the Albert Einstein College
> of Medicine.
>
> That is a good question, but the levels of hyperbilirubinemia in the
> patients treated with the drug were rather modest, and it\'s all
> unconjugated. Other studies looking at transfer of bilirubin across
> the placenta have shown that it transfers from baby to mother, but
> really minimally the other way.
>
> There are also case reports, for example, a case of Crigler-Najjar
> syndrome type 2, which for our purposes we could think of as a bad
> Gilbert syndrome, because there is a greater reduction in UGT 1A1
> activity.
>
> In that woman who was pregnant, she ran bilirubins of 8. She had
> normal delivery of child. That has been the experience with other
> patients. There is no problem with delivery of normal children in
> patients with Gilbert\'s syndrome, as well.
>
> DR. GULICK: Dr. Wood.
>
> DR. WOOD: This data was not presented by the FDA or the sponsor, but
> it was in the sponsor\'s brochure, specifically Table 8.3, that
> summarizes the adverse events in the pediatric population.
>
> One of the things that I noticed is that approximately 48 percent of
> the AEs have to do with cardiac issues in terms of either bradycardia,
> prolonged QT was actually seen in two patients. That is on page 157.
>
> I was wondering whether or not there was any correlation between these
> adverse cardiac events in terms of analysis of pharmacokinetic levels.
> I know that a dose has not yet been identified, but this is
> approximately 48 percent of the pediatric patients having adverse
> events related to EKG abnormalities. That is much higher than what has
> been reported in the adult studies.
>
> DR. SCHNITTMAN: The PACTG has a fairly unique approach in adverse
> events, and by the way, these adverse events were collected even for a
> first-degree heart block was considered an adverse event as an
> isolated thing to count even though it was associated with no
> symptoms.
>
> Overall, though, my understanding is that that was not an issue. We do
> have Dr. Rick Rutstein, who is the PI of that study, who can share
> with you his impression about the safety evaluation particularly on
> ECGs with the 1028 study.
>
> DR. RUTSTEIN: Rick Rutstein from Children\'s Hospital, Philadelphia.
>
> We used a very conservative rating of PR intervals and QTc based on
> age-adjusted limits, so that if you are 2 percent above, if you fell
> in the normal 2 percent elevated PR range for normals, you are
> considered an abnormal and an adverse event, so we have a high rate of
> first-degree PR elevations. None of them was significant. Two patients
> came off based on PR elevations before we had written a protocol
> amendment to specifically look at that. We had started the protocol
> before the initial EKG abnormalities had been available from the adult
> studies.
>
> Since we have done that, no patient has come off based on PR changes,
> no patient has had any symptomatic changes, and we have done holter
> monitors and everybody has had a mildly elevated PR interval while on
> study, and they have been normal, as well.
>
> DR. SCHNITTMAN: Thank you, Dr. Rutstein. We have been very aggressive
> in doing a very similar ECG type program as we did in adults.
>
> DR. WOOD: That is a very helpful clarification, thank you. I had a
> second question, and that was in terms of the drug interactions and
> recommendations. Particularly given the fact that the patients who had
> the most intense levels of elevated bilirubin also tended to be
> co-infected with hepatitis A, B, or C, are there any plans to do any
> studies examining atazanavir in patients who are taking ribavirin and
> PEG interferon, or have you all done any studies?
>
> DR. SCHNITTMAN: Ribavirin is definitely on the plans. It was my
> impression, though, that overall, bilirubin elevations were not
> significantly different in co-infected patients.
>
> DR. GULICK: Mr. Sharp.
>
> MR. SHARP: I am wondering about\--going back to the absorption issue
> again\--does high fat food have more of an effect on absorption than
> just a regular diet, and if so, is the FDA planning to put a special
> warning in the labeling? And I have another question.
>
> DR. SCHNITTMAN: Food of all types, both light meal and high fat meal,
> enhances the absorption and the concentrations of atazanavir, as well
> as diminishes the coefficient of variation, so that is why we
> recommend food in a general sense, and there is no restriction.
>
> MR. SHARP: So, there is no difference.
>
> DR. SCHNITTMAN: In single-dose studies, it looked like light meal was
> a little better than high fat meal, and multi-dose, vice versa, but
> there is no substantial difference.
>
> MR. SHARP: We saw the data on the contraceptives, but I wondering, it
> wasn\'t really significant, but it is an issue, and I wonder if there
> is going to be a specific warning about contraception
> coadministration.
>
> DR. BIRNKRANT: We can\'t comment on labeling at this point in time, as
> we haven\'t made our regulatory decision yet, but labeling in general
> reflects data submitted in an application.
>
> DR. GULICK: Last-minute burning information-based questions are
> welcome.
>
> Dr. Illingworth.
>
> DR. ILLINGWORTH: Just one question concerning the absorption of the
> drug. Is it dependent on fat absorption to be absorbed? It is lipid
> soluble? Is it absorbing the caller \[?\] microns How is it absorbed?
>
> DR. GRASELA: We don\'t have specific data regarding transport of the
> drug using caller microns to go through. We presume it is passive
> diffusion. We do have data at higher doses in which the exposure does
> not increase in proportion with the dose, suggesting is it
> dissolution-rate limited in its absorption.
>
> DR. ILLINGWORTH: If you do a postprandial lipemia study given the
> drug, is it in caller microns or not?
>
> DR. GRASELA: We don\'t have data specifically about that.
>
> DR. GULICK: Dr. Schnittman, you have the PI data?
>
> DR. SCHNITTMAN: The question that you asked before, we are putting up
> the slide.
>
> \[Slide.\]
>
> DR. SCHNITTMAN: This is from the 034 study in looking at virologic
> failures, but I want to focus on the bottom portion of the slide,
> which is the genotype. Number one, you see the I50L, which is the PI
> marker there. We have the K103N, not surprisingly greater on
> efavirenz, but we also have the distribution of nucleoside didovidine
> \[ph\] mutations, as well as the 184, and as you can see, they are
> comparable for both atazanavir and efavirenz.
>
> DR. GULICK: Does that mean that about half of patients who are able to
> be genotyped had no mutations at all, they failed with wild type?
>
> DR. SCHNITTMAN: That\'s correct.
>
> DR. GULICK: Dr. Fish, you have the honor of having the last question.
>
> DR. FISH: My question relates to our cover mentions that the
> atazanavir is available in the powder formulation, so I presume that
> is for the pediatrics.
>
> Is there data, use of this formulation in adults, for example, those
> that might have G-tubes, swallowing difficulties, et cetera?
>
> DR. SCHNITTMAN: No, at this point, there isn\'t. An important issue is
> that we have not demonstrated bioequivalence of that formulation in
> adults. That work is going on right now.
>
> DR. GULICK: Let me go ahead and stop us there. We will have time for
> additional questions within the discussion period, but that\'s a good
> start. It\'s 20 of 1:00, so let\'s break for lunch and we will resume
> at 1:30.
>
> \[Whereupon, at 12:40 p.m., the proceedings were recessed, to be
> resumed at 1:30 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> \[1:30 p.m.\]
>
> DR. GULICK: One announcement. If people could remember about the
> surveys, the conflict of interest surveys, please fill them out,
> complete them, and there is a box at the registration table where you
> can leave them. That would be appreciated.
>
> There was one issue in the question and answer period that we wanted
> to follow up on, which was the incidence of LFT abnormalities.
>
> DR. SIGAL: Yes. Thank you. I just want to make sure people leave with
> a clear impression of the data on the LFT abnormalities because the
> discussion focused on one study 007, and we want to make sure in the
> totality of the whole clinical experience, you have what we have in
> terms of the impression of the data.
>
> Michael Giordano.
>
> DR. GIORDANO: First, I would like to show a slide among co-infected
> patients to break down by study the frequency of Grade 3 elevations in
> transaminases.
>
> \[Slide.\]
>
> DR. GIORDANO: You can see that although more frequently elevated
> transaminases were observed among those who are hepatically at risk,
> those with co-infection, with every comparison to atazanavir, the
> frequency of those elevations was either equivalent or slightly less.
>
> I showed the composite slide, which is the overall frequency, so 10
> percent of patients co-infected with hep B and C, who received
> atazanavir, had a Grade 3-4 elevation in hepatic transaminases, 11
> percent on the comparator. When they were not infected with hep B or
> C, the frequency was 3 percent for atazanavir for a roughly 3-fold
> ratio, whereas, the ratio on comparators was 11 to 1.
>
> Also, with regard to the frequency of transaminase elevations across
> the entire program, when we look at Grade 3-4 elevations in particular
> for the Phase III programs, the frequency is comparable, and I think I
> showed you those numbers for the 034, the 043, and the 045 studies.
>
> DR. GULICK: Could we have the lights down, so that we could read the
> slide. Sorry, Michael.
>
> DR. GIORDANO: We can spend a little bit more time on this slide if you
> want. If you look at the top line, which is hepatitis B co-infection,
> it compares the frequency in co-infected patients for atazanavir
> versus comparators, and you will see the general trend is that the
> frequency is less. For atazanavir versus comparator, which is then
> reflected in the overall frequency of 3-4 elevations, on the bottom
> graph, and that is the slide I showed in the core.
>
> So, 10 percent of hep B co-infected patients, hep B/hep C co-infected
> patients experience a Grade 3-4, whereas, 11 percent of comparators,
> so the hepatic safety with regard to co-infected patients is
> comparable to that seen in comparators. When you build up to that
> number from the individual studies, you see the same trend.
>
> With regard to liver function abnormalities of all grades, I think, as
> indicated in the presentation, when you look at all grades in the
> Phase II studies, 007 and 008 study, there was an increased frequency
> of low-grade LFT elevations, ALT, AST in 007 and 008, that was not
> observed in our Phase III program, neither in 034 or 043 or 045
> studies.
>
> So, I wanted to just make those points.
>
> DR. GULICK: Thanks very much.
>
> We are now going to begin the open public hearing portion of the
> meeting, and we have had one person sign up to speak at the meeting.
> That is Rob Camp from the Treatment Action Group.
>
> Rob, you can use the podium up at the front if you like.
>
> **Public Hearing**
>
> MR. CAMP: Thank you very much.
>
> I would like to thank the FDA for allowing me to speak here today, and
> I would like to congratulate BMS on the amount of data that they have
> presented and the new data that they have presented today. It sort of
> makes my position paper that I finished yesterday at 2:30 really not
> very completely useful anymore because there is a lot of new data
> since yesterday at 2:30, but anyway, there are still a few points that
> I would like to make.
>
> A number of community groups from around the country have signed on to
> the paper, and they would like me to say a few things.
>
> First of all, we are happy, yet concerned, that the accelerated
> approval has been turned into traditional approval, partially because
> we feel that many of the studies, many of the questions that haven\'t
> been answered may not have to be answered, and the sponsor can in one
> way or another not get around to them.
>
> We hope that the FDA and BMS work together to answer the questions
> that a lot of people still have. We are a little concerned that the
> advertising restrictions that accelerated approval would have would
> not be lifted under traditional approval, and we really must stress
> that pharmacovigilance be an important part of the follow-up to this
> drug.
>
> In any case, I was very interested this morning, someone from the
> panel mentioned that we can possibly eliminate some people who tend to
> get hyperbilirubinemia by genotyping, and if that is really the case,
> we can possibly, by eliminating those people, give more atazanavir to
> people, up the dose, and make this from a moderately potent PI into a
> very potent PI. That might be something worth looking into by
> eliminating people who would automatically tend toward
> hyperbilirubinemia, people who already have Gilbert\'s syndrome, for
> example.
>
> The studies that still need to be done, I think all of the studies
> have already been mentioned this morning by the panel, and I would
> just like to underline them, PK studies with methadone, H2 blockers,
> rifampin, statins, vibrates, ribavirin, efavirenz, nevirapine,
> tenofovir\--I heard tenofovir was done, that\'s
> fabulous\--fosamprenavir, saquinavir, both formulations, and pegylated
> interferon. Also, Jules just reminded me that we should have toxicity
> and safety also on some of these things especially with the hepatitis
> C drugs.
>
> Long-term safety studies were also highlighted by the panel this
> morning and they are very significant and very important that they
> continue.
>
> It was disappointing to hear that the lipid changes don\'t also make a
> better lipodystrophy profile. That really is disappointing. One thing
> that we would like to possibly see in the labeling is a clear
> definition of lipid profile versus lipodystrophy. Having a good lipid
> profile doesn\'t mean you won\'t get lipodystrophy. I think that is
> very important, especially for users of this drug.
>
> I think clinical management, of course, as with all drugs, will be
> very important and if we can somehow really make this genotyping of
> Gilbert\'s syndrome work, then the worries about the masking of
> hyperbilirubinemia won\'t be such an issue; in other words, if you go
> to your doctor and the high bilirubins are automatically assigned to
> atazanavir but maybe it is from something else that won\'t be seen
> because automatically it will be assigned to atazanavir. I would just
> like to underline the importance to not forget that.
>
> So the etiology of bilirubins in the liver is still very important,
> especially probably with drugs like nevirapine that haven\'t been
> looked at together yet.
>
> I\'m curious, and you can answer this afterwards, but one question I
> had from this morning was the ddI used in the trials; was it the
> buffered ddI or was it another ddI and did it change according to
> trial. That might be interesting also in looking at the different
> results of some of the trials.
>
> What are the effects on lipids of ritonavir-boosted atazanavir? I
> think that has to be clearly defined and clearly spelled out in the
> label. I think that the FDA has to really consider, and the advisory
> panel has to really consider, what they are going to put on the label
> as far as if it is only atazanavir without ritonavir, then, what type
> of patient is it, and then with ritonavir, it is a different type of
> patient. I think those things have to be clearly defined before
> approval.
>
> The adherence and compliance issue is a little bit worrying, not in
> the sense that once a day isn\'t easy, but in the sense that if
> someone does miss one day, that\'s a big window that is open without
> drug for 24 hours, that might be considered serious.
>
> Little useful data has been generated so far for pediatrics, and we
> really hope that pediatric data is generated quickly.
>
> So, that is more or less for the clinical part. I would like to read a
> short note from the Fair Pricing Coalition, as well.
>
> They say that in this time of severe funding shortfalls at the state
> and federal levels, negotiations between BMS specifically and the
> Coalition of State ADAP Directors has stalled.
>
> I am here to express profound disappointment at BMS\'s failure to
> negotiate serious price discounts and freezes in good faith with state
> and territorial ADAP Directors.
>
> BMS\'s inaction will lead to the irreversible dismantling of ADAPs by
> forcing the programs to lower their financial eligibility, create
> barriers to needed medications through prior authorization procedures,
> and by the removal of drugs from ADAP formularies.
>
> With people living longer and the continuing new infection rates,
> publicly funded programs are stretched to the breaking point. Under
> the current economic climate, we are clearly in a new era that demands
> a complete rethinking about the pricing of HIV drugs.
>
> There has been nothing extraordinary about the cost of clinical trials
> required to bring these new drugs to market. Indeed, thanks to
> accelerated approval, development costs may be lower for many HIV
> drugs than for other drugs, while the duration of their use by
> patients can be greatly extended.
>
> Thus, the price of atazanavir should be price and cost-neutral for
> ADAP, Medicaid, and private insurers.
>
> Thank you very much.
>
> DR. GULICK: Thanks. Could the sponsor clarify the one question about
> the ddI formulation that was used on the studies?
>
> DR. SCHNITTMAN: Yes, ddI was used in 007, and that was the old
> buffered formulation. As we move to the experienced patient trials in
> which people selected the different nucleosides, at that point, EC had
> been approved and is being used in the studies.
>
> DR. GULICK: Thank you.
>
> That was the only person who signed up for the public part of the
> hearing. Is there anyone who didn\'t sign up who would like to make a
> statement at this point? Jules Levin.
>
> MR. LEVIN: I just have something real brief to say. First of all, I
> thought this was a good hearing. I have been to every hearing since I
> started this work about eight years ago, every HIV drug hearing, and I
> thought that for the first time, the FDA did what I thought was a good
> job in my experience, and I also think that the company did a very
> good job in addressing a lot of the concerns.
>
> The question was asked to me by some people, how come there was a
> public hearing today, is it because of all the issues, bilirubin, and
> so forth, or is it because the community met with the FDA and asked
> them to hold public hearings on drugs, and I don\'t know the answer to
> that.
>
> So, I thought that with short-term data, which is 48 weeks, 100 weeks
> data, is essentially short term, that the drug looks pretty good. I
> support the issues that have been brought up, bilirubin, and so forth,
> look pretty good.
>
> So, I personally really support approval. I don\'t think you need me
> to say that because I think it\'s going to get approved. But I think
> the community would support this, too, so I think I can speak for the
> community in saying that, as well.
>
> But what I would like to say is that I would like a longer term
> follow-up than 48 weeks and 72 weeks with regards to the concerns that
> we do have with regards to bilirubin and ALT elevations.
>
> I would like to see longer term safety and toxicity follow-up from the
> company, as well as from the government to make sure that this gets
> done.
>
> I still have some lingering questions about the LFT stuff. I
> understand that there was just some presentation, some data shown
> about how it doesn\'t appear as though there is an issue, but I would
> like this to be continued to be followed particularly for people that
> have co-infection with HCV and HIV.
>
> So, that is pretty much what I have to say.
>
> DR. GULICK: Thank you.
>
> Anyone else who didn\'t sign up who would like to make a public
> statement?
>
> Okay. We will close the open public part of the hearing and go to the
> Charge to the Committee.
>
> Dr. Birnkrant.
>
> **Charge to the Committee/Questions for Discussion**
>
> DR. BIRNKRANT: Thank you.
>
> As we heard this morning, HIV\--and we recognize this, the agency
> recognizes this\--is more of a chronic disease at this point, and we
> are looking at it somewhat differently than we looked at it many years
> ago given that not only is benefit important as we review these
> clinical trials, but risk becomes even more important than it has in
> the past.
>
> So, as you deliberate today, we will ask you to take into account the
> evaluation of the signals that were seen in the preclinical and the
> early clinical database.
>
> So, with regard to the first question, the safety and efficacy of
> atazanavir, we would also ask you to comment on the hyperbilirubinemia
> that was seen and the data that were presented, as well as the effect
> of atazanavir on conduction, namely, PR and QT intervals.
>
> With that, we would also like the committee to comment on the use of
> this drug in the populations that were studied and presented today,
> keeping in mind that the agency has not reviewed the efficacy data
> from 045.
>
> If you feel as though 045 is crucial to your answer, then, clearly,
> include that and explain that as you respond to the various questions,
> but again I would like to emphasize we have not reviewed that data to
> date.
>
> In addition, if you determine that this application should be
> approved, then, there are a series of questions that follow, namely,
> issues related to monitoring for LFTs, EKGs, should genotyping be
> done, et cetera.
>
> So, as you answer that question, keep in mind those issues.
>
> Please also keep in mind when you answer the questions the effect
> seen, as I said, in the different populations, and how the resistance
> data plays into your discussion.
>
> We also have a question related to additional studies that would be
> important for you to see and have the applicant conduct.
>
> With that, I would like to move to the discussion of the questions if
> that is okay with the Chair.
>
> DR. GULICK: Great.
>
> Question No. 1 to committee: Do the efficacy and safety of atazanavir
> support its approval for the treatment of HIV infection? As part of
> the discussion, please comment on: treatment effects in naive and
> experienced patients, hyperbilirubinemia observed in clinical trials,
> and the effects of atazanavir on PR and QT intervals.
>
> Let\'s take these one at a time. Let\'s start off with a discussion of
> the treatment effects seen in naive patients.
>
> Who would like to begin? Dr. Mathews.
>
> DR. MATHEWS: I could be very brief on that because that is the most
> clear-cut evidence, I think, that it clearly is active and it was
> compared to a very challenging comparator arm with
> efavirenz-containing regimen, so I feel very comfortable with that
> answer.
>
> DR. GULICK: Dr. Remmel.
>
> DR. REMMEL: At the 400 mg dose, clearly, there was good effect with
> atazanavir, but I am concerned about the pharmacokinetic variability
> of the drug with the 20-fold range and Cmins, and percent coefficient
> of variation around the variability.
>
> While the sponsor probably wouldn\'t want to encourage concentration
> monitoring, this is a major issue in terms of many of the protease
> inhibitors in particular, especially because they are all CYP3A
> substrates, and I think that we could see some benefit if that was to
> be done, but I would like to see some sort of indication in terms of
> how many patients who fell at the low end for the Cmins or area under
> the curve were actually failing and what is that component in terms of
> the efficacy of this drug.
>
> So, that is my only major comment there. In terms of the experienced
> patients\--
>
> DR. GULICK: Let me hold you on that, and we will stick with naive
> patients for now. Then, we will come back to experienced patients.
>
> Any other comments on the naive patient group or the data that we saw
> for naives?
>
> DR. ENGLUND: I think the data they presented was quite convincing and
> that for the real world where we are working, I particularly working
> with adolescents where pill burden is absolutely, for my patients, the
> number one concern that they have, of course, it is our job to work on
> safety, but pill burden is incredibly important, the number of doses a
> day, and this drug offers equivalency in terms of many of the other
> parameters.
>
> I am not worried about the effects of hyperbilirubinemia that have
> been presented so far although I think we should discuss this further
> later on, but in terms of the treatment effects seen in naive
> individuals, I think, yes, it is important and I think there is
> clearly a niche and that they have presented some good data to
> convince me that it would be a good thing.
>
> DR. GULICK: Let me just say to the committee that at the end of the
> discussion of the first question, we will take a formal vote, so
> don\'t feel compelled to ring in if you know how you are going to vote
> already. It is not necessary to do that, but thanks.
>
> Other comments on naive?
>
> Okay. Let\'s move to\--half a comment from Dr. Fletcher.
>
> DR. FLETCHER: Actually, I think these are probably just more some
> clarifying questions. In terms of the dosage forms that are being
> requested for approval, is the 100, 150, and 200 mg capsules or is it
> just 200 mg capsules, is it the powder, not the powder? I can\'t
> really tell from the information we have what the approval is actually
> being requested for, dosage form-wise.
>
> DR. MARCUS: It\'s for the 100 mg, 150 mg, and 200 mg capsules.
>
> DR. FLETCHER: The second question I have, it comes back to something
> earlier this morning, and that is the food effect on absorption. I am
> wondering, from the sponsor, I would just like to see a picture of
> what a recommended meal looks like\--well, okay, a description of what
> a recommended meal looks like, how many calories, fat, if it could be
> translated into what does someone really have to eat in order to get
> the optimal absorption for the drug.
>
> DR. GRASELA: In our single-dose food effect study, we look at both a
> \"light\" meal and a high fat meal. A light meal is approximately 350
> calories and approximately 25 percent fat, I believe. The high fat
> meal is approximately 950 calories and about 50 to 60 percent fat.
>
> DR. FLETCHER: In terms of an effect on bioavailability, you see no
> difference between the light meal and the high meal in terms of
> atazanavir concentrations?
>
> DR. GRASELA: In the single-dose study, the bioavailability was
> actually increased more with the light meal than the high fat meal.
> The variability was reduced in both meal types. When we did sort of a
> composite analysis following multiple dose administration, and it was
> confounded by the administration of saquinavir unfortunately, the high
> fat meal, light meal, were equivalent.
>
> So, therefore, in our view, it\'s a wash, and in the clinical trials,
> it was given without regard to the meal type.
>
> DR. FLETCHER: And that was answering my question, so in a study like
> 034, what was the recommendation, then, on the meal?
>
> DR. GRASELA: My understanding is that it was to be taken with a meal,
> but it was not specified.
>
> DR. GULICK: Mr. Sharp.
>
> MR. SHARP: As a treatment-experienced patient, I am concerned about
> approval of this drug in experienced folks. I am a little bit worried
> that\--
>
> DR. GULICK: Can I stop you just for a second? I want to stick with
> naive until we are done, and then we will pick up on experienced, I
> promise. In fact, maybe we will do it right now. Sorry. Go ahead.
>
> MR. SHARP: So, continuing on. I am concerned that more studies need to
> be done looking at experienced folks, and some of those studies would
> be just looking at the combinations. We are on so many drugs. The
> pharmacopeia is just huge and people like me who have been on all the
> drugs and are continuing to take prophylaxis therapies and everything
> else that goes along, I am really glad that people could get effect
> from the drug with one protease inhibitor use. I think that is really
> important to distinguish.
>
> But there are other studies that I think need to be carried out, and I
> am really concerned that if the drug gets full approval, as Rob said
> earlier, I am concerned that some of the follow-up studies will not be
> done. So, I just want to make that point.
>
> DR. GULICK: Dr. Fish.
>
> DR. FISH: An area of concern, I certainly think the data looks good
> for both naive and with the concerns as we will get to in terms of the
> experienced patient population, but for either group, as we move
> towards treatment simplification, and we are talking about once daily
> therapy in that push, already there are clinicians who sacrifice I
> think the didanosine and empty stomach piece in the interest of doing
> it once a day, and we will not be able to do that with this particular
> combination.
>
> So, special attention to use with didanosine in particular with
> atazanavir could cause potentially that treatment regimen to fail.
>
> In terms of the patient-experienced population, I think the take-home
> message for me is that it has a niche, but I am going to use
> resistance testing to guide me, and I very much appreciated the
> genotypic information that was offered today in terms of helping me to
> guide that treatment decision.
>
> DR. GULICK: Other comments on the efficacy and the experienced
> population? Dr. Mathews.
>
> DR. MATHEWS: There is a real dilemma, I think, facing the committee
> and the agency because if the agency has not reviewed the 16-week data
> on the PK-boosted regimen, and yet the data that was reviewed in
> experienced patients faces the treater with the decision of using a
> regimen which may have inferior virologic outcomes, but have a lot of
> advantages in terms of simplicity, tolerability, and so on.
>
> So, it is not as clear to just say it\'s efficacious in the case of
> highly treatment-experienced patients based on the data that is
> reviewed and reviewable at this point. You could say that it\'s
> superior to placebo based on the comparisons that were done in that
> trial, but inferior to a regimen containing Kaletra.
>
> What hasn\'t been talked about is what are the long-term consequences
> of using an unboosted regimen without atazanavir in terms of further
> accrual of resistance mutations and longer term significant virologic
> and then immunologic failure.
>
> So, I think we need to discuss that more.
>
> DR. GULICK: Dr. Fletcher.
>
> DR. FLETCHER: This would be a question I think probably more to the
> agency. If the committee were to recommend approval for
> treatment-experienced patients, would the agency consider, in the
> dosing recommendations, the use of the boosted atazanavir/ritonavir
> dose, so the 300/100 mg regimen, or does the dosing really have to be
> constrained to the 400 mg, once daily, dose?
>
> DR. BIRNKRANT: As of today, it would be restricted to the 400 mg dose.
> The PDUFA date, that is, the date by which a regulatory decision has
> to be made by law, is the 20th of June, so between now and then, there
> isn\'t that much time to review that additional data that came in
> late.
>
> DR. GULICK: Just to point out, it puts us, as a committee, in a little
> bit of an awkward position because we are seeing evidence of activity,
> but it is not as good as a comparator arm, at the same time, we saw
> preliminary activity which hasn\'t been reviewed by the agency, which
> seemed to suggest similar virologic effects to a Kaletra-based arm.
>
> In addition, the pharmacokinetics to support better drug levels and a
> better Cmin, when boosted with ritonavir, so I think I am seeing some
> shaking heads, that we are feeling a bit conflicted about this point.
>
> DR. BIRNKRANT: Well, it is also a dilemma for us, as well, to see
> snippets of data that look potentially promising, but given that it
> was submitted so late, it is difficult to review all of that data
> within such a short period of time.
>
> Given that, as you answer the question for the treatment-experienced
> population, please let us know how important to the entire committee,
> the data from 045 would be in order to put wording in labeling
> pointing to use of this drug in the treatment-experienced population.
>
> DR. GULICK: So, let\'s address that specific point from the committee.
> So, here is a study, we have seen the data, it has not been reviewed
> by the agency, and how important do we feel that that data is to
> include for the treatment-experienced population.
>
> Dr. Fletcher.
>
> DR. FLETCHER: Well, in my mind, it is the only data that really make
> the case from a clinical trial for using the drug in the
> treatment-experienced patient. If you have to look at just the 400,
> once daily, regimen versus Kaletra, it wasn\'t as good as other
> available agents.
>
> So, I think in terms of making the case for a role, the drug, safety,
> efficacy, and treatment-experienced, to me, 045 is essential.
>
> DR. GULICK: Other thoughts on that?
>
> Dr. Englund.
>
> DR. ENGLUND: I agree. I think it is important, but I also can sense at
> least from the people I work with, and I know the FDA appreciates
> this, too, is the sense of urgency. We have patients that are running
> out of alternatives and it is of concern. We don\'t want to jump the
> gun too early, but we would have a problem to recommend it for naive
> and think that it\'s not going to be used in another way.
>
> DR. GULICK: Other opinions about this? Dr. Mathews.
>
> DR. MATHEWS: Let me say that I think we would not be well advised to
> take the extreme position of saying that because it\'s inferior to a
> Kaletra-containing regimen, it shouldn\'t be approved for
> treatment-experienced patients.
>
> I think what should happen is that the data should be presented in the
> label to show that it did not perform as well as Kaletra, and the
> precise clinical situation where it might be used is going to involve
> individualization of therapy.
>
> I mean I have lots of patients who are having a lot of trouble taking
> Kaletra or other PI-based regimens that are very anxious to get to a
> simplified PI regimen. On the other hand, I am going to have to tell
> them, you know, you are barely controlled right now, and the small
> difference in efficacy between what you are on now and this more
> simplified regimen may cost you long-term virologic control, we don\'t
> know.
>
> But I think those are the discussions that are going to have to take
> place in the office.
>
> DR. GULICK: I would like to make a couple of points on this myself. We
> have been talking about experienced patients as if they were one
> group, and that is clearly not correct, and I think that that clouds
> our thinking when it comes to the optimal treatment of experienced
> patients.
>
> 043 was a study, yes, of experienced patients, but only 56 percent
> actually showed PI resistance upon entry into that study, and they
> were limited to have failed one protease inhibitor by history. So,
> that is what you would characterize really as an early failure group,
> and I think the 045 study looks at a more advanced group with more PI
> experience.
>
> Clearly, that is the biggest need in the clinic right now, is not so
> much the early failure people where you may have several options to
> choose from, but the later stages where you want some good options,
> and Chris\' important point that this is of benefit in a salvage
> regimen. They are the same principles that apply in a naive regimen -
> low pill count once a day actually also apply in the salvage setting,
> as well.
>
> The other point I wanted to make is that 043 really is not a study
> that we would do today because we would select, in a person who has
> failed one regimen, we would select the next regimen based on their
> resistance testing, which was not done in this study. It was done
> retrospectively to go back and look at where they were.
>
> So, really, it is difficult to apply that study to the optimal
> treatment of the experienced patient today. Current guidelines, as was
> reviewed earlier by Rich D\'Aquila and others say that you should do
> resistance testing in that setting. Pick the optimal regimen based on
> the results of resistance testing.
>
> Again, not to criticize that study, it was probably designed before
> that was true, but it needs some interpretation in terms of how you
> would do it.
>
> DR. BIRNKRANT: But if resistance testing were incorporated into the
> use of this drug, then, how would you feel using it then in a
> treatment-experienced population?
>
> DR. GULICK: You are asking me directly or shall we ask the committee?
> I will answer. How about that?
>
> I would say that based on the data that we have seen today, that in an
> experienced patient, you want to optimize their drug levels and that
> combining with low-dose ritonavir would be the way to go, analogous to
> all of the other approved protease inhibitors we have with the
> exception of nelfinavir. That is one man\'s opinion.
>
> DR. KOWEY: First of all, I am a very naive person when it comes to all
> this, so take this with a grain of salt, but looking at this from the
> point of view of the safety side, and you emphasized that earlier, I
> haven\'t seen any data in the so-called experienced patients that make
> me believe that they are at any more risk than someone who is
> relatively treatment naive.
>
> So, having said that, and looking at the numbers, there are
> responders. There clearly are people who are responders even though
> the numbers are not as robust as you would like them to be. So, I
> guess I am having a somewhat difficult time understanding why you
> wouldn\'t want, as long as the data come in looking the way that you
> think that they should look, and after a thorough analysis, why
> wouldn\'t you want this combination available for people who haven\'t
> responded to other therapies as long as there is not extra safety
> concerns, which as I said, so far, looking at the data very
> superficially, we haven\'t really seen.
>
> You have got gain, and you don\'t have too much of a wash, why not?
>
> DR. BIRNKRANT: We have only reviewed 16 weeks of data. We haven\'t
> reviewed the 24-week data for safety yet. So, if we think that would
> be important. We don\'t want to rely on the 16-week data for use in
> this population just based on the 16 weeks. We want to see the 24-week
> data to make a decision.
>
> DR. GULICK: Dr. Remmel and then Dr. Tephly.
>
> DR. REMMEL: There is, of course, another class of experienced patients
> to consider, and those would be patients who already have disturbed
> lipid profiles and who you want to switch to lower their cholesterol
> or lower their triglycerides especially, and that may be in a slightly
> different class than what we are talking about in terms of failure.
> That clearly would be advantageous for many patients in addition to
> simplifying their regimen.
>
> So, that might be a little bit of a separate category that one might
> consider.
>
> DR. GULICK: Dr. Tephly.
>
> DR. TEPHLY: Exactly. I was going to make exactly the same point, that
> we can\'t forget the advantage of the lipid-lowering quality of this
> particular agent.
>
> DR. GULICK: Other comments on the experienced? Dr. Kumar.
>
> DR. KUMAR: I want to echo some of the comments that Dr. Mathews had
> said. In the treatment-naive patient, I think it is an excellent drug,
> it\'s a drug that I feel very, very comfortable with, but in the
> treatment-experienced patient, using it by itself, with unboosted
> dose, my concern is that failure begets failure, and in that setting,
> despite its convenience, the dosing, that it may lead to the
> development of more and more resistant mutants, so that is really what
> I am concerned about, using it as a single dose of 400 mg without
> boosting.
>
> DR. GULICK: Dr. Fletcher.
>
> DR. FLETCHER: Again, another question of the agency. It\'s this issue
> again about what if there was a recommendation for approval, what
> could go on the label in the pharmacology section. Could information
> on boosting be put into that section, or again, would the label really
> be constrained to information on the 400 mg dose?
>
> DR. BIRNKRANT: There is a possibility that perhaps some PK data could
> be placed into the label in the appropriate sections.
>
> DR. GULICK: Let\'s consider hyperbilirubinemia observed in the
> clinical trials so far. Comments on that? Dr. Tephly.
>
> DR. TEPHLY: This particular drug is not the first one, I guess, to
> have demonstrated hyperbilirubinemia, so there is a precedent here
> already. I don\'t believe there has been a single case of
> hyperbilirubinemia reported in an adult where there has been any
> toxicity due to this particular substance other than its cosmetic
> problem.
>
> How far one goes down in age group is something that needs other
> comments, people who have had more experience in this, but I have had
> a number of experts, that in discussion on this subject, who have
> dealt with pediatric age groups, and other than the yellow color, the
> only problem seems to be the living life, and I am talking now about
> Crigler-Najjar patients who have values that are up in the
> extraordinary level, 100 mg/dl, and so forth.
>
> Their only problem is that they want a liver transplant because they
> look yellow, and I don\'t believe that, unless someone has data from
> hyperbilirubinemia exclusive of hepatic disease, that there is any
> potential toxicity.
>
> Now, in the very, very young, of course, there has been published some
> information on its deposition in the caudate nucleus and other
> extrapyramidal portions of the brain, and that is an area that I think
> needs to be discussed possibly in the future. There is no data on that
> now.
>
> I know a little bit about UGT 1A1, and the bilirubin is a specific
> substrate for this protein, however, we published a paper last year
> showing that there are two binding domains on this protein, and that
> bilirubin glucuronidation is not inhibited by a number of other agents
> which are also metabolized through the catalysis of this protein.
>
> I believe that the steroid binding site is different than the
> bilirubin binding site, as well, and certainly different than the
> opioid binding site in this protein, so the drug-drug interaction may
> not be as important also as one might consider when one takes into
> account the substrate specificity of this protein.
>
> To summarize, I do not see any problem of the bilirubin levels that
> are reported in any of the work that has been demonstrated here, and I
> would suggest that there probably won\'t be any problems in the future
> including drug-drug interactions with agents that attack the bilirubin
> binding site with several exceptions, and those have been reported in
> this work already.
>
> DR. GULICK: Thanks.
>
> Dr. Remmel.
>
> DR. REMMEL: There are a couple of exceptions, and it may play
> importance in certainly African populations and the Mediterranean
> area, and that has to do with cholelithiasis. There have been reports
> in terms of cholelithiasis in Gilbert\'s syndrome in beta-thalassemia,
> sickle cell anemia, and glucose-6-phosphate dehydrogenase
> deficiencies.
>
> In fact, in sickle cell anemia patients, cholecystectomy is the number
> one cause of surgery in those patients. So, where you have a situation
> where you have a higher red blood cell turnover and a higher
> hemoglobin turnover, that is being metabolized down to bilirubin,
> theoretically, there could be a concern there.
>
> Now, we do have a high African-American population who are taking
> these drugs, so that would be just a cautionary statement that those
> may be patients that we might want to watch for in terms of gallstone
> formation.
>
> The other comment I had is there has been an interesting recent study
> that bilirubin is an excellent oxidant, in fact, it may be helpful for
> preventing ischemic heart disease, so that may be an additional
> benefit actually in a secondary mechanism.
>
> DR. GULICK: Dr. Sherman.
>
> DR. SHERMAN: As a hepatologist who is frequently asked to evaluate
> patients with elevated bilirubins, as well as other problems, I also
> have a particular interest in this area. First, Gilbert\'s is not a
> disease, Gilbert\'s is a polymorphism that may, in fact, confer some
> benefit as was indicated in more than one area. There is evidence of
> anti-proliferative effects of unconjugated bilirubin.
>
> So, what we see in terms of elevated bilirubin in this process is not
> the same as what we see in a cholestatic process. Someone mentioned
> early today a trimethoprim sulfa, which can cause a cholestatic
> process, but it\'s a conjugated hyperbilirubinemia.
>
> The unconjugated hyperbilirubinemia seen here is not a disease, and
> that needs to be emphasized. However, the fact that patients have more
> cholecystectomies associated with hyperbilirubinemia is true, and it
> is due to a problem that exists in the community, that often patients
> who show up with some vague abdominal pain and an elevated bilirubin
> are not fractionated or fractionated or not recognized, and that leads
> those patients often to inappropriate surgery.
>
> So, the problem here is one of education and recognition. The company
> has indicated that they have a plan in place to deal with this
> education, and that is going to be very important, but it is going to
> need to be emphasized in the label that this is a known side effect,
> again not a disease, of the use of this medication, and that just
> because a patient\'s bilirubin is elevated, doesn\'t mean that they
> have significant underlying liver disease.
>
> Emphasis on the use of indirect bilirubin as a measure is important.
> There were some questions raised about the utility of screening
> patients for Gilbert\'s, and certainly the assays at least in research
> laboratories are available. I am not aware of a commercial test yet
> for Gilbert\'s. I wouldn\'t be surprised if some specialty labs are
> beginning to look at that.
>
> However, most of these patients can be identified, the ones at
> greatest risk, simply by looking at their baseline bilirubin and
> looking again for the direct versus indirect fractionation, and you
> can make that determination before the patient ever starts the
> medication.
>
> I do question whether this, in fact, should be classified as a
> toxicity with dose reduction recommended at a certain level, because
> again, if you accept that this unconjugated hyperbilirubinemia is not
> a disease, then, there is little reason to do a dose reduction unless
> for the cosmetic reasons that a patient doesn\'t like the color of
> their skin and sclera, and if that is an issue, then, maybe this was
> not the best drug for them in the first place because you don\'t want
> to drop the dose and have problems with viral breakthrough because you
> are dropping the dose for the wrong reason.
>
> DR. GULICK: Let\'s pursue that point for a minute. So, as I understand
> that the current proposal is not having dose reduction at all in the
> label, but recommending that Grade 4, which is greater than 5 times
> the upper limit of normal, bilirubin, would be considered to
> discontinue the agent. That is the proposal.
>
> DR. MARCUS: That is correct.
>
> DR. GULICK: Dr. Sherman, what do you think about that?
>
> DR. SHERMAN: I think there is no reason to drop the dose based on that
> level if it is due to this drug. Again, a primary unconjugated
> hyperbilirubinemia that is not in the setting of sepsis, where you
> could have hemolysis and DIC.
>
> DR. GULICK: Is there any bilirubin where you would change your mind
> and recommend discontinuing the agent, if I pin you down for a level,
> that makes you uncomfortable to continue?
>
> DR. SHERMAN: I would not stop the drug for that reason ever, but I
> don\'t think we are going to see levels in this disease\--
>
> DR. GULICK: Fifty, 60?
>
> DR. SHERMAN: Well, you won\'t see that in this disease process.
>
> DR. GULICK: Dr. Tephly.
>
> DR. TEPHLY: I wholeheartedly agree. I don\'t think one should\--this
> is not lead poisoning where you treat a blood level in children. I
> don\'t believe in treating a blood level. I don\'t think that is
> appropriate.
>
> DR. GULICK: Dr. Fish.
>
> DR. FISH: I think this will be patient-driven, and we have the
> indinavir experience. It was less frequent with indinavir, but we
> certainly learned to manage that, and we occasionally saw bilirubins
> go to 6 or 7. If the patient gets clinically jaundiced and they are
> terribly bothered by it, they are going to want to come off the drug.
>
> I think importantly, probably with indinavir, it was not of a
> frequency where we discussed that as a side effect when we started
> treatment. We talked about kidney stones and other things. But with
> this drug, I think it will be important for us, as clinicians, to
> discuss this with the patient, so that they are aware upfront that it
> could occur, in fact, maybe we could say it may well occur, and yetis
> clearly not harmful and be very reassuring upfront.
>
> I think we will get a lot of people through that if they do go into
> these higher levels of hyperbilirubinemia, they may want to
> discontinue because of the cosmetic effect.
>
> DR. GULICK: Shall we move on to the cardiac conduction part of the
> question? Let\'s actually start with the QT interval.
>
> Comments about what we saw? Dr. Morganroth.
>
> DR. MORGANROTH: I think the principal dataset that is important is the
> 076 trial, the so-called definitive trial. It is not perfectly
> definitive, doesn\'t have a positive control, has almost enough
> females to look at that issue. I guess I am not too troubled by the
> dose, the super-therapeutic dose 800 because of the discussion that
> occurred. That is sort of a bit of a limitation, but nice to have of a
> wider range, but I am not sure because of the need to use normal
> volunteers and the bilirubin, and the ethics of all that, so it is not
> too unreasonable that the 400 and 800, and as was pointed out by the
> sponsor, the concentration differences even more than 2X, which, of
> course, is important.
>
> The lack of a positive control, in my opinion, in this particular
> trial should be given little weight versus medium weight or more than
> that, because they had adequate numbers of ECGs, you know, over 10.
> Usually, 10 to 15 is the right number. They had a nice sample size,
> and they did adequate measurements in terms of manual, central lab,
> and they had a placebo, and they had it sounds like enough of a
> washout period that carry-over effects are probably not an issue.
>
> The lack of any signal, meaning that the signal was negative by
> Fridericia\'s, which is, in my opinion, the only thing that counts, I
> would not think that Bazett\'s should be used at all, that the fact
> that there was both negatives compared to placebo versus anything else
> make me very comfortable that the lack of the positive control is not
> critical, because I think the purpose of the positive control is to
> get these trials done with adequate sample size, with adequate number
> of measurements and adequate corrections and the like, and if not, you
> know, if there is something shorted by a good design in that regard,
> then, the positive control, of course, is the way to check that.
>
> If someone wanted to use only 30 patients in a crossover instead of
> 72, or someone wanted to use 60 CGs instead of more, or what have you,
> so I wouldn\'t be too troubled by the positive control, because I know
> in the agency\'s analysis, that was an issue.
>
> So, it is not perfect, but in my opinion, it is pretty close to being
> definitive, and without a signal on the QT, save for the 3A4
> interaction issue, I think I would not be concerned at all about the
> QT.
>
> DR. GULICK: Dr. Kowey.
>
> DR. KOWEY: I will be a little less kind, I think, not that I
> think\--this is obviously a very difficult problem area, and I do want
> to compliment the sponsor because I think that they have, to this
> point, done a fairly good job of trying to understand two different
> issues.
>
> By the way, QT interval, I have heard a lot of people talk about
> conduction abnormalities, QT is not a measurement of conduction, it is
> a measurement of repolarization. We do have a conduction problem, and
> that is the PR interval, and we have a repolarization issue, which is
> the QT interval.
>
> I am not saying that just to be petty, but I think we need to be clear
> that there are two separate ECG issues that have to be dealt with.
>
> As I said, I think that there has been an honest attempt to try to
> understand this, but there are many things about this particular
> dataset which I think are somewhat disturbing, and we need to make
> sure everybody understands.
>
> Number one, I think that the preclinical studies are inadequate. I
> think stopping with a HERG assay and then one measurement of action
> potential duration in a Purkinje model, it used to be okay, and it is
> not okay anymore.
>
> I think the guidance document that is now in draft had made it fairly
> clear that we need to do a better job of understanding these drugs
> preclinically because it isn\'t just HERG. There are other mechanisms
> by which drugs may affect repolarization, and there are other models
> now that are highly available and not expensive, easy to do, that can
> give you more information.
>
> So, when you get down to asking later about what kinds of things need
> to be done, I think I would like to see a better preclinical
> assessment of this compound.
>
> The second thing is that it is a noncardiac drug that is going to be
> administered by noncardiologists, which means that it is unlikely that
> anybody is going to be paying much attention to ECGs.
>
> We can pretend that somebody is going to get EKGs and look at them,
> but the fact of the matter is that when this drug is approved, it is
> going to be used by people who are not going to be looking at
> cardiograms.
>
> So, that raises the bar somewhat, and to the extent that I would like
> to know as much as I can possibly know about the worst case scenario
> that you can possibly get with a compound like this, again, both in
> terms of the PR interval and the QT interval.
>
> The third issue is that there is a metabolic inhibitor issue here. It
> is metabolized, and it is a common enzyme system, and we have spent a
> lot of time talking about this. Joel even brought it up in his talk
> about metabolic inhibitors and the importance. There is the
> opportunity here to have concomitant therapy which might grossly
> change the plasma concentration, in fact, we have seen that, that
> there are wide variations in plasma concentrations.
>
> Now, there is a table on page 175 of the briefing document in which
> the sponsor has presented plasma concentrations which are way up at
> the upper end, they use the worst possible correction formula, which
> was Bazett\'s, and still didn\'t see anybody go over 500 milliseconds.
>
> That is very, very reassuring, but it is in a retrospective kind of
> look at a dataset which is underrepresented by women who are typically
> the people that we worry about having QT interval issues, so I am also
> concerned about that.
>
> The PR interval issue again is an issue because people who take these
> medications, when they develop diseases that may not necessarily be
> related to HIV, maybe exposed to drugs, which can also have an effect
> on the PR interval, like calcium channel blockers, for example, and
> again, I think it is highly unlikely that people who are going to be
> prescribing this drug is going to be following electrocardiograms in
> people like that.
>
> So, again, I would like to see more information of what happens to
> conduction, PR interval, as well as repolarization at the extremes of
> plasma concentrations, and I don\'t think that that has been as well
> explored.
>
> Now, there is a good excuse for it. The excuse is that if you try to
> drive the plasma concentration too high, there is an issue with
> hyperbilirubinemia, but as I pointed out, I don\'t think that that
> would be an issue if you were to do studies in which the patients were
> not exposed or subjects were not exposed to that level of drug for too
> long a period of time, you might be able to gather more information
> about again the worst case scenario.
>
> What these things many times come down to are not a question of
> approvability. This is under an approvability question, and I
> apologize because I don\'t think that anything that I have said
> necessarily goes to approvability.
>
> I think that these questions more from the point of view of labeling
> than it is approvability, but in factoring in the benefit and the
> risk, I just don\'t\--I feel differently than Joel, I think, a little
> bit, in that I am a little bit more, maybe a moderately more worried
> about this as an issue for patients, and I don\'t want to see it taken
> off the table. I think it is something that really has to be dealt
> with in labeling.
>
> DR. GULICK: Let me just clarify one point. We are going to take a
> formal vote, so everyone will need to assess the risks and benefits,
> and come up with an answer for themselves, but in addition, our
> discussions are meant to help with the process of the labeling, so we
> are considering both here at the same time.
>
> DR. KOWEY: Of course, I understand that. I really don\'t think again
> that this is an approvable\--from my point of view\--an approvable
> issue. These things that I just raised, I think that they are issues
> from two aspects. One is more study, and the second is proper
> labeling.
>
> DR. GULICK: Mr. Sharp.
>
> MR. SHARP: I want to bring up again the issue of combining drugs and
> what that means for this effect that happens to people, both in the QT
> and the PR, concerned with\--you said that all the protease inhibitors
> have an effect on QT promulgation.
>
> After this drug is approved, doctors are going to give it to patients,
> and they are going to be taking all kinds of different combinations,
> so what does that mean in terms of these kind of\--even though we
> don\'t really see the QT as an issue, that much of an issue here, what
> does that mean in the real world.
>
> DR. KOWEY: Let me answer that. But I think that you just hit it right
> on the head, which is exactly what I was getting at. People are going
> to be exposed to many, many other kinds of drugs, and we have learned
> now our lesson that there are lots of drugs out there that not only
> affect repolarization, but can also affect conduction.
>
> That is why I am saying that the two things that need to be done, that
> I don\'t think have been done yet, or a much better job of defining
> this problem preclinically, that is, understanding exactly what is
> going on in preclinical models, and, secondly, really trying to find
> the worst case scenario, that is, exposing people to very high
> concentrations of this drug either by virtue of giving them high doses
> or using a metabolic inhibitor, and seeing what happens in the worst
> case to the QT interval, so that when this happens\--and the PR
> interval\--so that when this happens, we have some idea of what we can
> expect in the real world without anybody monitoring electrocardiograms
> because, let\'s face it, we may say we want that, but it is unlikely
> that it is really going to happen.
>
> DR. GULICK: Dr. Morganroth and then Dr. Wood.
>
> DR. MORGANROTH: I wouldn\'t want you to think that there is total
> consensus among cardiologists about this issue, so it requires me to
> make one point of disagreement with Dr. Kowey and point of agreement.
>
> In terms of the PR interval, which we jumped to, I totally agree. I
> think that is an important labeling issue, I think it is a real
> effect. I think it puts some patients at risk particularly when they
> have calcium blockers on-board, as demonstrated by that case of
> junctional rhythm and death that was described earlier. So, I totally
> agree with that.
>
> In terms of the other issue of whether or not it should be required to
> do sort of additional preclinical work on this drug relative solely to
> the QT issues, I have a disagreement because I think that I was very
> impressed that the HERG was not able to be 50 percent inhibited. The
> sponsor only showed it to get up to, if I recall, 30 percent or 32
> percent or something, so it couldn\'t even push it to 50 percent.
>
> Number two, I believe the sponsor did what I will call an almost
> definitive trial as described before, and I believe\--and this is
> where we might disagree\--I believe that the target species, man,
> trumps preclinical.
>
> So, what we might find in preclinical would be very interesting from
> an academic point of view, but would not influence me personally at
> all about whether this drug needs more monitoring or more concern
> about its effect on cardiac repolarization.
>
> I think the data we have, if you agree that the 076 is a near
> definitive or equivalent to a definitive trial, is negative, and it
> appears to be clearly that with no signal of the QT increasing, and as
> Peter pointed out, when you look at the isolated examples even in
> women, even using Bazett\'s, with these high concentrations\--now,
> there are not many because there is only a handful, half dozen or so,
> there was also a reduction in the QTc interval in those individual
> patients even by Bazett\'s or at least known change.
>
> So, I don\'t think that preclinical data would\--I don\'t have a
> question clinically that I need preclinical data to help me with,
> because I don\'t see any signal for the QT and I think a reasonably
> worked-up application.
>
> Could they do another definitive trial, single dose, with a metabolic
> inhibitor or ignoring the bilirubin issue and saying who cares if you
> push a normal volunteer up to 5 or 10 level of bilirubin, you know, I
> think you would probably get that by an ethics committee someplace,
> because it isn\'t the toxicity, as pointed out, you know, and maybe
> get it by. Today it is very tough.
>
> But I just don\'t see the need for that from the data we have to date,
> and it would make it from 90 percent definitive to 99 percent
> definitive perhaps.
>
> DR. GULICK: Dr. Wood.
>
> DR. WOOD: I would just like to echo the issues that have been raised
> regarding concerns with labeling. I think even though the reality may
> be that clinicians might not be inclined to do EKGs, I think it would
> be very, very important, since the PR intervals has consistently been
> an effect that has been seen, so that practitioners are going to have
> to be made aware.
>
> Specifically, there are a significant number of HIV-infected patients
> that have cardiomyopathy, that are on digoxin. There has not been any
> data presented regarding issues of prolongation of PR intervals in
> individuals who have an indication for a didge \[ph\] for
> cardiomyopathy, and I think it would be important, not only for didge,
> as well as other calcium channel blockers, but any class of cardiac
> drugs that may affect either conduction or repolarization in terms of
> some kind of warning and alert.
>
> As it relates to the use of the 300/100 dosing in
> treatment-experienced patients, there is no data that was presented by
> the sponsor regarding PR interval issues in that dosing, and I would
> be interested in knowing about that because clearly, the
> concentrations were higher, which probably is responsible for the
> superior virologic efficacy compared to the 400 daily, but I would
> also be concerned about the frequency of PR abnormalities with that
> dosing because we didn\'t see that data.
>
> DR. GULICK: Does the sponsor want to respond to that?
>
> DR. LAWRENCE: In my presentation, I lumped together treatment arms for
> the clinical studies, but we have that broken out by studies, so if
> you can present that.
>
> \[Slide.l\]
>
> So, if you look at the DASH 45 study, we did look specifically at a
> boosted regimen versus some comparators, and the incidence of
> first-degree AV block, 4 percent, is really right in line with the
> other treatment arms across a number of studies.
>
> DR. GULICK: Could we get a couple more comments on the PR interval
> itself? Dr. Morganroth, just about the findings we saw today?
>
> DR. MORGANROTH: I really don\'t have much to add than what Peter said
> earlier. I think the fact that in this development program, there has
> been no second and third degree blocks presented in the individual
> trials is somewhat comforting, but when one looks at specifically the
> couple cases that were culled out where someone was on verapamil or
> someone was a very high-risk cardiac patient, I mean I think the
> labeling can handle that and manage that to make sure that treating
> physicians be very careful about the use of this agent with any drug
> that affects AV node, that may be an indication for an EKG if they
> want to combine the drugs to make sure that after one reaches
> steady-state or whatever, that someone is not sitting with a
> junctional rhythm because the AV node has been knocked out.
>
> Again, most people would be symptomatic with that, with this kind of
> condition. They would complain of dizziness or their pulse would be
> very slow, et cetera, so I think that would be clinically, usually
> evident, but in the label, one should be alerting physicians about the
> interaction at the AV node. That is clear.
>
> In terms of how important that is, you know, without seeing any second
> or third degree blocks, it is going to be an uncommon, you know, I
> wouldn\'t say rare, but it is going to be an uncommon phenomenon, and
> I think risk management should handle it.
>
> DR. GULICK: Dr. Kowey.
>
> DR. KOWEY: Well, there is always concern about how data that you see
> inside a very well done, well supervised clinical trial, how that
> applies to the universe of practitioners once the drugs are out and
> used, and you mentioned didge, cardiomyopathy patients also get
> exposed to beta blockers these days at a very high clip.
>
> It is an interesting paradox because we are talking about heart block
> which predisposes the bradycardia, which is a very strong risk factor
> for the development of torsades for drugs that prolong the QT
> interval.
>
> So, you could envision a scenario where a patient becomes very
> bradycardic and is exposed to a higher risk of developing torsades,
> which is the rhythm that Joel was concerned about, based on QT
> prolongation because of this very unusual combination of
> electrophysiological effects.
>
> I am also kind of left with\--it is an outside calcium channel
> blocker, and I guess that is the mechanism for the PR prolongation
> although we don\'t really talk about that very much. I mean the
> mechanism of PR prolongation here, we are assuming it\'s calcium
> effect, but as Joel pointed out, it does have a minor effect on sodium
> currents, and in that one very, very severe case, not only did the
> person develop AV block, but they also developed bundle branch block,
> which is not what you expect from a calcium channel blocker, but you
> might see with a sodium channel blocker.
>
> So, there is enough here that again I think it really does bear
> careful attention in terms of what you tell practitioners when the
> drug is available to them.
>
> DR. GULICK: Dr. Kumar.
>
> DR. KUMAR: I just have a question to both our cardiology consultants.
> Could you comment\--and I had asked this earlier on\--in clinical
> practice, if you use thiazide diuretics with this and patients become
> a little hypokalemic, what would happen to either the PR or the QT
> interval, and would that have a clinical relevance?
>
> DR. KOWEY: Hypokalemia? Hypokalemia is a very important parameter for
> the QT prolonging effect because hypokalemia itself prolongs the QT
> interval, and we know is a risk factor for the development of torsades
> when patients are given drugs which prolong QT interval.
>
> So, hypokalemia is something that we assiduously avoid in people who
> receive QT-prolonging drugs for these reasons. So, it is important.
>
> DR. MORGANROTH: In this case, if atazanavir does not affect the QT
> interval, then, hypokalemia and bradycardia prolong the QT just as
> Peter said, and has its own consequences from those primary
> conditions, but you wouldn\'t have to worry about any interaction if
> the drug doesn\'t prolong the QT.
>
> If the drug does prolong the QT, which I don\'t find evidence for, as
> you know, at this point, that becomes important labeling information,
> which often says do not use this QT-prolonging drug in conditions such
> as heart failure, atrial fibrillation, all the points that I had made
> on one of my earlier slides of all the mitigating factors that can
> also affect the QT, and you get two QT prolonging at a time, you can
> get knocked over the hill with a bad arrhythmia.
>
> But just the isolated factor itself of having heart disease or
> hypokalemia or bradycardia that is severe can, in fact, in some
> patients, cause torsade.
>
> DR. GULICK: Let me just try to summarize what we have said, and then
> we are going to take a formal vote on this. Regarding atazanavir for
> the naive population, there was a consensus that the drug is clearly
> active, that we saw convincing data compared to a tough comparator,
> which was an efavirenz-based regimen.
>
> People noted the convenience in terms of pill burden once a day and a
> general impression that the side effect profile was reasonable in the
> naive patient population.
>
> A couple of cautions where PK variability, and we had spoken some
> about food effects. In terms of the experienced population, that
> presented much more of a quandary to us and to the agency is what we
> heard.
>
> We saw evidence of activity, but this drug less good virologically to
> the comparator arm, which was Kaletra based. The committee had a
> consensus that there was more concern about the activity of atazanavir
> alone in a treatment-experienced population.
>
> We were interested to see the ritonavir-boosted data, but appreciate
> that this hasn\'t been adequately reviewed and that we don\'t have a
> lot of follow-up information there.
>
> The suggestion by Dr. Fletcher that perhaps PK information could be
> included in the label to help the clinician decide what to do was
> greeted with some enthusiasm, and then the point to make that
> resistance, as it should be used in the treatment-experienced
> population as consistent with general guidelines.
>
> Other advantages of the drug in naive patients also apply to the
> experienced populations, and then the point made that when we talk
> about experience, we are usually talking about virologic failures, but
> Dr. Remmel made the point that another version of a
> treatment-experienced population are those who are doing well, but are
> having hyperlipidemia, and so using atazanavir in that population, we
> also saw some evidence that that would be a good use of the drug.
>
> Some concerns in this group - drug-drug interactions because
> experienced patients often are on multiple concomitant drugs. Again,
> the feeling that atazanavir alone perhaps is not the optimal therapy
> or the optimal way to use the drug in this population.
>
> Hyperbilirubinemia, people felt generally comfortable. We have a
> precedent with indinavir although it occurs less frequently. Several
> people said this is not a toxicity, this is not a disease, it is
> really cosmetic, that education and recognition are probably the keys,
> and emphasis that this is indirect bilirubinemia, and that dose
> reduction was not supported by the committee on that basis.
>
> Concerns about bilirubin, we heard a little about certain populations
> in pediatrics, gallstones were also raised.
>
> In terms of the cardiac effects, QT interval, the 076 study felt not
> to be perfect, but pretty darned good, that there was not a signal
> using Fridericia method of the QT interval.
>
> There was some disagreement about the need for further study in
> preclinical, and the point made that man is a pretty good model for
> men, and some disagreement about monitoring, whether routine EKGs or
> symptom-based would be appropriate, but no consensus.
>
> The big caution here is using this drug with other inhibitors of the
> 3A4 enzyme system. In terms of PR interval, felt that this is a real
> effect and that some populations could be at risk particularly those
> with concomitant diseases or are on other medications including
> calcium channel blockers. Again, some disagreement about the need for
> monitoring, the need for warning, and some reassurance that there was
> no secondary or third degree heart block.
>
> With that, we are going to go ahead and take a formal vote, and the
> question that we are going to answer is do the efficacy and safety of
> atazanavir support its approval for the treatment of HIV infection,
> and the answer is yes or no.
>
> Drs. Sun and Morganroth are not eligible to vote, so we will start
> with Dr. Kowey and go around the table. A yes vote is for approval,
> and a no vote is against approval.
>
> DR. KOWEY: Yes.
>
> DR. GULICK: Dr. Fish.
>
> DR. FISH: Yes.
>
> DR. GULICK: Dr. Washburn.
>
> DR. WASHBURN: Yes.
>
> DR. GULICK: Dr. Illingworth.
>
> DR. ILLINGWORTH: Yes, I approve.
>
> DR. GULICK: Dr. Remmel.
>
> DR. REMMEL: Yes.
>
> DR. GULICK: Dr. Tephly.
>
> DR. TEPHLY: Yes.
>
> DR. GULICK: Dr. Wood.
>
> DR. WOOD: Yes.
>
> DR. GULICK: Dr. Mathews.
>
> DR. MATHEWS: Yes.
>
> DR. GULICK: Dr. Fletcher.
>
> DR. FLETCHER: Yes.
>
> DR. GULICK: Mr. Sharp.
>
> MR. SHARP: Yes.
>
> DR. GULICK: Dr. Sherman.
>
> DR. SHERMAN: Yes.
>
> DR. GULICK: Dr. Englund.
>
> DR. ENGLUND: Yes.
>
> DR. GULICK: Dr. Kumar.
>
> DR. KUMAR: Yes.
>
> DR. GULICK: Dr. DeGruttola.
>
> DR. DeGRUTTOLA: Yes.
>
> DR. GULICK: And the Chair votes yes, making it unanimous, 15 votes for
> yes, and zero votes for no.
>
> With that, let\'s take a 10-minute break.
>
> \[Break.\]
>
> DR. GULICK: Welcome back, everybody. We are going to go ahead and
> consider the next few questions.
>
> Question No. 2. Does the safety profile of atazanavir warrant
> additional clinical or laboratory monitoring? Some of the things that
> have been at least suggested in our previous discussion so far; liver
> function tests including bilirubin, EKGs, resistance testing. A
> suggestion was made about drug concentration or TTM for atazanavir,
> and then even Gilbert\'s gene testing has been raised in previous
> discussions.
>
> So, we should focus on those and other thoughts about monitoring.
> Let\'s start with EKGs.
>
> Dr. Morganroth.
>
> DR. MORGANROTH: I personally don\'t see any indication for requiring
> an EKG to initiate therapy. I think that for the PR interval where
> this is an issue of even considering any type of EKGs, I think that it
> would be prudent to obtain an EKG in a patient who you want to use
> atazanavir with a drug that affects AV nodal conduction - calcium
> blockers, beta blockers, et cetera, or in a high-risk patient who is
> known to have AV nodal conduction disease - digoxin, you know, other
> manifestations have already been discussed at length.
>
> So, there, I am not sure how that works in a label because there is
> lots of issues. I think the guidance should be that this interaction
> may cause things and that one can sort them out with an
> electrocardiogram. I generally don\'t like to see that, sort of like
> required or implied to be required, because of all the complex
> reasons, problems that that causes.
>
> DR. GULICK: Dr. Kowey.
>
> DR. KOWEY: The PR interval issue I agree with. I am having a little
> bit of a difficult time with this because specifically, and we are
> going to probably continue to argue about this, Joel and I, but in the
> absence of what I consider to be adequate preclinical data, I am
> having a difficult time deciding whether I want to give this drug to
> somebody who has long QT syndrome, which is potentially what could
> happen if you said you don\'t have to get a baseline electrocardiogram
> to give this drug to somebody, you can just give it without knowing
> what the QT interval is.
>
> The only population that I would be concerned about is somebody who
> happened to have the long QT syndrome and I didn\'t know it, and I
> gave this drug to them. Now, Joel is coming from the point of view, I
> think, without putting words in his mouth, that this drug doesn\'t
> really have an effect on the QT interval, and I am coming from the
> point of view, well, gee, it comes from a family of drugs where we
> know that these drugs have an effect on HERG.
>
> HERG is not the only mechanism by which these drugs can prolong the QT
> interval. There are other mechanisms for QT prolongation other than
> just the HERG. As I said, in the absence of really knowing enough
> about this drug\'s basic electrophysiology, the one population that I
> just can\'t answer is a long QT syndrome patient.
>
> DR. GULICK: Can you tell us, what is long QT syndrome and how common
> is it?
>
> DR. KOWEY: It is a genetic heritable disease. Patients have one of a
> variety of abnormalities usually of a potassium current, although
> there are some sodium currents which can also be affected, and the net
> effect is that these people have a delayed repolarization, which is
> reflected on the surface ECG as a long QT.
>
> They are susceptible to development of that arrhythmia that Joel
> showed you on the slide, and that happening either spontaneously or
> under conditions in which their QT intervals is further prolonged
> either by an electrolyte abnormality, for example, or the concomitant
> use of a drug which prolongs the QT interval unwittingly given to
> them.
>
> Although it is not a very common disease, in fact, it\'s a relatively
> uncommon disease, there are families of these individuals. We discover
> more of them all the time. It is really kind of difficult to tell you
> exactly what the prevalence of it is, but it is not a common problem.
>
> DR. GULICK: Can you give us a feeling for that? Just for the
> prevalence.
>
> DR. MORGANROTH: Yes. The prevalence is about 1 in 5,000 for the gene
> mutation. There are people who don\'t know their part of the family or
> that have some subclinical disease, but it is not that different,
> frankly, if you have a patient who is on a long QT-producing drug. It
> seems to me it is not just long QT syndrome you are pointing out, it
> is that it is someone who is on some other drug that we know that
> causes a long QT, or develops hypokalemia, et cetera.
>
> The question is under those circumstances, do you believe that this
> compound affects the QT, and if it does, then, you should be
> uncomfortable and want to have some kind of prohibition in the label
> to use it for all kinds of conditions as if it were a long QT, it
> seems to me.
>
> So, I think I would argue that you have to drop back and say do you
> think this drug affects the QT or not, and if it does, then, you have
> got a whole labeling issue and monitoring issue. If it doesn\'t affect
> the QT in man, then, you don\'t have any of those issues, I would
> argue.
>
> Therefore, you have to determine how you make that judgment, and it
> seems to me that if you did a preclinical additional testing, and
> let\'s say you found this drug affected IKS\--
>
> DR. KOWEY: It doesn\'t.
>
> DR. MORGANROTH: Okay, that\'s right, they looked at that.
>
> DR. KOWEY: Try something else.
>
> DR. MORGANROTH: Whatever it is, it affects IK something, because there
> is a lot of IKs. So, it affects IK something and you learned that by
> doing preclinical testing, or it looked bad in a wet preparation or
> something. Then, I would argue hmm, boy, I would want to do a
> definitive trial in man to see if that is true in the target species.
>
> So, that is where we disagree in terms of whether or not the human
> definitive trial trumps anything you see in preclinical, and no matter
> how bad how the preclinical looks, if you do adequate studies in man,
> and there we can discuss how adequate the studies are in man including
> the 076 trial, but if you have done an excellent job there or good
> enough job there, then, you should be comfortable that it doesn\'t
> affect the QT, you don\'t have to raise the labeling issues about it,
> I would argue.
>
> DR. KOWEY: There is two fundamental problems. One is that\--maybe
> it\'s because I do some of this for a living, but I do believe that
> there are preclinical models that help you to understand the liability
> of the drug, and, number two, no, I don\'t think that 76 is the
> definitive study because the doses that were used are not custom\--we
> customarily drive the doses higher.
>
> Now, the exposures were fairly high for 800, but they still were not
> of the order that we usually see in trying to construct the worst case
> scenario especially when there is a metabolic inhibitor issue, and
> especially when the drug comes from a family where we know that those
> drugs have an effect on cardiac repolarization.
>
> So, I don\'t look at 76 as being the definitive study that answers all
> the questions that we need to answer, and therefore, I am not
> comfortable saying that there is no need for ECG monitoring of
> patients for QT prolongation.
>
> DR. GULICK: Let me pin you down then. We have just voted to approve
> this drug, the label is going to be written. Do we require EKGs for
> every person routinely at baseline who starts this drug?
>
> DR. KOWEY: Until I have more information about this drug to tell me
> that and to convince me that there is not a QT effect that I need to
> worry about clinically, the answer is yes.
>
> DR. GULICK: Dr. Morganroth?
>
> DR. MORGANROTH: I would say absolutely no. Of course, you have to
> expect that, right? But I would say absolutely no because there is a
> history in the agency of approving QT prolonging drugs without such a
> requirement.
>
> Take moxifloxacin, which some of the people here in this room know
> more about than I do, I guess, or at least as much, about the QT
> issues, and that is a drug that affects clearly cardiac repolarization
> and HERG, is used in fairly sick people, you know, people with bad
> infections, it\'s a fluoroquinalone, and there is no requirement in
> Europe, Canada or U.S. for any baseline ECG monitoring.
>
> I am only specifically address the issue of do you need an EKG to
> start a drug that has a prolongation in the QT. Now, I would argue in
> this case, at best, we are not 100 percent certain. We would agree
> that we don\'t know 100.0 percent whether this drug affects the QT,
> and even if we are suspicious that it might, it can\'t be by enough or
> by a large magnitude because we would see some signals of that in man,
> in the study that was done.
>
> So, therefore, I don\'t see why one would want an EKG at baseline,
> taking agency and practice into mind.
>
> DR. KOWEY: The case of moxifloxacin, as well as ziprasadone, where
> again ECG monitoring was required, where datasets, in my opinion, were
> complete, that is, the drugs were worked up, there was definitive
> clinical information, about as definitive as you can possibly get, and
> I was much more comfortable with being able to answer the question
> that you are asking.
>
> I guess it\'s a philosophical thing. If you don\'t know the answer to
> the question definitively, what do you do, do you assume you are okay,
> or do you assume you are not okay? I think that is what you are
> hearing here, and my answer is you assume\--I am sorry, I can\'t
> assume you are okay\--and what Joel is saying, well, it can\'t be that
> bad, so you probably are okay, and that is the philosophy. It is more
> of a philosophical difference, I think, than it is a data-driven
> difference.
>
> DR. GULICK: So, we have a difference of opinion from our cardiologist
> consultants. Anyone else on the committee want to ring in on the
> philosophical issue here?
>
> Dr. Mathews.
>
> DR. MATHEWS: I don\'t think this is a philosophical issue for me. I
> think whether it is or it isn\'t a direct effect on the QT interval, I
> think numerically, a much more common problem is going to be the
> metabolic inhibitor effect, which is real and uncontested.
>
> Putting something in the label obviously is the first level of dealing
> with this, but in terms of educating physicians about these drug
> interactions, most of us do not read the labels. I think more and more
> people are using palm pilots or the internet to check for drug
> interactions, but as a person who was involved in a near fatal
> reaction with verapamil, a beta blocker, and another protease
> inhibitor with asystole, I think guidance needs to be given on not
> something that says use caution, but exactly what is the recommended
> monitoring if you are going to put someone on combinations like that.
>
> Could one or both of you address that situation in terms of what would
> be the recommended monitoring in terms of frequency, you know, when
> the electrocardiograms?
>
> DR. MORGANROTH: I think there is no disagreement that for the PR
> interval issue, as Peter correctly said, we recommend that you
> absolutely consider the PR and the QT, two different separate issues.
>
> For the PR issue, which is an AV nodal conduction, there is just no
> question, this drug affects it, it affects it predictably, it is dose
> related, and therefore, when you give it to a high-risk patient who
> has already got their PR interval in bad shape or potentially in bad
> shape, that you are going to want to look at the PR interval when you
> add this drug.
>
> So, I don\'t think there is any controversy there. What you are
> hearing is the controversy is the other half, the other issue, which
> is the QT. I think that the issue of whether you need an EKG to
> initiate drug therapy to make sure the patient doesn\'t start with a
> prolonged QT, is a matter of philosophy, I would guess. I mean it
> depends on how you interpret the data, and we interpret the data
> somewhat differently, and therefore, we come to different conclusions
> as to whether or not the EKG should be done because if you are not
> certain of the knowledge, Peter\'s argument, I guess, is we should to
> an EKG.
>
> I am more comfortable with where we are with the knowledge, and even
> if there was some effect, I think tradition and history, as I said
> before, has not usually required a QT at baseline. So, I am not going
> to get an answer that is going to be a consensus of your two
> cardiologists that are sitting at the table.
>
> DR. GULICK: Mr. Sharp, Dr. Fletcher, and then we need to move. Oh,
> sorry, Dr. Birnkrant.
>
> DR. BIRNKRANT: If I could just interject at this point, given that we
> have two cardiology consultants sitting at the table with differing
> opinions, perhaps we could hear from Bristol-Myers Squibb\'s
> cardiologist, Dr. Ruskin, to hear his opinion on this issue.
>
> DR. GULICK: Break the tie, you mean.
>
> DR. BIRNKRANT: Exactly.
>
> DR. RUSKIN: Jeremy Ruskin. I am a cardiac electrophysiologist at
> Massachusetts General Hospital.
>
> I guess I will just try to make some very brief comments. I see no QT
> effect here at all. I don\'t see anything that would be gained by
> doing additional preclinical work because generally, additional
> preclinical work is done to address a small signal that is seen in the
> clinical development program, and to try to get a comfort level about
> relative safety particularly I think Dr. Kowey is referring to the
> wedge preparation, which looks at transmural dispersion of
> refractoriness. For me, that has no relevance in this particular
> development program because I see no clinical effect whatsoever.
>
> The PR interval effect, I think is unequivocal, dose dependent, and
> not clinically significant when the drug is used by itself. The
> concern I have with this drug and all the drugs in this class is that
> they are 3A4 inhibitors, and drugs like verapamil, which are very
> potent negative chronotropes and negative inotropes, will be amplified
> dramatically when they are used with protease inhibitors.
>
> The cases that you have heard about are not due to AV block. They are
> due to sinus arrest with asystole or a junctional rhythm, and that is
> due to the effect of excessive exposures to calcium blockers either
> alone or in conjunction with a beta blocker in the setting of 3A4
> inhibition.
>
> So, for me, that is the major concern, and electrophysiologically, in
> terms of this drug alone, I have no concern about the QT effect
> because I think there is none, and with regard to PR, I think there is
> a numerically and statistically significant effect when the drug is
> used alone, but I think it is clinically insignificant except when
> combined with other drugs.
>
> With regard to Dr. Kowey\'s concern about exposures, I would say that
> it is important to remember that this drug is a 3A4 inhibitor and a
> substrate, but when you use it in conjunction with ritonavir or other
> 3A4 inhibitors, the exposures that you get are significantly less than
> you get with 800 mg, and we have got the data on 800 mg that you have
> seen with regard to QT, and there is no effect.
>
> DR. GULICK: So, you would recommend not doing an EKG routinely at
> baseline?
>
> DR. RUSKIN: I would absolutely not recommend baseline EKG screening.
> There are drugs in widespread clinical use with unequivocal QTc
> effects, measurable, defined, undeniable, that are used for much less
> serious situations than this, for which ECG screening is not
> recommended. I think it would have no role here except in the settings
> that have been described, that is, someone with known pre-existing
> heart disease, someone in whom you are considering the use of a
> concomitant calcium blocker or a beta blocker, all the things that as
> clinicians, we know to be associated with risk when you have a 3A4
> inhibitor on-board. In those situations, there is no question that ECG
> should be done.
>
> DR. GULICK: Thanks.
>
> Mr. Sharp, then Dr. Fletcher.
>
> MR. SHARP: That sounds like a labeling concern to me. What concerns me
> about requiring people to get an EKG before they take this drug is
> access, and will that bar them from getting access to the drug because
> they don\'t have access to an EKG. I don\'t know how common, not often
> in every doctor\'s office, and sending them to a specialty is a
> problem.
>
> DR. GULICK: Dr. Fletcher, then Dr. Kumar.
>
> DR. FLETCHER: My comment really goes back to a point that Dr. Mathews
> made about drug-drug interactions, and I guess specifically then to
> the 045 data and whether any information on the boosted dose of
> atazanavir can be put in the label.
>
> Obviously, the 045 data are out there and it seems to me that if
> atazanavir is finally approved by the agency, that clinicians in some
> cases will use atazanavir with ritonavir. So, it seems to me we can\'t
> ignore that, and therefore need to find some way\--and I think the
> agency and the sponsor certainly must have some ability to work out
> something acceptable\--where at least pharmacokinetically, those type
> of data are there, I think because they directly go to this risk issue
> we are talking about here with now atazanavir being used with one of
> the most potent CYP inhibitors that we have.
>
> So, while I think the issue bears on the 045 and data in treating HIV
> treatment-experienced patients, I think it really also comes in, in
> this risk issue with drug-drug interactions.
>
> DR. GULICK: Dr. Kumar.
>
> DR. KUMAR: My concern comes to the fact that data\--that swayed me
> into saying that with the 300, 100 milligram dose. But that is not the
> dose that we approved, but that would be the dose that is most
> commonly going to be used in treatment-experienced patients, but we
> have no safety data on that.
>
> The only safety data that I can see is on the bilirubin level, that we
> have all agreed is not a toxicity data, but there is nothing on what
> happens to the PR interval, the QT interval, or any of the other
> safety information with that dose, but just the dose that is going to
> be used in treatment-experienced patients.
>
> So, I think not to be upfront in getting more safety information until
> we are sure that there is no safety concerns, I think is a big
> mistake. I don\'t know what exactly, how many EKGs, when the EKGs,
> that is beyond my area of expertise, but I think without that safety
> information, all we saw was some tantalizing information of the
> effectiveness, but nothing on safety.
>
> DR. GULICK: I thought we did see some\--I see lots of shaking heads
> over there\--didn\'t you show us a slide with the\--could you show us
> that slide again? If you could walk us through this again, that would
> be helpful.
>
> \[Slide.\]
>
> DR. LAWRENCE: This is a breakdown by study of the PR interval data
> focusing on incidence of first-degree AV block. So, in the DASH 45
> study, we do have electrocardiograms on study and incidents of
> first-degree AV block for the boosted regimen is 4 percent, so this
> contrasts within the study with 6 percent in the atazanavir/saquinavir
> arm, and 4 percent in the Kaletra arm.
>
> If you march across the other studies, it is right in line, if not, a
> little bit less than the experience in some of the other studies.
>
> DR. SCHNITTMAN: Let\'s show the core safety slide on 045, as well.
>
> \[Slide.\]
>
> As presented earlier, here is the Grade 2-4 related AEs through 24
> weeks, so again this is not reviewed by the agency, this is our
> updated data here showing those that had greater than 5 percent of
> subjects with these AEs.
>
> Essentially, the incidence of jaundice in the boosted setting is
> slightly higher than what we saw in unboosted, but not substantially
> higher, and otherwise, the safety profiles are quite remarkably
> similar to the unboosted setting.
>
> DR. GULICK: So, just to say again, we are in a bit of an awkward
> situation to have some preliminary data that hasn\'t been well
> reviewed by the agency, let\'s face it.
>
> DR. LAWRENCE: I could also show QT data from the DASH 45 study.
>
> DR. GULICK: Sure.
>
> \[Slide.\]
>
> DR. LAWRENCE: So this will be the same layout as the PR data I just
> showed you, looking for outlier values by gender. Normally, we would
> have a greater than 500 row, but those were zeros across the board, so
> a very low frequency of subjects with values just outside of the
> normal range defined by gender. Again, here is 45.
>
> DR. GULICK: These are 16-week follow-up or 24-week follow-up?
>
> DR. LAWRENCE: These electrocardiograms represent, in the different
> studies, there was a different frequency of collection, but, for
> example, in 43, we collected electrocardiograms baseline, Week 2, Week
> 12, Week 24. In 45, we collected at baseline and Week 4, so they do
> reflect some chronic dosing.
>
> DR. KUMAR: For the 045 data, is that safety data the end of 16 weeks,
> 24 weeks, what time period did you show us?
>
> DR. SCHNITTMAN: That particular slide was the 16-week safety update.
> Now, that was actually in the hands of the agency.
>
> DR. GULICK: So, that was 24-week that he showed before.
>
> DR. KUMAR: And this one?
>
> DR. SCHNITTMAN: This one was cut at pretty much at the time of the
> safety update, but as I said, patients were getting it at zero, Week 2
> or 4 and Week 12, so they would have had two or three sets of three
> EKGs probably by the time they entered this dataset.
>
> DR. GULICK: Okay. We are going to need to keep moving here, so again,
> going back to the question of EKG monitoring, difference of opinion on
> routine EKG monitoring, more concern in patients with pre-existing
> heart disease or going on concomitant meds, such as calcium channel
> blockers.
>
> Then, the point made again that a ritonavir-boosted regimen could
> provide some more concern for using\--or concern in terms of levels.
>
> We are supposed to consider other parts of monitoring. Let\'s go to
> liver function test monitoring.
>
> Dr. Sherman.
>
> DR. SHERMAN: We already had considerable discussion about the
> bilirubin and I don\'t think we need to reopen that at this point. The
> question is other liver function tests monitoring, and I am not quite
> as sanguine about that. I am concerned about patients on these
> medications being followed for evidence of liver toxicity, and I think
> there should be a regular monitoring schedule for liver enzymes
> recommended.
>
> I don\'t know what that is going to be, certainly an early timepoint
> sometime between 4 and 12 weeks would certainly be reasonable after a
> baseline value is obtained to look for changes.
>
> However, data from the ACTG and other sites suggest that toxicity
> associated with PIs as a class can occur almost at anytime out in the
> course of following patients, maybe between the six month and a year
> mark just as common as before. So, repetitive monitoring with liver
> enzymes is probably indicated.
>
> That is the big issue in terms of basic monitoring. I will have some
> comments later in terms of perhaps future studies that may be needed
> to raise the bar with some of these issues, but I don\'t think they
> are applicable here.
>
> DR. GULICK: Other comments on routine LFT monitoring besides what was
> said? Dr. Fish.
>
> DR. FISH: The chemistry panels that we typically order just have the
> total bilirubin on them. These are designed based on kind of the
> Medicare guidelines as what they will cover, and so on, so just that
> caveat of requesting the indirect at least once probably when a
> patient has hyperbilirubinemia to prove that it is indirect.
>
> DR. GULICK: Dr. Sherman.
>
> DR. SHERMAN: That\'s interesting because I think that is an issue and
> there is another monitoring issue related to bilirubin, and that is
> that a change that occurs, suppose a patient starts the drug and their
> bilirubin goes to 1.9, 2.2, which would be a fairly common range for a
> patient particularly with a heterozygote, Gilbert\'s.
>
> I think that one of the issues is how do you not miss, not drug
> toxicity, but the evolution of another hepatic process, and if we are
> going to get liver profiles over time, then, a later change in
> bilirubin certainly should be noted as something that requires further
> evaluation of etiology and that she should not just assume then from
> that point on that, well, this patient is on this drug, and bilirubins
> are up, and we never have to worry about it.
>
> DR. GULICK: Other comments?
>
> Okay. Resistance testing. I guess our consensus before was that we
> should follow standard guidelines and a that treatment-experienced
> patient should have resistance testing prior to starting the regimen.
> That is not different than current guidelines.
>
> Gilbert\'s genetic testing. Dr. Sherman, you mentioned before is not
> really routinely available.
>
> DR. SHERMAN: It is not routinely available and as I indicated, I did
> not feel it is routinely indicated because you can look at a much
> cheaper assay to determine if Gilbert\'s is present.
>
> DR. GULICK: Then, Dr. Remmel, you suggested maybe TDM would be an
> interesting thing to think about for this drug.
>
> DR. REMMEL: Certainly, the sponsor has shown, at least in a naive
> patient population, that we have good effect with this drug, however,
> I think this would be helpful. I mean I personally believe that we can
> learn something from doing this. We have other drug classes where we
> do it routinely, epilepsy is certainly an area that I have been
> involved with a long time, and we do that routinely.
>
> It is not something sponsors like to hear, but I think that we can
> understand more about this drug. It does have a very large variability
> in the PKs when it is not taken with a boosted ritonavir dose, and I
> think getting an idea of at least a trough concentration given the
> cost of these drugs and if there is a demand, there will be
> availability to do the levels. There is already a company set up to do
> that, so it is really not overly burdensome.
>
> Now, it may be overly burdensome for certain patients and certain
> types of practices, but I think from the company\'s standpoint, I
> would want to know where is my trough levels. It might help me to
> better design a Phase IV trial. It certainly would be useful in a
> situation when we have experienced patients and we are talking about
> failure, that should be just as important as genotyping and
> phenotyping.
>
> DR. GULICK: Dr. Fletcher, anything to add?
>
> DR. FLETCHER: I would agree. I think as a Phase IV study, this would
> really be a worthwhile study to consider. It actually goes to Dr.
> Sun\'s question about what was the incidence of pharmacokinetic
> reasons for failure in patients, and if you look at the
> well-controlled pharmacokinetic studies that the sponsor presented,
> the range of trough concentration goes down to 12 nanograms per ml,
> which is below the adjusted IC50 and I think has to clearly put a
> patient at risk of failure.
>
> So, if there is a strategy by which not only in the experienced
> patient that Dr. Remmel talked about, but in the naive patient where
> the best response is always to the first regimen. If there is an
> opportunity to improve the rates of response in naive patients, I
> would think that would be good for patients, good for the sponsor to
> take a look at. So, I would encourage some serious look at whether
> therapeutic drug monitoring could improve response of patients to this
> drug.
>
> DR. GULICK: Any other routine clinical or laboratory monitoring that
> we want to suggest or talk about?
>
> Dr. Remmel. I don\'t mean for future study, but for the label now.
>
> DR. REMMEL: I am not sure where this fits, but in terms of drug
> interaction profiling.
>
> DR. GULICK: Let\'s come back to that one. That is an important point,
> but let\'s come back.
>
> Dr. Englund.
>
> DR. ENGLUND: I think the one thing the sponsor has shown is the effect
> if someone is positive hepatitis B, hepatitis C, which, in fact,
> should be routine care for patients anyway, but I think in this
> particular case, the physicians taking care of patients should know
> the patient\'s hepatitis status, not that you would necessarily stop
> it, as we said, but that would help to explain after you initiated
> therapy.
>
> DR. GULICK: Good point.
>
> So, consensus sounds like routine monitoring of transaminases to
> fractionate bilirubin if it\'s elevated as per clinical practice, to
> check baseline hepatitis serologies, and again a disagreement on EKGs
> in the routine setting, but indicated in other settings.
>
> Resistance testing is clinically indicated and none of the other tests
> routinely is the consensus of the committee.
>
> Let\'s move to Question 3 because Dr. Illingworth has to leave in a
> couple minutes anyway.
>
> Does the effect of atazanavir on lipid parameters offer patients a
> clinically significant advantage over other treatment options? Dr.
> Illingworth, let\'s start with you.
>
> DR. ILLINGWORTH: Yes, I think it does. I think the rise of about 15
> percent in LDL and the rise in triglycerides on other protease
> inhibitors, and the lack of effect of this drug are very positive
> benefits. Obviously, the long-term therapy is important.
>
> You are going to also, by using this, you are going to have less
> patients who are on statins or other drugs that may interact with
> other drugs. So, atorvastatin, simvastatin, those are metabolized by
> the cytochrome p450/3A4 system, so not being on those may have
> benefit.
>
> So, monitor the lipid profile, but obviously, if a drug does not have
> any adverse effects on plasma lipids, that\'s positive.
>
> DR. GULICK: Could you comment on the fact that we didn\'t see effects
> on lipodystrophy or cardiovascular events?
>
> DR. ILLINGWORTH: Probably the time frame to show an effect on
> cardiovascular events in patients without known cardiovascular disease
> or without particularly high levels of LDL, you are going to take five
> years to show a benefit in prime intervention.
>
> In second intervention, patients with known vascular disease, then,
> obviously, the second intervention trials are shown in about the first
> two years even in patients where the LDL is down about 100. So, if you
> have somebody with known vascular disease, getting the LDL down lower
> has benefit, that is clear.
>
> There have been five big trials with simvastatin, pravastatin,
> lovastatin, and in the recent publication last year, the Heart
> Protection from Rory Collins at Oxford showed a benefit even in
> patients with LDLs of 100 that are starting out with vascular disease,
> getting it lower.
>
> Beyond the NCP3 panel, one of the debates we had was, ,well, should we
> have the optimal LDL equal to or less than 100, which was on the NCP2
> panel, or less than 100. The vote was less than 100. The clinical
> trial data gets more and more beneficial, that lower is better.
>
> So, using a drug for HIV, that does not adversely affect lipid
> profiles, I think is very positive events.
>
> DR. GULICK: Again, could you comment on the lipodystrophy? We heard
> that there was not a lot of difference in the self-reported
> lipodystrophy. Is it a timing issue again?
>
> DR. ILLINGWORTH: It may well be, yes. We don\'t really know what
> causes lipodystrophy in all these patients anyway.
>
> DR. GULICK: Other comments? Dr. Kowey.
>
> DR. KOWEY: I guess I am a little hung up on the term \"clinically
> significant.\" First of all, I agree that if you had your druthers,
> you would love to see a drug like this not raise LDL levels and not
> raise cholesterol levels, there is no question, but there is a
> statement in here that says \"clinically significant advantage.\"
> Unfortunately, because of what you said, and I agree completely, there
> is not enough time in these trials to really see the effects. The age
> groups are wrong, these people don\'t have a cardiovascular disease
> going in. There is really no reason to think that you would have seen
> a difference. I mean it would have been impossible to see a difference
> in cardiovascular endpoints.
>
> So, again, it is very analogous. The question is in the absence of
> definitive information, what do you say. I think it is reasonable to
> say it is better to have a low cholesterol than a high cholesterol, it
> is better to have a low LDL than a high LDL, but this says
> \"clinically significant advantage,\" and I don\'t know has that
> really been proven for this dataset. I guess it\'s a question.
>
> DR. GULICK: Dr. Illingworth, a response?
>
> DR. ILLINGWORTH: One of the issues I put in, and I know I was going to
> give you, for Phase IV studies, were we to look at markers of vascular
> information, so look at perhaps the effects of different protease
> inhibitors in different treatments for HIV on things like high
> sensitivity C-reactive protein is a marker for vascular information,
> HSCRP.
>
> DR. GULICK: Mr. Sharp.
>
> MR. SHARP: I guess something that concerns me is once the drug is
> approved and marketed, how the company is going to advertise for the
> drug. Do they tell everyone that it is good for\--that it improves
> lipodystrophy? People in the community and patients especially don\'t
> really know the difference between elevated lipid levels and body
> shape changes, and they consider them all one thing, so I would just
> urge that once a drug is approved, that it is marketed towards saying
> that is has a less effect on lipid levels than lipodystrophy.
>
> DR. GULICK: Maybe we could ask Dr. Grunfeld to comment on this.
>
> DR. GRUNFELD: Carl Grunfeld, Professor of Medicine, University of
> California at San Francisco.
>
> I agree with Dr. Illingworth that we don\'t know the cause of
> lipodystrophy. In fact, there is a debate as to what the syndrome or
> syndromes are, and I think you can look at it as two components,
> lipoatrophy and lipohypertrophy. There are associations of lipid
> abnormalities or glucose abnormalities with the fat changes, but I
> believe there is no credible evidence linking any of the metabolic
> changes as causal towards the fat changes.
>
> Mr. Sharp is correct that not everyone in the community or among
> investigators understand it. So, for other drugs, there is not an
> inherent link between any particular metabolic change and any
> particular change in fat distribution causally in that direction
> metabolism to fat distribution. There is no reason to expect, at this
> early point, in trials there to be a change here.
>
> The fat changes reported in the early dexa data show an increase in
> fat consistent with return to health, and no sign of the lipoatrophy,
> which is the most stigmatizing version, but again, it is only 48-week
> data at which point you would only expect to see return to health, and
> not the onset of lipoatrophy.
>
> The causal link between any of the drugs in the class is of great
> debate among the researchers in the field.
>
> DR. GULICK: As long as we have you there, let me pose this question
> directly to you. Does atazanavir, its effects on lipids, offer a
> clinically significant advantage over other treatment options?
>
> DR. GRUNFELD: Well, I think we may need some comments from Dr.
> Pearson, but I would actually like slide 69 up. I agree with Dr.
> Illingworth that any change, particularly now that we know that people
> are at high risk and Dr. Pearson will address that, would be better,
> and I think Dr. Pearson would be better to address the risk.
>
> \[Slide.\]
>
> But this is an example of the use of lipid-lowering agents in trials,
> and I want to point out that particularly in the experienced patients
> where we have a bigger effect, the amount of lipid lowering agents in
> the comparator was much higher than in atazanavir in 043, and in the
> comparator of lopinavir/ritonavir in 045 versus atazanavir/ritonavir
> in 045.
>
> The actual use is lower, indicating that among other things, this is a
> major concern among practicing physicians, that people are being
> aggressively treated because the risk factors are high in HIV
> population indicating the need for aggressive treatment, and there is
> less need for treatment with less complications.
>
> I think the terms of risk profile would be better addressed by Dr.
> Pearson.
>
> DR. GULICK: Okay.
>
> DR. PEARSON: I am Tom Pearson, Professor and Chair, Community and
> Preventive Medicine, University of Rochester. I also direct the
> Preventive Cardiology Clinic where we have been seeing increasing
> numbers of patients with HIV positivity and with lipid abnormality,
> and I think have been looking for options for them.
>
> I think in trying to rationalize what Dr. Kowey and Dr. Illingworth
> said was I agree with Dr. Illingworth that these lipid changes of 15
> to 20 percent for LDL and 20-plus percent for triglycerides are those
> that we oftentimes try to attain with lipid medications lowering them,
> so this is somewhat the flip side.
>
> But I also agree with Dr. Kowey that this is a young group. The recent
> Fozetti \[ph\] study in The New England Journal, only 11 percent of
> those individuals were above the age of 55, 2 percent apparently,
> nationally, are above the age of 55.
>
> This is an epidemic in progress, in happening, not here yet. So, I
> would like slide 6A5, talking about the risk of this group because in
> my experience, clinically, this is a group with a lot of risk factors
> that really haven\'t happened yet.
>
> \[Slide.\]
>
> You can see here. This is from the DAD study, 23,000 HIV-positive
> patients. You can see that high level of smoking. These are risk
> factors that occurred probably even before HIV positivity.
>
> You have some others. Dr. Grunfeld, for example, is an author of some
> of the first studies showing that elevated triglycerides are, in fact,
> characteristics of HIV-positive patients, and then you have some risk
> factors that are probably due to therapies, such as protease
> inhibitors.
>
> So, if I could then relate these as important 6U5. What we know from
> the Framingham heart study is that in the presence of other risk
> factors, that increase in cholesterol from low to high has a much
> greater absolute change.
>
> On the bottom, you see various combinations as you go from left to
> right, to more and more risk factors. Again, we are showing a multiple
> risk factor profile in the HIV-positive patient currently.
>
> You can see as you go from 185 to 335 in cholesterol, you see this, as
> you get more and more risk factors, these large absolute changes. So,
> if we were in the right age group, here, these individuals being in
> their mid-50s, we would be seeing this in the HIV population.
>
> I think this is what we want to avoid, and we want to come up with
> options that I can give in my preventive cardiology clinic to the
> HIV-positive patients in sending a letter back to the referring
> physician about some other options for them.
>
> DR. GULICK: Thank you.
>
> Other committee members who would like to ring in on this issue? Dr.
> Englund.
>
> DR. ENGLUND: As a pediatrician, I would like to say that we have very
> grave concern about having high cholesterol levels in our very young
> kids when we expect them to live for 20 and 30 more years.
> Unfortunately, you don\'t have quite enough data for us, so I can\'t
> say it, but I would say that in the future, that is what we can look
> forward to.
>
> We are very concerned with having even moderately high levels, and I
> think our pediatric colleagues can speak to that, in some of our kids.
>
> DR. GULICK: Dr. Kumar.
>
> DR, KUMAR: I do agree that there is a very favorable lipid profile,
> but I do want to add and the sponsor themselves had said that any
> information on lipodystrophy was only passively collected, there was
> no concrete attempt to collect this data.
>
> So, all we can say is that it has a favorable lipid profile.
>
> DR. GULICK: I wanted to raise an issue where I heard something
> different from the sponsor and the agency, and it was about the study
> of people on nelfinavir who switched to atazanavir, and the sponsor
> said that there was a return to baseline levels of lipids and
> triglycerides, the agency said that it wasn\'t really baseline, or
> maybe I misunderstood, but could we get some comments on that, did I
> mishear that?
>
> DR. MARCUS: I don\'t think we have any major disagreement on this
> point.
>
> DR. GULICK: So, you would agree that they went to baseline?
>
> DR. MARCUS: Yes. I actually put up a slide looking at triglycerides
> over time for studies 007 and 008, and not the switch study.
>
> DR. GULICK: Thanks for that clarification.
>
> Dr. Mathews.
>
> DR. MATHEWS: I just want to make a point regarding what is known or
> not known about when the drug is combined with ritonavir or other
> protease inhibitors, because, you know, until a study is done
> comparing the boosted to the unboosted regimen, at least when I asked
> this morning, the sponsor didn\'t have any specific comments about how
> much of the effect might be attenuated.
>
> So, in the treatment-experienced patient where there will be a
> tendency to use it in that way, I think the label should not overstate
> the benefit in terms of lipids until there is data on that point.
>
> DR. GULICK: Could the sponsor, do you have data from 045?
>
> DR. GIORDANO: Yes. Again, the data that I have, 045, are comparative
> data, atazanavir with ritonavir versus lopinavir with ritonavir, so I
> would like to show the 045 LDL cholesterol data, so 6G8.
>
> \[Slide.\]
>
> Again, with regard to LDL cholesterol, you see large differences in
> the LDL cholesterol values at the end of 16 weeks of therapy with
> atazanavir with ritonavir, which is in green, or lopinavir/ritonavir
> as a comparator, which is in orange.
>
> Similar effects are seen if I showed you total cholesterol. What I
> will show you now are fasting triglycerides, so 6J8.
>
> \[Slide.\]
>
> Again, in green, and in blue are the two atazanavir arms. The green
> reflects atazanavir boosted with ritonavir. Through 16 weeks, there is
> very little change in the fasting triglycerides, whereas, the
> comparator agent lopinavir/ritonavir is associated with a 34 percent
> increase in triglycerides.
>
> So, the patient who is facing the choice at the time of needing a
> treatment regimen when they are heavily treatment-experienced, would
> have significantly lower lipids if treated with ritonavir/atazanavir
> as opposed to lopinavir/ritonavir.
>
> DR. MATHEWS: Yes, but that isn\'t the question that I was asking. It
> was the effect of boosted atazanavir compared to unboosted. In one of
> the slides that Dr. Grunfeld showed, when you looked as an indicator,
> the proportion on lipid-lowering therapy in experienced patients from
> unboosted, it was like 4 percent boosted, it was 7 percent, which is
> nearly twice as much.
>
> So, I think it is relevant to know what the direct comparison is, how
> much of the benefit is lost if it\'s boosted.
>
> DR. GIORDANO: We don\'t have data which is a head-to-head comparison
> of atazanavir boosted versus unboosted, so I can\'t answer that
> specific question, sorry.
>
> DR. GULICK: Dr. Sherman.
>
> DR. SHERMAN: Actually, before you leave, the same subject. Do you have
> the data broken out about patients that were not on any lipid-lowering
> agent and the comparison between the arms?
>
> DR. GIORDANO: The data that I have shown you reflect data through
> institution of a lipid-lowering drug. We also did sensitivity analysis
> to look at what happens to the effect when you added those values
> should lipid-lowering therapy be added.
>
> Interestingly, the only time it makes any significant differences on
> the experienced patient studies, because far greater numbers of
> lopinavir/ritonavir subjects instituted therapy for high lipids, so
> that brought down the means for the lopinavir/ritonavir arm because
> they were censored.
>
> So, independent of the analysis done either if you include
> lipid-lowering agents in or not, the same statistical differences are
> observed, and the same large differences are observed.
>
> DR. GULICK: Let me bring us to a close on this question.
>
> The question, atazanavir\'s effects on lipid parameters offer a
> clinically significant advantage over other treatment options, the
> consensus of the committee is yes, that there are clinical benefits.
> The immediate ones are reducing the number of anti-hyperlipidemic
> agents that are needed, so this improves convenience.
>
> As was stated by Dr. Illingworth, reductions in cholesterol LDL and
> triglycerides on other studies we know provide benefits. It is
> probably too early to tell, as several people mentioned, whether these
> will have repercussions on cardiovascular events here.
>
> The HIV-infected population is younger than other populations that
> have been studied, but may have more other risk factors, such as
> smoking, and as Dr. Englund pointed out, the pediatric population
> presents an interesting group because we are going to be treating
> patients for years with some of these agents.
>
> There was a sense that we need more information on lipodystrophy, and
> we heard that there is really a disconnect. We don\'t know the
> mechanism of lipodystrophy, there may be a disconnect between
> hyperlipidemia and lipodystrophy.
>
> Finally, concerns about using boosted atazanavir with ritonavir on
> lipid levels, and we saw some early data from the sponsor.
>
> Let\'s move to Question 4. Based on resistance data, what
> recommendations would you have regarding the use of atazanavir in
> naive and experienced patients?
>
> A thought-provoking question clearly. Let\'s start off with the naive
> group. So, we have heard a story about atazanavir, that it has a
> signature mutation which is unique, which retains sensitivity or
> perhaps provokes hypersensitivity to other protease inhibitors.
>
> Does that impact on your choice of agents for naive patients in
> general? Is that a good thing?
>
> Dr. Fish.
>
> DR. FISH: As a sequencer, this is going to be a great drug, so for
> naive patients, the comment was made in terms of regarding doing
> resistance testing very early on. Someone mentioned the revision of
> the guidelines for use of resistance testing.
>
> If we go there, then, that would help us even further in ferreting out
> those few naive patients who might get some mutation that was
> transmitted, some PA mutation where atazanavir might have decreased
> susceptibility, but otherwise, it looks very good in the naive patient
> population, and we have good options afterward for when a patient
> might fail if they are failing that component of their cocktail.
>
> DR. GULICK: Can I make a comment myself, that a lot of what we heard
> in the presentations today were about the initial segmentary mutation
> that you see with atazanavir, and actually the statement was made more
> than a few times that resistance uncommonly develops to atazanavir.
>
> But I guess what I would point out is in the studies, when people
> broke through, when they had virologic failure, they were quickly
> attended to, resistance testing was sent, and this was acted on quite
> quickly.
>
> In clinical practice, that is often not what happens, people continue
> regimens in the presence of ongoing viral replication for longer
> periods of time, and I don\'t know if we have data to show for this,
> but with other protease inhibitors, that leads to an accumulation of
> mutations and eventual cross-resistance to the class.
>
> DR. COLLONO: Rich Collono again, BMS.
>
> Let me just show you two context slides and then I will show you a
> specific slide to that answer, because there wasn\'t much really
> discussed about the I50L, and we need to understand where the I50L is.
>
> Could I have B1, please.
>
> \[Slide.\]
>
> Again, the resistance profile is quite distinct and we have a very
> unique signature mutation. I just want you to understand why the
> signature mutation actually comes up. In treatment-naive patients, 100
> percent of the time we find 23 isolates give rise to the I50L.
>
> In treatment-experienced, if you use atazanavir and saquinavir, one
> never sees the I50L. Instead, you go down a bunch of normal pathways
> that you would see with other PIs.
>
> When you treat with atazanavir or boosted atazanavir, the experienced
> population, we have nine isolates, about 20 percent, that actually do
> give the I50L mutation, so it is not just naive, it is also those
> treatment-experienced patients that are susceptible to atazanavir at
> baseline.
>
> If I can have the next slide, B2, please.
>
> \[Slide.\]
>
> The consequence of having the I50L mutation is shown here. Taking all
> those isolates that I showed you on the previous slide and simply
> dividing it into three groups, those that came up with the I50L, which
> are shown in green, you get specific resistance as mean change from
> baseline, just to orient you on the slide.
>
> You get a mean change of 10-fold to atazanavir, so atazanavir\'s
> specific resistance which people have referred to, but as you can see,
> you get an increase of susceptibility to each of the other PIs across
> the board, and this is pretty universal whether it is from naive
> patients or from experienced patients.
>
> In contrast, if you get atazanavir resistance through a different
> pathway, it does not involve the I50L, then, you clearly see what you
> have here in the blue bars where you get resistance to atazanavir, but
> you also get increased resistance to the other PIs.
>
> The third one is just saquinavir/atazanavir, which is not important
> other than to say that clearly you get resistance to atazanavir and
> saquinavir, again increasing the resistance level to all of the PIs.
>
> Now, as to your question, what happens after that, if I can have B-14,
> please.
>
> \[Slide.\]
>
> Once that I50L mutation is there, we have, unfortunately, only two
> isolates, but perhaps it starts to answer the question. We have very
> few, as you can see, I50L isolates to deal with, but we have two, one
> that continued on for 12 weeks, one that, more importantly, continued
> on for 24 weeks.
>
> Here is the profile again where you have resistance to atazanavir, you
> have increased susceptibility by the numbers being 0.4, 0.3, et
> cetera, to the other PIs, and I have viral load here. As you can see,
> there was really no change in viral load over the 12 weeks.
>
> More importantly, for the one that was for an additional 24 weeks, we
> see no real change in increased resistance to atazanavir. We maintain
> this phenotype associated with the I50L, that is, increased
> susceptibility to the other PIs. Again, viral load is very steady and
> stable.
>
> If you look at the genotype of those two sets of isolates, in the
> first set, you see no additional mutations being put in, despite
> continuing on atazanavir.
>
> In the second set, we see a couple mutations bouncing around, 16
> disappears, comes back. We don\'t think it is really relevant. 33F
> comes up, 64V comes up on top of this background, but again, there is
> no real impact on the phenotype. So, this is the data we have now,
> very limited, but to answer your question, this is the data that we
> have.
>
> DR. GULICK: So, 100 percent of these two patients did not have any
> evolution. As a virologist, Rich, would you like to predict what will
> happen as people continue to stay on this longer term?
>
> DR. COLLONO: Of course, they are going to evolve to additional ones,
> but it is not\--I guess the key point with the 50L, it is not a quick
> stepping stone where you get 50L and immediately go on to the next
> version. We have no indication of that in vitro or clearly in a couple
> clinical patients that we have.
>
> DR. GULICK: Let me ask you two follow-up questions. When you call
> someone \"treatment experienced,\" that is on the basis of history or
> those people have evidence of protease inhibitor mutations in the
> slide that you showed?
>
> DR. COLLONO: The treatment experienced were basically entry into the
> program, qualified for the entry into those experienced programs. It
> doesn\'t necessarily mean that they were resistant to multiple PIs.
>
> DR. GULICK: So, that is my question. If someone has PI resistance
> mutations, goes on atazanavir, have you ever seen, in that scenario,
> that they only come through with an I50L as their next mutation?
>
> DR. COLLONO: Yes. Of those nine isolates that developed the I50L, all
> of those developed an I50L on top of an atazanavir resistance
> background, or in one case, we have one in the boosted from 045,
> actually, that was resistant to four PIs on baseline, but the I50L
> also. So, yes, it does happen, it is not just in a background of no
> resistance.
>
> DR. GULICK: Great. My second specific question is do we have any
> clinical data from someone who was naive, went on atazanavir, failed
> with the I50L, and then went on to another protease
> inhibitor-containing regimen, is there any clinical data?
>
> DR. COLLONO: There is no clinical data.
>
> DR. GULICK: Dr. Sun.
>
> DR. SUN: I have sort of a similar question, which is did any of these
> patients, when you detected the I50L, and thought maybe it was due to
> adherence or compliance issues, go back on atazanavir.
>
> Sort of the corollary would be, if the answer is no, is it your
> interpretation of the data that the I50L is sufficient to confer
> clinical resistance to atazanavir by itself, so analogous to the 184V
> for 3TC or the NNRTI mutations?
>
> DR. COLLONO: The I50L, by itself, when you put it into recombinant
> clones as a single mutation, will give you a decrease in
> susceptibility, but the I50L alone does not give you a resistance
> level high enough to overcome the PK multiple that we have.
>
> So, the I50L is always in a background of 10, 12, 14 other mutations.
> We have no clinical isolates that only developed the I50L. There are
> just, of course, other mutations there. There is just no pattern to
> those mutations that are also occurring with I50L. It is just a
> background that you would find with resistance to many PIs.
>
> DR. GULICK: Dr. DeGruttola.
>
> DR. DeGRUTTOLA: Actually, that was my question. For the patients that
> you showed in the naive study, where 100 percent of them had developed
> the I50L, I think you just answered it, that there is a variety of
> different types of mutations that they develop, but I was wondering if
> you can just expand on that a little bit more, basically, typical for
> proteases in general.
>
> DR. COLLONO: I can actually, probably show you that. Go to D2, please.
>
> \[Slide.\]
>
> Again, this is just really comparing for a different reason, but it
> gives you the answer, I think, that you want, comparing the background
> for responders, the ones that develop I50Ls and the ones that do not
> develop I50Ls when they become resistant.
>
> Again, this is a subset of all the substitutions that we have looked
> at, but these are the ones that seem to have some differences between
> those three groupings. The only four mutations positions, at least
> with this particular analysis, that showed any kind of predictive
> nature, was an amino acid change at 14, usually 14R, that seemed to
> correlate with\--you can see the green bar\--seemed to correlate with
> I50L, the presence of a 46I also seemed to correlate, and also an 88D.
>
> Then, on the opposite side, if you had a 90M, you tended to have the
> opposite relationship, so the 90M, you had less likelihood of getting
> the I50L. But apart from those mutations, there is really nothing
> different between the responders, I50Ls, and non-I50Ls.
>
> DR. GULICK: Dr. Remmel.
>
> DR. REMMEL: Given the durability, even with the I50L, do you have
> information on the fitness of the virus with just I50L mutants? You
> talked a little bit about an N88, which is a compensatory mutation to
> increase the fitness.
>
> DR. COLLONO: Yes, we can talk about fitness. Just give me one second
> here.
>
> As you point out, we have done this different ways. Of course, we have
> done it more traditionally with just drawing the virus and seeing what
> the fitness is, and then, in addition, we have actually gotten data
> from ViroLogic on a number of these isolates.
>
> If I can have C10, please.
>
> \[Slide.\]
>
> Again, this is the more traditional growth curve, if you will. We took
> two clinical isolates with these backgrounds and put them into a
> recombinant clone, a laboratory isolate. The laboratory isolate is
> shown in green, and there is a normal growth curve over a period of
> days.
>
> If you put in the number back, the 12 amino acids that we found as
> clinical isolate, you get the yellow curve, and the only difference is
> you put in the 50L and minus the 23, and you get this again,
> significantly growth-impaired virus.
>
> Then, from the virologic data that we have, RCs, as you can see, we
> have this list here, but the vast majority of these, all but two,
> actually have an RC of 15 or less, so these are significantly impaired
> viruses. We have never had a 50L-containing virus that seemed to grow
> like normal or in wild type virus.
>
> DR. GULICK: Other comments from the committee on resistance in terms
> of using this drug in naive patients?
>
> Dr. D\'Aquila, can I put you on the spot to comment on that point?
>
> DR. D\'AQUILA: I would be happy to, Trip.
>
> I think the data are promising. They suggest the possibility that not
> only will future treatment options be open to the naive patient who
> fails atazanavir, but the potential that the other drugs in this class
> might actually work better.
>
> I think that remains to be proven. There are some preliminary data
> looking at viruses that are hyper-susceptible, increase susceptibility
> to amprenavir that were presented recently, in February.
>
> There is also a couple of studies looking at non-nucleoside RT
> inhibitor, hyper-susceptibility, where in both of those situations,
> the viruses that had increased susceptibility in vitro, when that drug
> was used, there was a better viral load response than was seen against
> viruses that had normal wild type susceptibility.
>
> We just don\'t have that clinical data today, but I think I would
> expect that that is what you would see. Again, that is in the
> situation where this change in susceptibility leads to something
> greater than a 0.4 fold or I should say a number that is smaller than
> 0.4 in a shift in IC50.
>
> I don\'t know what sort of effects will be seen if the I50L comes in a
> background where there is some other resistance mutations already
> present, and the I50L modulates the resistance downward, maybe not all
> the way to fully wild type virus.
>
> That may not give us the same effect. There may still be resistance
> present although it is possible that even in the situation of
> decreased resistance, we will see some degree of improved responses,
> but I think the greatest potential is in the situation where you have,
> first, PI failure, and that introduction of I50L leads to increased
> susceptibility to other PIs, and potentially, you could follow up with
> a regimen that will work better than it would have worked otherwise.
>
> DR. GULICK: Thanks.
>
> Other comments on this population? Let\'s shift gears and talk about
> what did the resistance data imply about the use of atazanavir in
> experienced patients. We saw lots of evidence for cross-resistance in
> the highly PI-experienced patient. Maybe we could also think about
> again atazanavir by itself versus boosted atazanavir.
>
> Dr. Fletcher, why would a boosted ritonavir containing atazanavir
> regimen work better against a resistant virus?
>
> DR. FLETCHER: Well, I think, to use the term from the sponsors, the PK
> cushion. You have an inhibitor that is going to raise the atazanavir
> levels, and in the case of viruses that have decreased susceptibility,
> it will provide the more typical type of relationship between the
> concentration of drug and the concentration that the virus needs to
> inhibit it.
>
> I think it seems from a regulatory sense, I think the real issue is
> what type of information here do you try to communicate to the
> prescribers, you know, to the patients, to the individuals that are
> going to be using this drug, and beyond just those pharmacologic
> understandings now is when I totally have no expertise, but people
> talked about what a cut point might be, at least with the phenotypic
> assay.
>
> I think I would leave it to others to comment on that, but that at
> least to me, there seemed to be some discrimination there in terms of
> responders and non-responders. I think that could be very, very useful
> information to convey somehow again to prescribers and to patients
> that would be taken the drug.
>
> DR. GULICK: Dr. Kumar, can I pick on you and say, as a clinician, how
> are you going to use atazanavir in the experienced population based on
> resistance issues?
>
> DR. KUMAR: I am struggling over that. As I have said several times
> before, I have a great deal of comfort in my naive patients, and in my
> mind, it is very clear that even if they fail, I have a part of where
> to go, but I am not that sure in the treatment-experienced patients,
> so I will stop right there.
>
> DR. GULICK: Dr. Fish, can I pick on you, too?
>
> DR. FISH: Sure. I think that the data that was presented by the
> sponsor, the issues come up more with three or more PI use, so I
> think, you know, just like we use with other drugs, we have some
> information in terms of what mutations are going to confer decreased
> susceptibility and, you know, rapid utilization of genotypic testing
> and phenotypic when it is available to guide patients with resistance
> and determine whether or not it is a viable option, going be how we
> will use it in clinical practice.
>
> So, I don\'t see that it will necessarily be a lot different and time
> will tell how many are susceptible and how many are not, but it seems
> to me it would be fairly similar as we use resistance testing to guide
> our treatment decisions currently.
>
> DR. GULICK: Dr. Mathews.
>
> DR. MATHEWS: I think the dilemma is going to be what cut points are
> established by the companies that are doing a particular phenotypic
> testing because in the experienced patients, you are often dealing
> with patients who have resistance to most of the protease inhibitors
> and if this goes forward saying the cut point is 2.5, which somebody
> had mentioned earlier this morning, you know, that is not even in the
> same ballpark as some of the other clinically derived cut points for
> boosted protease inhibitors.
>
> So, I think very clearly, more information needs to come forward on
> what are realistic cut points, clinical cut points, in terms of
> initial loss of response and complete loss of response, you know, or
> major loss of response, because again in that setting, you are often
> having to choose among all poor options.
>
> As I said earlier this afternoon, if you are trying to trade off
> toxicity, simplicity, lipid stuff with virological efficacy or
> effectiveness, having a more precise estimate of what the
> pharmacodynamic response pattern is in experienced patients is very
> important.
>
> DR. GULICK: We have been struggling all afternoon with the issue of
> using atazanavir alone versus atazanavir/ ritonavir in the experienced
> population given the limited preliminary data that we saw in terms of
> efficacy, available safety data, and the available PK data.
>
> Do people have some final thoughts about how that is kind of balancing
> out in their heads? Dr. Remmel.
>
> DR. REMMEL: Again, I think this is where sometimes a pharmacokinetic
> evaluation could be helpful. If you had a 5-fold increase in
> resistance, and you have a patient with a longer half-life, you might
> feel more comfortable about raising the dose slightly to make sure
> that you have a good therapeutic window.
>
> Patients with shorter half-lives, you feel like you can\'t reliably
> raise that window. Because of a 24-hour dosing interval, you could go
> to a more frequent dosing interval or perhaps go to a boosted regimen.
> We haven\'t really talked about giving the drug on a BID schedule, but
> many patients could adhere to that schedule, and that might solve some
> of those problems.
>
> So, it would just depend on what that ratio is. Again, if you are
> going to do this without any kind of guidance in terms of where your
> concentrations are, and you are just going to use phenotyping and
> genotyping, that may make some of those decisions more difficult to
> make.
>
> DR. GULICK: Other thoughts about atazanavir versus boosted atazanavir
> in the treatment-experienced population given everything we have seen?
> Dr. Englund.
>
> DR. ENGLUND: I don\'t think I can tell. I think in my patients, they
> are all going to have been exposed to ritonavir\--the patients that I
> am going to be using it for, the most are going to be very
> treatment-experienced with ritonavir, so it is going to limit some of
> the options I have.
>
> I guess one of the things I would like to say is I would wonder
> whether any cut points should be on labeling as it is. I think the cut
> points are very test-dependent, they change over time depending on
> which company does it and who is going to be doing it two years from
> now, and which methodology they are going to be using.
>
> I think that we, as a committee, should recommend that it be done
> prior to\--I would recommend that it would be done prior to using it
> in the treatment-experienced patients, but I don\'t think we have
> enough data to be addressing that, and I also think the methodologies
> could change over time, so that is where I would be coming from.
>
> I would be concerned about ritonavir-experienced patients when you are
> talking about the boosting issue.
>
> DR. GULICK: Dr. Fish.
>
> DR. FISH: I think we know that the first HAART regimen is the best
> chance, the second HAART regimen is the second best chance, so it will
> be tempting to want to use the ritonavir boosting, so you get long
> durability of that regimen, but it will also be a tradeoff in terms of
> the potential side effects potentially into the impact on lipids that
> have been elucidated. They will come into play under those decisions,
> I think, as well.
>
> So, I think the practice will be if the knowledge is out there and the
> information that this works and is the strategy. I think in clinical
> use, a lot of that will probably happen, i.e., boosting.
>
> DR. GULICK: Other thoughts on that?
>
> Okay. So, what did we say? First of all, as a committee, we have said
> that resistance testing is something that should be in the label, and
> that has been true of the last couple of approved drugs, that we do
> find it helpful.
>
> Dr. Englund\'s concerns about making cut points too early without
> validated data is a caution to that.
>
> In terms of the impact of what we have seen about resistance data on
> the naive population, I think we find this signature mutation story
> intriguing, but we would like to see some clinical data to show that
> sequencing of protease inhibitors really has clinical value to do it,
> but it is an intriguing story.
>
> In terms of the experienced population, the point made before that
> this is a heterogeneous population with lots of different levels of
> experience that clearly we will want to use resistance testing here,
> that the drug likely has, well, we saw data to support that it has
> activity in people with one or two PIs, but as you increase the number
> of PIs and the number of mutations, cross-resistance does become an
> issue.
>
> Then, we went back to our debate about boosted atazanavir versus
> atazanavir with differences of opinion, but some people leaning
> towards the boosted as being the optimal regimen in a highly
> treatment-experienced patient.
>
> Then, the point that we made earlier today that the attractive
> features of the drug in naives are also attractive in salvage in terms
> of convenience, tolerability, and lipid profile.
>
> The last question is recommendations for Phase IV studies. Luckily, we
> have been talking about these all day and I have been keeping a list,
> so let me just read through the list and then maybe we can prioritize
> them and say what we think might be the most interesting.
>
> Some of the ones that we have mentioned over the course of the day -
> resistance studies, clinical follow-up of people who fail with
> atazanavir as their first protease inhibitor and then go on to another
> protease inhibitor, is that of clinical benefit.
>
> More studies on lipodystrophy long term, cardiovascular events long
> term, as well.
>
> Let\'s see, dose reduction of bilirubin, I guess we sort of canned
> that idea earlier today and thought that that is not something we
> would like to see pursued.
>
> Pharmacokinetic interactions with some important drugs. Some of these
> are already in progress, such as methadone. Other drugs mentioned over
> the course of the day, H2 blockers, rifampin, statins, fibrates,
> nevirapine, tenofovir in progress we heard, ribavirin, and interferon
> were some of the ones mentioned. There may be others.
>
> Long-term safety was a recurring theme today, long-term follow-up of
> the bilirubin, liver function tests, and again cardiovascular
> complications and lipodystrophy.
>
> More information on atazanavir boosted with ritonavir. Adherence
> information, pediatrics, longer term follow-up. More than once,
> pharmacokinetics particularly in terms of drug monitoring as an
> explanation for virologic failure, TDM as a possible mechanism of
> that.
>
> Mentioned more than once today was the issues about a QD regimen and
> might that put people at risk if they drop a dose on a QD regimen.
>
> We heard from our cardiology consultants some debate about whether
> further preclinical assessment would be of interest in terms of QT and
> PR effects. Also, looking at more clinical expiration of that
> including the so-called worst case scenario.
>
> Then, later on, markers of vascular inflammation was suggested by Dr.
> Illingworth on this way out the door.
>
> Anything I missed in terms of Phase IV? Oh, I missed a lot. Drs.
> Englund, DeGruttola, and then Sherman.
>
> DR. ENGLUND: Powder pharmacokinetics or powder or solution, not just
> for children, but certainly for older people G-tubes.
>
> DR. DeGRUTTOLA: I don\'t think you missed this, I don\'t know if it
> was discussed, but I just want to raise the issue of doing more
> clinical studies of the relationship between genotype and clinical
> response in treatment-experienced patients.
>
> DR. GULICK: Dr. Sherman.
>
> DR. SHERMAN: You know where mine will be. In the patients with more
> advanced liver disease, patients with cirrhosis and both compensated
> and decompensated cirrhosis, you have hepatically metabolized drug,
> and I think you need more data because we are seeing more and more
> liver disease in these patients.
>
> The follow-on to that is that we are beginning to transplant patients
> with HIV, and we already know that several of the PIs have a huge
> interaction with FK and cyclosporin. We really, really need to know
> the interaction here, so that we can evaluate dosing issues in those
> patients, not just H2 blockers, but PPIs because of the issue of
> gastric acidity, and actually the PPIs are much worse than the H2s in
> terms of neutralizing stomach acid over extended periods of time.
>
> The final one, not really so much a direct recommendation to the
> sponsor, but something to think about as we begin to raise the bar on
> liver issues is, you know, we have been using the sort of artificial
> surrogates of liver injury including the concept of Grade 3/Grade 4
> toxicities for management of patients with potential liver toxicity,
> in terms of deciding cutoffs.
>
> We know that patients with much lower ALTs over long periods of time
> can manifest significant progressive liver injury evidenced by
> scarring in the liver, and therefore, if we are going to have agents
> that we are going to keep patients on for years, we need to be
> beginning to assess what happens histologically over extended periods
> of time in at least some of these patients.
>
> DR. GULICK: Dr. Fletcher.
>
> DR. FLETCHER: My comment in some way follows Dr. Sherman\'s. This is
> on drug interactions. So, there is not only a need, I think, for
> knowledge of whether there are some other interactions out there\--and
> you ran through that list of those\--but there is also, I think, a
> need for how you are going to manage some of these interactions.
>
> Let me turn to a specific question, oral contraceptives. I am
> wondering if the sponsor has now some recommendation that they have
> thought about putting in a package insert about the management of that
> interaction.
>
> DR. SCHNITTMAN: We have actually been in discussions with the agency
> over this because of the increased levels. I mean, number one, we
> don\'t at least have to be concerned about loss of activity of the
> OCs, but there is the increased levels, and I think, as has been
> suggested already today at the meeting, using the lowest effective
> dose for that purpose would be appropriate. So, we will have further
> discussions with the agency on that.
>
> DR. FLETCHER: I guess that gets to the question, what is that? Let me
> try to push you a little bit more. What would you propose to say in a
> package insert? So, here is the interaction between ethinyl estradiol
> and norethindrone. The levels of both are increased, so to say use the
> lowest effective dose, well, how do you know what the lowest effective
> dose is until it fails?
>
> DR. SCHNITTMAN: Well, no, I mean I think the concern is on the up side
> there, you know, with the recent reports about long-term usage of
> these agents, and I think that is going to require a lot of thought
> about the appropriate wording on this, because this is a relatively
> recent kind of concern overall, I think that we haven\'t seen in
> labels before.
>
> DR. FLETCHER: Just one more. So, that is my issue. I think that is not
> enough, at least for some of these interactions, to just say that
> there is an interaction there. I think some type of guidance to the
> clinician in what to do in terms of managing the interaction, I think
> is really necessary.
>
> I think the additional issue that it seems to me you are going to have
> to work out is what do you say about ritonavir. If there is in the
> label, then, some mention of using boosted atazanavir, the drug
> interaction issues have to then talk, not only about atazanavir, but
> are going to have to talk about ritonavir interactions, as well.
>
> So, it seems to me it adds a much greater degree of complexity in that
> section than I have probably seen before. I guess maybe it\'s like the
> Kaletra label, but there you don\'t have a choice. You get both drugs
> together and so there is not an issue of separating one or the other.
>
> Here, there really is the issue of atazanavir interactions that can be
> separate then from atazanavir and ritonavir interactions, and I think,
> to me, this needs certainly more study, but probably also a lot more
> thought about how that will get put into a label.
>
> DR. GULICK: The agency has faced this before with amprenavir. How did
> you address that?
>
> DR. BIRNKRANT: I don\'t think I can recall that at this point in time
> of the day.
>
> \[Laughter.\]
>
> DR. GULICK: Fair enough.
>
> Dr. Remmel.
>
> DR. REMMEL: While this isn\'t necessarily a Phase IV study, I think
> preclinically, there are a number of other drug interactions and
> effects on enzymes on CYP2B6, which is important for efavirenz and
> nevirapine metabolism. You had alluded to some inhibition of 2C9 and
> 1A2 and maybe getting a better definition of what those Ki\'s are,
> what the degree of inhibition is going to be.
>
> We have a lot situations here where you write in the therapeutic
> range. You have got 2 micromolar for UGT 1A1, you have got 2.5
> micromolar for 3A4, you have got 10 micromolar for the calcium
> channel, and you have got the mean Cmax at being about 4.5 micromolar,
> and concentrations are going to make a big change in terms of those
> drug-drug interactions. So, some maybe guidance in terms of banning
> also might be important.
>
> I didn\'t see quite as much information as I would like in terms of
> each of those particular enzymes and what will be done there, but I
> think that would be useful to do.
>
> DR. GULICK: Dr. Mathews.
>
> DR. MATHEWS: I already mentioned the study that I thought should be
> done, a direct comparison of boosted versus unboosted for the lipid
> effect, but perhaps that could be studied in the context of another
> naive trial to look at boosted versus unboosted atazanavir to improve
> the long-term response rate, because as we have already commented on,
> for whatever reason, you know, 65 percent, whatever it was, suppressed
> at 48 weeks is not optimal obviously, so that is another study I think
> that could be considered.
>
> DR. GULICK: Dr. Fish.
>
> DR. FISH: I think it was Dr. Remmel\'s suggestion, but I think it is a
> great one, for the treatment-experienced patient, comparing boosted
> ritonavir with BID atazanavir, and most of the patients who are in
> highly salvaged situations are on twice-a-day regimens anyway.
>
> DR. GULICK: How are we doing, Dr. Birnkrant, have we lived up to your
> expectations here?
>
> DR. BIRNKRANT: Exceeded them.
>
> DR. GULICK: Great.
>
> DR. BIRNKRANT: I have very high standards, so that is a plus.
>
> DR. GULICK: Then, we will adjourn the meeting. Before I do that, I
> would like to thank the sponsor for their presentations, thank the
> agency also for their presentations, thank all of our committee
> members for hanging in there except the ones who left, and thanks to
> the audience.
>
> \[Whereupon, the meeting was recessed at 4:35 p.m., to reconvene the
> following day, Wednesday, May 14, 2003, at 8:00 a.m.\]