ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ANTIVIRAL DRUGS ADVISORY

 COMMITTEE MEETING

VOLUME I

Monday, November 1, 1999

8:30 a.m.

Gaithersburg Holiday Inn
2 Montgomery Village Avenue
Gaithersburg, Maryland

PARTICIPANTS

Scott M. Hammer, M.D., Acting Chairman
Rhonda W. Stover, R.Ph., Executive Secretary

Committee Members:

Henry Masur, M.D.
James J. Lipsky, M.D.
Roger J. Pomerantz, M.D.
John D. Hamilton, M.D.
Brian Wong, M.D.

Consultants:

Joseph S. Bertino, Jr., Pharm. D., Consumer Representative
Wafaa El‑Sadr, M.D., M.P.H.
Judith Feinberg, M.D.
Jeffrey B. Kopp, M.D.
Women. Christopher Mathews, M.D., M.S.P.H.
Sharilyn K. Stanely, M.D.
Joel I. Verter, Ph.D.
Ram Yogev, M.D.

Guests:

Paul Kimmel, M.D.
Jeffrey Schouten

FDA:

Douglas Throckmorton, M.D.
K. Struble, Pharm. D.
Jeff Murray, M.D.
Heidi Jolson, M.D., M.P.H.
Sandra Kweder, M.D.
Greg Soon, Ph.D.

C O N T E N T S

Introductions	5

Conflict of Interest
 Rhonda Stover, R.Ph.	6

Introductory Comments,
 Heidi Jolson, M.D.	8

Sponsor Presentation:

Overview of Development Program,
 Howard Jaffe, M.D.	20

Clinical Trial Results,
 Jay Toole, M.D., Ph.D.	26

HIV Resistance Studies,
Norbert Bischofberger, Ph.D.	53

Phase IV Plans and Concluding Remarks,
 Howard Jaffe, M.D.	62

FDA Presentations:

NDA and Clinical Development Overview and Summary
of Efficacy: Adefovir 120 mg.
 Kimberly Struble, Pharm. D.	67

Statistical Review of Study 417: Adefovir 60 mg vs 120 mg,
Greg Soon, Ph.D.	79

Summary of Safety and Virology Substudy
and Overall Conclusions,
 Kimberly Struble, Pharm. D.	86

Committee Discussion 	103

Open Public Hearing:

Sandra Burchett, M.D.	196

James Jones, M.D.	198

Paul Cimoch, M.D.	200

C O N T E N T S

Charles Farthing, M.D.	203

Howard Grossman, M.D.	205

David Hardy, M.D.	210

David Margolis, M.D.	214

Joseph McGowan, M.D.	215

Mr. Peter Hale	219

Mr. William Bahlman	223

Mr. Max Delgato	228

Mr. Timothy Christy	229

Mr. Hosam Chreim	231

Ms. Amy Sullivan 	231

Mr. Francois Ouliez	234

Mr. Michael Marco	238

Questions to the Committee and Discussion 	241

P R O C E E D I N G S
Introductions
DR. HAMMER:  I think I would like to begin by having the members of the committee and the agency introduce themselves.  Dr. Bertino, would you identify yourself for the transcriptionist and the audience, please?
DR. BERTINO:  Joseph Bertino, from the Clinical Pharmacology Research Center Basset Health Care, in Cooperstown, New York, and I am serving today as the consumer rep.
DR. EL‑SADR:  I am Wafaa El‑Sadr, Harlem Hospital in New York.
DR. STANLEY:  Sharilyn Stanley, Texas Department of Health.
DR. FEINBERG:  Judith Feinberg, University of Cincinnati, Infectious Diseases.
DR. MATHEWS:  Chris Mathews, University of California at San Diego, Department of Medicine.
DR. YOGEV:  Ram Yogev, Children's Memorial Hospital, Chicago.
DR. HAMILTON:  John Hamilton, Duke University.
DR. MASUR:  Henry Masur Clinical Center at NIH.
DR. LIPSKY:  Jim Lipsky, Clinical Pharmacology, Mayo Clinic, Rochester, Minnesota.
DR. HAMMER:  Scott Hammer, Infectious Diseases, Columbia University.
MS. STOVER:  Rhonda Stover, FDA.
DR. POMERANTZ:  Roger Pomerantz, Infectious Diseases, Thomas Jefferson University in Philadelphia.
DR. VERTER:  Joel Verter, George Washington University, guest statistician.
DR. KOPP:  Jeffrey Kopp, Nephrology, NIDDK.
DR. KIMMEL:  Paul Kimmel, nephrologist, George Washington University, leave of absence NIDDK.
MR. SCHOUTEN:  Jeff Schouten, ad hoc community representative from Seattle, Washington.
DR. THROCKMORTON:  Douglas Throckmorton, nephrologist in the Cardiorenal Division, Food and Drug Administration.
DR. STRUBLE:  Kim Struble, FDA.
DR. MURRAY:  Jeff Murray, FDA.
DR. JOLSON:  Heidi Jolson, FDA.
DR. KWEDER:  Sandra Kweder, FDA.
DR. HAMMER:  Thank you very much. I would like to turn it over now to Ms. Stover, who will read the conflict of interest statement.
Conflict of Interest
MS. STOVER:  The following announcement addresses the issue of conflict of interest with regard to this meeting, and is made 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: In accordance with in accordance with 18 United States Code 208 full waivers have been granted to Drs. Mathews, Hammer and Masur.  A copy of these waiver statements may be obtained by submitting a written request to the FDA's Freedom of Information Office, Room 12A‑30 of the Parklawn Building.
In addition, we would like to disclose that Dr. El‑Sadr's employer, the Harlem Hospital, was previously involved in an NIAID study of adefovir dipivoxil.  Dr. El‑Sadr had no involvement whatsoever in this trial...[house audio system problems]... because these studies are not primary studies to be discussed, the agency has determined, notwithstanding these involvements, that the interest of the government and the Dr. Hammer's participation outweighs the concern that the integrity...[house audio system problems]...therefore, Dr. Hammer may participate...[house audio system problems]...  In the event that discussions involve any other products or firms not already on the agenda for which an FDA participant has 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 firms whose products they may wish to comment upon.
DR. HAMMER:  Thank you.  I would like to turn now to Dr. Jolson who will make some introductory comments.
Introductory Comments
DR. JOLSON:  Good morning. I would like to welcome everyone to today's meeting in which we will discuss the application for accelerated approval of adefovir dipivoxil for the treatment of HIV.
First, I would like to extend a special welcome to our invited consultants who are joining the committee today.  I would also like to welcome Gilead Sciences, the sponsor of today's application.
The efforts of Gilead in developing this product should be commended for three specific aspects of their overall drug development.  Specifically, I would like to acknowledge their efforts in conducting investigations for treatment experienced patients; their ongoing commitment to providing an avenue for expanded access; and their development of a sizeable database on viral resistance.
[Slide]
The database supporting today's application is complex in several respects.  Before we hear the actual data presentations, I thought it might be useful to provide some of the regulatory framework and other points to consider as a backdrop for today's deliberation.
Because it has been about a year since this committee has considered an application for accelerated approval, which was the abacavir NDA, I would like to start today's meeting with a very quick review of FDA's provisions for accelerated approval.  Next, I will explain how the Division of Antiviral Drug Products actually implements this regulation with regard to what we expect to see in submissions for accelerated and later traditional approval of antiretrovirals, and the advice we will provide on trial design.  As you will hear more about today, the development of adefovir raised several challenges, and I will discuss how the general requirements for accelerated approval have been tailored to the circumstance of this application.
As the committee is aware, the sponsor elected to pursue marketing a dose that is lower than that studied in most of the Phase III development because of dose‑limiting nephrotoxicity.  Therefore, I will briefly discuss our guidance to sponsors in similar circumstances, that is, whenever a product change is made that significantly impacts the pharmacokinetic profile of an already studied drug.  Last, I will end with some general points to consider on equivalence trial design and labeled indications that I would like the committee to bear in mind as they consider today's application.
[Slide]
Most of you are already aware that the accelerated approval regulations were enacted to allow patients with serious and life‑threatening illness access to approved, safe and effective therapies where the approval would be based on endpoints that would occur at a time point earlier in trials than the ultimate disease outcome of irreversible morbidity or mortality.  Hivid or ddC was the first product for HIV to be approved under this regulation, and Agenerase or amprenavir was the most recent.
This provision is intended to be applied to those therapies that provide a meaningful therapeutic benefit to existing treatment, and the regulations provide examples such as demonstration that a new product can treat patients unresponsive or intolerant to available therapies, or demonstration that a new product is associated with an improved response over available therapies.
The phrase "meaningful therapeutic benefit" is obviously highly subjective, and in practice we have accepted a variety of ways that a product may be considered as having a therapeutic advantage, including an improved efficacy or safety profile, an improved dosing schedule, a novel mechanism of action, or a different clinical cross‑resistance profile.
The key feature of this regulation is that it provides for initial or accelerated approval based on either surrogate endpoints which are laboratory based, such as HIV RNA and CD4 for HIV therapeutics, or clinical endpoints that would occur earlier in the disease process and before irreversible morbidity and mortality.  At some time post‑marketing a sponsor may then apply for traditional approval on the basis of additional data to verify the clinical benefit of the initial finding.
[Slide]
Given that the accelerated approval provisions are not limited to HIV, the division has needed to develop guidance for how these regulations are to be implemented in the ever‑changing field of HIV therapeutics.  The division's approach to accelerated approval has evolved considerably over the years reflecting changes in clinical management, the availability of potent therapies, and the availability of standard assays for the measurement of HIV RNA.  Our current advice on this topic is available in a draft guidance document to industry.  It is available on the web site noted on the slide, and reflects the consensus reached at the July, 1997 Surrogate Marker Advisory Committee meeting that demonstration of sustained viral suppression is evidence of clinical benefit.
I will briefly comment on a few key features of our guidance.  In general, for accelerated approval the division expects that a new drug application will contain the results of at least two adequate and well‑controlled trials that provide safety, laboratory and clinical data on patients through at least 24 weeks of treatment in all patients.
Further, it is expected that the plans for traditional approval will be solidified and trials will be well under way prior to granting an accelerated approval.
Traditional approval may be subsequently considered on the basis of data reflecting treatment through at least 48 weeks.  Often this longer‑term data comes from the same studies that were submitted in the original NDA.
[Slide]
Our guidance also provides some general advice on trial design, and provides for flexibility, the choice of overall design as appropriate for the patient population, and the hypothesis to be tested.
In the spirit of accelerated approval, sponsors are specifically encouraged to investigate their product in the patient population most in need of new therapeutic options, specifically the heavily pretreated patient population.  Because we support the use of more than one investigational product in a protocol and recognize its need, particularly for treatment experienced patients, our guidance includes the reminder that registrational studies need to be designed to demonstrate the contribution of each investigational component of regulatory interest.
Last, in the era of multi‑drug regimens for HIV and other concomitant medications, we stress the need to evaluate the potential for drug‑drug interactions prior to launching large clinical studies.  This recommendation is based on the concern that unexpected drug interactions may both adversely impact patient safety and product efficacy.
[Slide]
There are two important caveats regarding the accelerated approval regulation and our guidance on its implementation.  First, as mentioned, this regulation allows approval based on endpoints that can be measured at earlier time points in clinical trials, and this is the major feature that provides for earlier access to approved therapy.  However, accelerated approval does not change the standard of evidence for efficacy required by the Food, Drug and Cosmetic Act as amended in 1962.  This amendment stipulates the requirement for substantial evidence, which is defined as evidence from adequate and well‑controlled investigations that allow the conclusion that the drug will have the effect that it claims.
The second caveat is that our guidance outlines a minimum set of clinical requirements for an accelerated approval application.  There will be, inevitably, circumstances where longer duration or additional data are necessary to evaluate unique safety or efficacy issues prior to approval.
[Slide]
As you will hear in the presentations today, two additional expectations for the submission of an accelerated approval NDA for adefovir were discussed with the sponsor.  Both of these requirements were necessitated by the identification of dose‑limiting nephrotoxicity with adefovir during the conduct of the principal Phase III trials.
First, based on the discussion with the advisory committee members, the division recommended that at least 48 weeks of data at the proposed marketing dose be provided with the initial NDA submission.  This length of follow‑up was recommended because available data at the time suggested that nephrotoxicity did not become readily apparent until at least 20‑24 weeks of dosing.
Second, the sponsor was made aware that because substantial clinical development of the 120 mg dose had already occurred, comparability between the 120 mg dose and the 60 mg proposed for marketing dose would need to be conclusively established.
[Slide]
There are a variety of circumstances when there is a substantial change in the pharmacokinetic profile of an already studied drug, either pre‑ or post‑approval.  Although today's application provides for a change in dose due to toxicity considerations, other examples include changing the frequency of administration for convenience, such as changes from TID to BID regimens or BID to QD regimens, and changes in formulations, such as enteric coating.
[Slide]
The recommendations on this slide would apply to any of these circumstances.  So, in any of these circumstances that were just outlined, sponsors are required to establish the comparability between the old and the new product regimen by providing either data that the pharmacokinetic difference isn't clinically relevant or clinical trial data to demonstrate comparability of clinical benefit with the new product.
[Slide]
For approved, well‑established products we are often asked why there need be a requirement for new clinical trial data.  In general, when changes significantly impact on the pharmacokinetic profile we require clinical data to provide assurance that the new product, dose or regimen is safe and effective and not inferior to the already proven product.  For antivirals, shorter‑term data of several weeks is inadequate to demonstrate comparable efficacy because differential resistance may not become apparent until later in treatment.  Similarly, it is extremely difficult to establish compelling pharmacokinetic‑pharmacodynamic relationships based on shorter‑term clinical data.
In practice, we have routinely advised sponsors that the division will accept and review trial data reflecting 24 weeks of treatment, with a Phase IV commitment to provide at least 48 weeks of follow‑up.
[Slide]
The trial that is submitted to establish the comparability of the proposed dose for marketing with the originally studied adefovir dose, and that is trial 417, is a critical component of the overall adefovir application.  Trial 417 is an active control, equivalence design trial, and I would like to provide some points for the committee to consider when interpreting trials with this design.
The agency as a whole has had a great deal of experience analyzing results from equivalence trials across a broad range of therapeutic indications, and this division has had some experience with equivalence trials for both non‑HIV and HIV indications in selected settings. However, we have had very limited opportunity to consider an equivalence trial as the basis of approval of an antiretroviral in the complex setting of combination drug therapy and treatment experienced individuals, and we will look forward to the committee's discussion of this issue as it relates to today's application.
The three slides that follow cover some general points to consider about interpretation of equivalence design trials.  My reference for these comments is available on the CDER web page in the form of a draft guidance that was developed by the ICH, the International Conference on Harmonization, on the choice of control groups in clinical trials.
[Slide]
The intent of an active control equivalence trial is to show the efficacy of the test drug by showing that it is as good as, equivalent and not inferior to a known effective agent.  This design raises an inherent critical question of whether the trial is capable of distinguishing active from inactive treatment.  The capability of a study to do just this rests on the critical assumption that the active control drug, in this case for today's application it is the 120 mg dose of adefovir, will have had an effect of a defined size in the study.  In the absence of a placebo comparator, the efficacy of the active control relies on implicit historical experience such that trials of the active control, when adequately powered, regularly distinguish active drug from placebo in a similar patient population and under similar conditions of use.
[Slide]
A second point to consider relates to the so‑called non‑inferiority margin.  Prior to initiating the trial an equivalence or non‑inferiority margin is established, also called the delta.  This margin is the degree of inferiority of the test drug compared to the control that the trial will attempt to exclude statistically.  However, there in general are no agreed upon statistical conventions for an acceptable margin of inferiority.  These are matters of clinical judgment and are determined on a case by case basis.  In general, the margin chosen for a trial cannot be greater than the smallest effect size that the active trial would be reliably expected to have compared with placebo in a setting of the planned trial.  Even smaller margins based on clinical judgment may be desired.
Our draft guidance suggests that a delta of 10 percent may be used for sample size calculations, with the caveat that smaller or larger deltas may be acceptable depending on the expected effect size of the active control. These considerations raise questions about how acceptable non‑inferiority margins should be determined for antiretrovirals used in combinations, especially when the product of interest is unlikely to be the more potent component of a particular combination regimen.
[Slide]
The last point to consider on the interpretation of equivalence design trials is a reminder to take into account the particular study circumstances that may make treatment arms look more similar in a trial of this design.  A few of the factors that may reduce the trial's ability to detect true differences include poor compliance, or discontinuation of therapy, substantial loss to follow‑up, overall poor responsiveness of the study populations to treatment effects, and use of concomitant medications that may interfere with the ability to assess the contribution of the test drug.
[Slide]
I will close my remarks with a comment relating to the sponsor's proposed indication and the division's policy for labeled indications for antiretroviral drugs.  The labeled indications for antiretrovirals, as everyone knows, have evolved considerably over the past decade, reflecting both the availability of more products and recommendations for their use in combination.  Currently, unless a product has a significant safety or efficacy limitation it would receive the indication on the slide.
Other indications can always be considered, and for today's application the sponsor has requested a more limited interaction for patients with prior nucleoside analog treatment experience based on safety considerations.  However, because the labeled indication does not limit how a product is used in clinical practice, we will ask the committee today to consider risks and benefits both for the proposed indicated population and for the broader population of HIV‑infected individuals in whom the product might be used in clinical practice.
Thank you for your attention, and we will look forward to discussion and deliberation on the questions that this application poses.  Dr. Hammer, I will turn the meeting back to you.
DR. HAMMER:  Thank you very much, Dr. Jolson, for putting the framework together for our meeting today.  I would like to turn now to the sponsor presentation from Gilead Sciences and Dr. Jaffe, I believe, will open the presentation.
Sponsor Presentation
Overview of Development Program
DR. JAFFE:  Good morning.
[Slide]
My name is Howard Jaffe, from Gilead Sciences, and today we are here to review our new drug application for adefovir dipivoxil for the treatment of HIV‑infected patients.
Joining me from Gilead are Jay Toole, who will review the results of our clinical trial and Norbert Bischofberger, who will review our HIV resistance studies.  Additionally, we have various consultants who have participated in the adefovir development program who are here to provide their insights as well.  We ask that you hold your questions until the end of our presentation.
When we began testing adefovir in 1994 the only available HIV therapies were nucleoside RT inhibitors. Since then the landscape of HIV therapy has changed dramatically, as have the number of treatment options.
[Slide]
Captured on this slide are the percent of HIV treated patients according to ART regimens received and the mean length of time on each regimen.  As you can see, 41 percent of patients are currently receiving their first ART regimen for an average of about 11 months; 23 percent of patients are on their second regimen for an average of about 8 months.  The last grouping, those patients representing about one‑third of the patients receiving HIV therapy, received their therapies on average 5‑8 months.
The complex and interrelated issues of viral resistance inherent difficulties and drug toxicity lead to a successionally declining course with each new treatment regimen.  Patients in the second and third groups have an urgent need for new treatment options, and these are the patients for whom adefovir dipivoxil is intended.
[Slide]
Adefovir dipivoxil is the pro‑drug of adefovir, the first of a new class of nucleotide analog for reverse transcriptase inhibitors.  It has a unique resistance profile with activity in HIV resistant to 3TC, as well as virus with combined AZT and 3TC resistance.  This is important because over 90 percent of patients will pass through AZT and 3TC treatment during their course of therapy.
Additionally, unlike other antiretrovirals, the use of adefovir is unlikely to lead to the development of resistance and, therefore, the likelihood of limiting future treatment options is low.
Adefovir also has once daily dosing, without dietary restriction, and this is particularly attractive for simplifying dosing regimens and for particular clinical settings, such as those requiring directly observed therapy.
The most important risk of adefovir is dose‑limiting nephrotoxicity.  However, through extensive clinical testing of 120 mg once per day, twice the dose sought for approval, the risk of nephrotoxicity has been well characterized.  It can be monitored with monthly routine lab tests and, importantly, when it does occur it is largely reversible with drug discontinuation.
[Slide]
To understand the potential benefits of adefovir, we need to start with its virology.  In vitro adefovir selects for the J65R and K70E RT mutations.  The K65R has been seen in association with ddI and ddC use.  The K70E mutation is a novel mutation.  Both mutations have been observed only rarely.  Most importantly, adefovir maintains activity against HIV resistant to nucleoside RT inhibitors.
Dr. Bischofberger will review the clinical virology in more depth later on in our presentation.  However, we should take note that adefovir has increased activity against 3TC resistant virus, the M184V mutation, and while it has less activity against high‑level AZT resistant virus, the combination of high‑level AZT resistance and 3TC resistance renders the virus near wild type in terms of susceptibility to adefovir.  This compliant resistance genotype, high‑level AZT and 3TC, is a highly prevalent genotype in treatment experienced patients.
[Slide]
Looking at the risks of adefovir, nephrotoxicity is the major dose‑limiting toxicity.  It has a consistent pattern of onset and can be readily monitored.  Together, serum creatinine and phosphate are highly sensitive and specific for detecting adefovir‑related nephrotoxicity.  Consistent with a predominantly proximal tubular effect, decreased bicarbonate, non‑nephrotic range proteinuria and glycosuria may also be observed.  Changes in creatinine and phosphate form the basis for management guidelines for drug discontinuation, with mild changes in creatinine, that is 0.5 mg/dL increases above baseline or decreases in serum phosphate to less than 1.5 mg/dL, leading to drug discontinuation.  Clinical trial results demonstrate that adherence to monthly monitoring and management guidelines are necessary to reduce the risk of clinically significant toxicity.
[Slide]
In considering our data package, it is necessary to review various program milestones.  Clinical testing began in 1994 and included short‑term dosing, monotherapy versus placebo studies for up to 12 weeks of doses ranging from 125 to 500 mg once per day, with the demonstration of good tolerance, significant anti‑HIV activity and the unique resistance profile.
We met with FDA in 1996 to discuss a program for potential licensure.  At that time, one pivotal study, study 408, was discussed in which patients failing background antiretroviral therapy would have 120 mg of adefovir or placebo randomized to their therapy.
The program continued to move forward and, in December of 1997, we initiated an expanded access program at the 120 mg dose for patients who previously failed nucleoside RTIs and protease inhibitor therapy.  However, shortly afterwards, with the unblinding of study 408, the extent of adefovir‑related nephrotoxicity became evident.  Given the therapeutic index for the 120 mg dose, we and the FDA sought the guidance and advice of the Antiviral Advisory Committee last year in a closed meeting.  At that meeting, we discussed the target interaction; we discussed the size and duration of the safety database, in which we adequately characterized the risk and reversibility of nephrotoxicity; and we discussed dosing regimens, including looking at doses at 60 mg once per day.  With the successful completion of studies involving 60 mg, we filed our NDA in June of this year.
[Slide]
Today, we return to review these new results which include over 5000 adefovir‑treated patients with up to 3 years of follow‑up.  The risk and reversibility of adefovir‑related nephrotoxicity has been well characterized.  The mechanism of toxicity is better understood, and management guidelines have been refined and broadly tested in an expanded access program.  We have chosen the 60 mg once per day dose on the basis of results from monotherapy and combination therapy studies.
[Slide]
Based on the risks and benefits associated with adefovir, we are seeking a second‑line indication for use in combination with other antiretrovirals for the treatment of patients with clinical immunologic or virologic progression despite prior RT inhibitor use.
Dr. Toole will now review the clinical trial results.
Clinical Trial Results
[Slide]
DR. TOOLE:  This morning Gilead Sciences will present clinical trial results for 120 and 60 mg dose levels of adefovir dipivoxil.  Although seeking approval at the 60 mg dose level, we were well into our Phase II/III studies at the 120 mg dose before recognizing that nephrotoxicity was the most important dose‑limiting toxicity.  This led us to investigate the 60 mg dose for activity and an improved safety profile.
Our NDA was submitted for both of these doses in over 5400 patients including over 500 females, over 1600 African American and Hispanic patients, as well as 38 children.  These patients were administered adefovir once daily on the basis of a long intracellular half‑life of up to 30 hours for the active moiety.
Adefovir dipivoxil is an oral pro‑drug with good bioavailability in a fasted or fed state.  Following absorption of the pro‑drug, adefovir is eliminated by urinary excretion with equal contributions from both filtration and secretion.  Adefovir is not a substrate inhibitor nor inducer of the cytochrome p450 enzyme system.
Based on several studies, there is no evidence for drug‑drug interactions from the nucleoside class AZT, 3TC or abacavir; from the non‑nucleoside class delavirdine or efavirenz; from the protease inhibitor class indinavir, nelfinavir and saquinavir.  There has been a slight increase in ddI exposure observed at the 60 mg dose, however, there is no increase in ddI‑related adverse events in patients that received the 120 mg dose of adefovir and ddI.
Earlier this year at the retrovirology conference, pharmacokinetic data were presented from ACTG 359 which indicated an interaction with adefovir, delavirdine and saquinavir.  However, as just stated, these observations are not consistent with our data.  Additional pharmacokinetic results are pending from the ACTG 398 which will also include saquinavir.
[Slide]
For the clinical trial overview I will briefly discuss our Phase I/II dosing experience which provides information on our short‑term dosing.  Then I will discuss in more detail study 408, which was our registrational study and which is important because it has extensive follow‑up which has allowed us to characterize the resolution of nephrotoxicity.  In addition, I will discuss CPCRA 039, which is important because it provides long‑term placebo control data whereas, in study 408 patients received placebo for 24 weeks before receiving adefovir dipivoxil in the open‑label phase.  Study 411 provides important controlled efficacy information in treatment naive patients.
[Slide]
We conducted two Phase I/II studies, studies 402 and 403, which examined once daily dosing from 125‑500 mg for 2‑12 weeks duration.  In these studies we observed dose‑dependent, reversible side effects, primarily gastrointestinal symptoms as well as asymptomatic transaminase elevations.  We also observed asymptomatic decreases in serum carnitine, and this has led us to provide supplementation for our Phase II/III studies.
We observed anti‑HIV activity which was similar whether patients were treatment naive or treatment experienced.  We also saw a similar reduction in HIV viral load across the dose groups.
[Slide]
An example of this can be seen in study 403, which was a randomized, placebo‑controlled study with a 6‑week double‑blind phase followed by a 6‑week open‑label phase.  Shown here are the mean changes from baseline with 95 percent confidence intervals, showing that for both doses there is about a 0.4 log decrease in baseline, and at all time points they are statistical significantly different from placebo based on a non‑overlap of the 95 percent confidence intervals.
The activity observed is maintained out through week 12 and, importantly, patients who received placebo who go on to receive adefovir in the open‑label phase also show a 0.4 log decrease.  Based on better tolerability of the lower dose, we chose a 120 mg dose for our Phase III study, study 408.
[Slide]
In this study, patients were randomized to receive either adefovir or placebo entered onto a background regimen in heavily pretreated patients, and these patients had a median duration of prior treatment of over 3.5 years.
The study was conducted with a 24‑week double‑blind period followed by an open‑label phase.  The entry criteria were that patients had to be on a stable regimen for at least 8 weeks, and HIV RNA greater than 2500 and CD4 counts greater than 200.  The primary efficacy endpoints were average change, denoted as DAVG24, in both HIV RNA and CD4 cell counts.
[Slide]
There were 442 patients randomized to the study, and the arms were well matched at baseline, with a mean HIV RNA of about 30,000, mean CD4 cell count of about 350, and the patients were also well matched for their background regimen.  Adefovir was well tolerated over 24 weeks, as indicated by 18 percent and 14 percent from the active and placebo groups discontinuing: 13 percent of patients discontinued adefovir for an adverse event, and the majority of these were due to gastrointestinal symptoms or transaminase elevations.
The activity we observed was consistent with that seen in study 403, as shown by the mean change from baseline of the two treatment arms.  Again, we see about a 0.4 log change from baseline at week 24, and at all time points during the study this activity was significantly different from placebo as shown by the non‑overlap of the 95 percent confidence intervals.  At week 24 the difference is significant with a p‑value less than 0.001.  The activity seen at week 24 is maintained out through week 48.  Patients who received placebo and then went on to receive adefovir in the open‑label phase also show a 0.4 log decrease after 24 weeks.  Importantly, this difference between the placebo group and the active group is consistently observed independent of age, gender, race, HIV RNA or CD4 cell strata, or is independent of whether the patients were receiving a protease inhibitor at baseline or not.
[Slide]
The DAVG24 was also significant, as shown here looking now at the mean DAVG24 using the bDNA assay, which is the particle specified assay.  There was a minus 0.24 log change compared to little change for placebo.  Prior to unblinding these samples were also assayed using the PCR technique and, as shown, these results were confirmatory.
[Slide]
 DAVG24 for CD4 was not significant, as shown here.  But looking at the changes for week 24 for mean and median both favored the active group, and these were significantly different.
[Slide]
During the first 24 weeks we observed few grade 3 or 4 clinical adverse events, as shown here, and these were limited to headache and diarrhea.
[Slide]
There were more grade 3 or 4 laboratory abnormalities, and the most common was elevation in creatinine kinase.  However, this occurred more commonly in the placebo group compared to the active group.  ALT and AST transaminase elevations, as well as hyperbilirubinemia, were observed more commonly in the active arm.
[Slide]
To expand our view to look at all patients who received adefovir as well beyond 24 weeks, there was a total of 403 patients, including 187 patients that were initially randomized to receive placebo.  This group had a median duration of treatment of 9 months, extending out to 2.5 years, and a median duration of follow‑up of 20 months, extending out over 3 years.
[Slide]
The grade 3 or 4 clinical abnormalities observed in the overall study again showed gastrointestinal symptoms but now we see the emergence of nephrotoxicity, reported as a Fanconi‑like syndrome, in 1 percent of the patients.
[Slide]
The laboratory abnormalities associated with nephrotoxicity were more common.  These were defined as a creatinine increase of 0.5 mg/dL or greater, hypophosphatemia, decreased serum bicarbonate, proteinuria and glycosuria.  For these parameters, these correspond to grade 2 or higher laboratory abnormalities.  These were defined on the basis of variability observed in the placebo group during the first 24 weeks of the study.
[Slide]
Shown here is the Kaplan‑Meier analysis looking at the time to onset for serum creatinine increase of 0.5 mg/dL or greater looking at the percentage of patients out through week 80, and shows that prior to week 20 there were very few events, after which the event rate increases reach an apparent plateau with about a 50 percent incidence at week 80.
Looking at a serum creatinine of 2 mg/dL or greater, an absolute value, again shows very few events prior to week 28, then out through week 80 about 5 percent of the patients are affected.  This demonstrates that these abnormalities are common in adefovir‑treated patients.
[Slide]
Looking at the severity of these abnormalities based on the data supplied to the central laboratory, grade 2 abnormalities were observed in about 5 percent of the patients.
[Slide]
The delayed onset for nephrotoxicity was also observed with hypophosphatemia, with a similar time to onset as that observed for serum creatinine increase.  The severity, as shown by the grade of toxicity, indicates that 42 percent of the patients developed hypophosphatemia less than 2.0, with 2 percent of the patients developing a grade 4 abnormality.
[Slide]
Many of these patients developed both of these abnormalities concomitantly, and that is shown in the following Venn diagram.  Of 168 patients that developed a serum creatinine increased, represented here, 117 had concomitant hypophosphatemia.  Similarly, for the 166 patients that developed hypophosphatemia, as shown here, 49 developed that in isolation.
[Slide]
These patients with nephrotoxicity were followed for resolution, and the criteria were that resolution must be sustained through last follow‑up.  For increased creatinine, decreased bicarbonate or phosphate, the definition was that it had to be sustained within 2 standard deviations of the mean change from baseline observed in the placebo group during the first 24 weeks of the study.
For proteinuria it had to be sustained less than or equal to 1+, and for glycosuria less than or equal to trace.
[Slide]
Two standard deviations for serum creatinine is 0.4 mg/dL.  Shown here is the Kaplan‑Meier looking at the resolution to that level for the 168 patients who had a 0.5 mg/dL increase from baseline.  Looking at the percentage of patients out through week 100, this demonstrates that the median time to resolution was approximately 17 weeks, and that with extended follow‑up greater than 95 percent of the patients will have resolved.
[Slide]
Resolution for the other laboratory parameters are summarized here, showing that resolution has a median time of 16 weeks for proteinuria and, as I just showed you for creatinine, 17 weeks.  Importantly, for each of these parameters the Kaplan‑Meier's indicate that greater than 95 percent of the patients will resolve.
[Slide]
These observations are based on a Kaplan‑Meier analysis.  The observed data are shown here and indicate that from 10 percent to 19 percent of the patients that developed the abnormality did not resolve at last follow‑up.  However, looking at this group of patients that remain unresolved, with regard to median follow‑up time, it indicates that, as shown in this column, their duration of follow‑up is limited when comparing those patients to the patients that have resolved which have a median time of follow‑up of 50 weeks.
[Slide]
The conclusions drawn from study 408 are that we observe a durable reduction in HIV RNA in RTI‑experienced patients.  That reduction was a 0.4 log decrease and it was independent of age, gender or race.
Activity was also observed in patients that received adefovir in the open‑label phase, and this activity observed after 24 weeks was maintained out to 48 weeks of dosing.  Adefovir dipivoxil is well tolerated through 24 weeks, during which we primarily observed gastrointestinal side effects.  After 24 weeks dose‑limiting nephrotoxicity was observed, and this demonstrates the value of monthly laboratory monitoring.
In addition, and importantly, through Kaplan‑Meier analysis, greater than 95 percent of the patients are estimated to resolve.
[Slide]
The 120 mg dose of adefovir dipivoxil was also utilized in study CPCRA 039.  This study was sponsored by the NIH and conducted by the Community Program for Clinical Research on AIDS, a network of over 100 community based clinical practices.
In this study patients were randomized to receive either adefovir or placebo added onto background therapy.  The primary endpoint was survival.  Additional secondary clinical efficacy endpoints included progression of disease as well as development of opportunistic infections.  The original sample size was 2200 patients.
In August of 1998, following a recommendation by the DSMB, the study was discontinued, and that was in recognition of the decline in the event rate following the introduction of protease inhibitors, which would have required the study to enroll over 4000 patients to be adequately powered.  At that time, just over 500 patients were enrolled and it was deemed impractical to continue.  The study was not discontinued for safety reasons and, in general, the safety profile observed was consistent with that observed in study 408.
Because of the long‑term placebo control, this study provides important safety data, and also allows us to characterize the background of renal‑related laboratory abnormalities.
[Slide]
The data here provide a safety overview for study 039 and show that by 12 months the discontinuation rate is similar between the active group and the placebo group, with 38 percent of the patients discontinuing adefovir compared to 32 percent on the placebo arm.  An identical percentage of patients developed either a grade 4 adverse event or a toxicity which required discontinuation.  With the exception of nephrotoxicity, these abnormalities are equally distributed in the two treatment groups.  There were more patients on placebo, 31 percent compared to 25 percent, that had grade 4 adverse events.  There were 17 deaths on the active arm, 16 deaths in the control arm, and 1 death in each treatment group had renal failure as an investigator‑assessed contributor to mortality.
[Slide]
The laboratory abnormalities associated with nephrotoxicity are shown here, and indicate for the placebo group that 2+ proteinuria was observed in 21 percent of the patients.  Six percent of the patients developed a serum creatinine increase of 0.5 or greater, and 8 percent of the patients developed hypophosphatemia to less than 2 mg/dL.
Comparing the active group to the placebo arm for changes in creatinine and phosphate indicate that these changes are more sensitive markers than glycosuria, and more specific markers than decreased bicarbonate or proteinuria.
Also, looking at the changes in serum creatinine and hypophosphatemia shows that the 27 percent and 24 percent is notably less than that observed in study 408 where this event rate was 40 percent for each of these markers.  This may reflect the fact that there was increased investigator awareness in study 039, as well as the implementation of monthly monitoring which was required in study 039 whereas in study 408 monthly monitoring was done through week 24, after which it was done on an every 2‑month basis, at which time patients were at greatest risk for development of nephrotoxicity.
[Slide]
While the safety conclusions from study 039 are generally consistent, the effect on viral load was not.  There was no difference between adefovir and placebo at either 6 or 12 months.  However, the study was not optimally designed to look for virologic efficacy.  That is, unlike study 408, changes in background retroviral therapy were permitted any time prior to, at, or following randomization.  Therefore, a stable baseline viral load was not established.  In addition, there was no viral load entry criterion or stratification based on that criterion.
This led to an imbalance in baseline viral load where the placebo group had a 3‑fold higher viral load compared to the active arm.  Possibly due to this increased viral load in the placebo arm, there was a significant increase in the addition of antiretroviral therapy by month 2 compared to the active arm.
[Slide]
Studies 408 and 039 were conducted in treatment experienced patients.  We also looked at adefovir activity in treatment naive patients in study 411.  This is a randomized study of adefovir and indinavir in combination with either AZT, 3TC or D4T, and there was a control arm of AZT, 3TC and indinavir.  Patients were antiretroviral naive, with CD4 counts greater than 100, and HIV RNA greater than 5000.  The baseline characteristics showed a mean HIV RNA log of 4.6 and a mean baseline count of around 400.
[Slide]
There were 224 patients randomized into one of five treatment groups, either the control arm, one‑third adefovir‑containing 3‑drug regimens, or a quadruple drug regimen.  The primary endpoint was the proportion of patients that had less than 400 copies/mL at week 20.  Secondary endpoints included changes in HIV RNA.
[Slide]
Starting with the primary endpoint, this graph looks at the percentage of patients from baseline to week 20 that have less than 400 copies/mL using an intent‑to‑treat analysis.  As shown, both the control group as well as the adefovir plus 3TC arm have similar activity.
[Slide]
A summary of the week 20 efficacy data for the control group as well as the 3 adefovir‑containing 3 drug regimens is shown here looking at HIV RNA less than 400 with an intent‑to‑treat analysis or looking at the mean change in HIV RNA at week 20.
Looking at these percentages, the data indicate that the adefovir‑containing 3 drug arms have similar activity compared to the control arm with respect to HIV RNA less than 400.  In addition, similar activity is observed when looking at the mean change from baseline at week 20.  Also, comparing the data from patients that were receiving adefovir plus 3TC plus indinavir to the control column indicates that adefovir can substitute for AZT with resulting similar efficacy.
Comparing the data in this column, where patients received adefovir and AZT and indinavir, indicates that adefovir can substitute for 3TC, again, with resulting similar efficacy.
[Slide]
The quadruple drug regimen data provided no additional efficacy beyond the 3‑drug regimens.  Substitution of adefovir for either AZT or 3TC resulted in similar efficacy when looking at the proportion of patients that had less than 400 copies/mL or HIV RNA changes from baseline to week 20.
The incidence of nephrotoxicity and the lack of a dose response observed at the 125 mg and 250 mg doses led us to examine a 60 mg dose for activity and an improved safety profile.
[Slide]
For the clinical trial overview of 60 mg, I will discuss study 420, which was our monotherapy study; study 417, which directly compares the 60 mg and 120 mg dose levels; and I will also discuss our experience from expanded access for the first 1000 patients that received adefovir at the 60 mg dose level.
[Slide]
Study 420 was a randomized, double‑blind, placebo‑controlled study with patients randomized 2:1 active to placebo in therapy‑naive patients.  The study was for 4 weeks, and the entry criteria were HIV RNA greater than 5000 and CD4 cell counts greater than 150.  The because characteristics for the 2 treatment arms were well matched, and the primary efficacy endpoint was average change, denoted as DAVG4, over the 4 weeks of dosing.
[Slide]
The efficacy results we observed were consistent with our earlier studies, as shown by looking at the mean change from baseline out through week 4 comparing the 2 treatment arms.
For the 60 mg dose we observed about a 0.3 log decrease from baseline, which at each time point is significantly different from placebo as demonstrated by the non‑overlap of the 95 percent confidence intervals, and the corresponding p‑values at each time point are shown below.
Consistent with the drug effect following completion of dosing at week 4, there is a return towards baseline in the active arm.  The DAVG4 also shows significant activity.
[Slide]
Here, we are again looking at the mean DAVG4.  There was a minus 0.3 log change in the active group, little change in the placebo group, and the result was highly significant.
[Slide]
The conclusions from this study are that adefovir monotherapy at 60 mg provides significant anti‑HIV activity compared to placebo.  In addition, the effect is similar to that observed in earlier studies at the 125 mg and 250 mg doses in studies 402 and 403 which were for 2‑6 weeks duration.
[Slide]
To establish equivalence of the 60 mg and 120 mg doses, we conducted study 417. This study was a randomized, double‑blind study of adefovir at 2 dose levels in combination therapy.  In this study patients had to be protease inhibitor naive and have at least 4 weeks of prior nucleoside experience, with HIV RNA greater than 5000 and CD4 cell counts greater than 100.
The objectives of the study were to determine the relative tolerability of the 2 doses, as well as to establish equivalence of the 2 doses with regard to anti‑HIV activity.
[Slide]
There were 214 patients randomized, 109 to the low dose, 105 to the high dose.  There was additional randomization to one of three treatment arms, either a dual protease where patients received nelfinavir and saquinavir, or nelfinavir plus one nucleoside reverse transcriptase inhibitor, or saquinavir plus one nucleoside reverse transcriptase inhibitor.  The NRTI was chosen from among AZT, 3TC or D4T depending upon the patient's prior experience.
[Slide]
The baseline characteristics for the patients were well matched, with mean HIV RNA of about 40,000, mean CD4 cell counts of about 360.
[Slide]
The patient disposition out to week 20 indicates the 60 mg dose is better tolerated in the 120 mg dose.  As shown here, 14 patients discontinued the low dose compared to 26 at the high dose.  Three of these were due to adverse events at the low dose compared to 13 at the high dose.  Again, we observe a dose relationship for gastrointestinal toxicity as 2 discontinued for that reason at the low dose compared to 9 at the high dose.  One patient at the low dose and 2 patients at the high dose discontinued for transaminase elevation.  Two patients in the higher dose group discontinued for reasons unrelated to adefovir.
[Slide]
The better tolerability at the lower dose is also shown by looking at the time to discontinuation from the overall study.  Shown here is a Kaplan‑Meier analysis looking at the percentage of patients out to week 48 that discontinued the study, indicating that at the higher dose the percentage is always greater than at the lower dose.  This result is statistically significant.  It is also important to note that many patients discontinued from both dose groups after week 24 due to insufficient viral load suppression.
[Slide]
The primary efficacy endpoint of the study was the proportion of patients with less than 400 copies/mL at week 20.  Secondary endpoints included changes in HIV RNA from baseline out through week 20.
[Slide]
The 2 doses have similar activity, as shown by this graph which shows the percentage of patients from because out to week 20 with less than 400 copies/mL using an intent‑to‑treat analysis for the 60 mg dose and the 120 mg dose, with the 60 mg dose resulting in 41 percent of patients at week 20 less than 400 compared to 31 percent of the patients at the 120 mg dose.
[Slide]
The primary objective was to establish equivalence, and the criteria we employed was a 2‑sided 95 percent confidence interval for the difference in the primary efficacy endpoint.  To demonstrate equivalence of the lower dose, the lower boundary of the 95 percent confidence interval could be no greater than minus 10 to minus 12 percent.  Applying these criteria, we found that equivalence was established.
[Slide]
This summarizes the data  for the equivalence analysis using 3 different methods.  First, looking at the intent‑to‑treat analysis where missing observations are considered failure, as just shown in the previous graph, there were 41 percent of the patients at the low dose, 31 percent of patients at the high dose, an actual difference of 10.7 percent, and a lower bound of the 95 percent confidence interval of minus 1.7.
Looking at the as treated analysis, there were 48 percent of the patients at the low dose, 45 percent of the patients at the high dose, an actual difference of 3.3 percent, and now the lower bound of the 95 confidence interval with this analysis was minus 11.3.
Because the higher discontinuation rate observed at the higher dose could be biasing the intent‑to‑treat analysis, we also performed an analysis where the last observation was carried forward to week 20.  Using this method, there were 42 percent of patients at the low dose, 37 percent of the patients at the high dose, a difference of 5.4 percent, and now the 95 percent of the lower bound is minus 7.3.
So, for each of these methods the lower bound of the 95 percent confidence interval was less than minus 12 percent in magnitude.
[Slide]
The study was not powered to look for differences either between the arms or within the dose groups of each arm.  However, a notable difference was observed when looking at the saquinavir plus NRTI arm, as shown here, in which 49 percent of the patients were less than 400 at the low dose compared to 20 percent at the high dose.  However, it is important that this large disparity was not observed at week 12, with the corresponding percentages of 54 percent for the low dose and 40 percent for the high dose.  In addition, the other saquinavir‑containing arm does not show disparity, where 42 percent and 44 percent of patients at the low and high dose respectively were less than 400 using an intent‑to‑treat analysis.
[Slide]
The difference between doses in this treatment group is less striking when looking at the changes at week 20 in viral load.  As shown here, minus 1.3 logs for the low dose, minus 1.1 logs for the high dose, and to put this in perspective, this represents a 95 percent decrease in baseline viral load and this represents a 92 percent decrease from baseline viral load.
The 2 dose groups also show similar activity when looking at all time points from baseline out to week 20.  That is shown on this plot, which demonstrates similar activity, and at week 20 both dose groups have approximately a 1.2 log decrease from baseline.
[Slide]
Although there were no differences in efficacy observed between the 2 doses, there was a significant difference in safety.  That is demonstrated by this Kaplan‑Meier analysis looking at the time to onset for serum creatinine increase of 0.5 mg/dL or greater.
Looking at the percentage of patients out to week 48 demonstrates that each time there is a higher percentage of patients with this abnormality in the 120 mg dose group, and this result is significant, as shown here.
[Slide]
There is a difference as well for graded toxicity with regard to serum creatinine, as shown here, where 3 patients at the higher dose group had a grade 2 abnormality, whereas no patient at the 60 mg dose group had a grade 2 or higher abnormality.
[Slide]
There was also a significant difference for the development for hypophosphatemia, as shown by this Kaplan‑Meier which again looks at the percentage of patients from baseline out to week 48, and again demonstrates that at each time the percentage is higher in the 120 mg dose group and, again, the result is significant.
[Slide]
Looking also at the graded toxicity for hypophosphatemia also indicates, again, a difference, with 23 percent of the patients in the high dose group developing grade 2 or higher toxicity and about 16 percent of the patients in the low dose group developing a grade 2 or higher abnormality of serum phosphate.
[Slide]
The conclusions we can draw from this study are that drug regimens containing 60 mg of adefovir are equivalent to regimens containing 120 mg of adefovir with regard to the proportion of patients with less than 400 copies/mL at week 20.
In addition, changes in HIV RNA are indistinguishable for the 2 dose levels.  The 60 mg dose is better tolerated than the 120 mg dose with regard to both gastrointestinal side effects and nephrotoxicity.
[Slide]
From the data collected in this study, as well as studies 408 and 411, we conducted a multivariate analysis looking for risk factors which are associated with the development of nephrotoxicity.  There were 4 baseline factors which had either a significant increased or decreased risk for the development of either creatinine increase or hypophosphatemia.
Non‑Caucasian patients had a decreased risk for both creatinine increase as well as hypophosphatemia, and these data are also consistent with that reported for study 039.
Decreasing baseline phosphate, as well as increasing baseline age, were both associated with an increased risk for the development of increased creatinine or hypophosphatemia.  Supporting the observations in study 417, the higher dose was associated with a 2‑fold increased risk for creatinine increase and a 1.8‑fold increased risk for hypophosphatemia.
[Slide]
To provide additional safety data for the 60 mg dose, we looked to our expanded access program in which we have administered both dose levels.  This is an open‑label program in which we registered almost 800 sites and close to 2000 physicians.  This group of physicians were responsible for 70 percent of the antiretroviral prescriptions last year in the U.S.
Through October 4, 9000 patients have been enrolled, including over 3000 at the 60 mg dose level.  The analyses I will discuss will focus on the initial 1000 patients that received 60 mg, and this group of patients has a median duration of therapy of 6.1 months with a range out to 16.2 months, and 604 patients have received greater than 6 months of dosing and 43 patients have received greater than 12 months of dosing.
[Slide]
The baseline characteristics for this group of patients is significant with the inclusion of over 30 percent of patients from minorities.  These patients have a baseline HIV RNA of 100,000, and these patients were receiving a median of 4 concomitant antiretroviral agents.
[Slide]
Although this study is still ongoing, this Kaplan‑Meier shows the time of study drug discontinuation for the 60 mg dose looking at the percentage of patients out through week 48, and indicates that the median time to study drug discontinuation is approximately 9 months.
In order to receive monthly drug supply, monitoring of creatinine and phosphate is required.  This has allowed us to assess the development of nephrotoxicity in the study, as based on the case report forms.
[Slide]
Shown here for serum creatinine, about 3 percent of the patients have developed a grade 2 or higher laboratory abnormality.
[Slide]
Looking at hypophosphatemia, approximately 17 percent of the patients developed a grade 2 or higher laboratory abnormality, and this percentage of patients is similar to what we observed in study 417 for the 60 mg dose.
[Slide]
To summarize our clinical trial results, we observe a consistent 0.3 to 0.4 log decrease, corresponding to a 50 to 60 percent decrease from baseline, in viral load.  The anti‑HIV activity of triple drug regimens is similar for those containing either the 60 mg or the 120 mg dose of adefovir.
The most important dose‑limiting toxicity is nephrotoxicity.  However, this can be recognized with routine monthly laboratory monitoring and, importantly, Kaplan‑Meier estimates indicate that greater than 95 percent of the patients will resolve following drug discontinuation.  The 60 mg per day is better tolerated than the 120 mg per day, and based on the activity is a clinically superior dose.
[Slide]
At this time, Dr. Norbert Bischofberger will discuss our HIV resistance studies.
HIV Resistance Studies
DR. BISCHOFBERGER:  Good morning.  Ii am Norbert Bischofberger, from Gilead Sciences.  Phenotyping and genotyping are becoming increasingly important for the management of HIV‑infected individuals and may provide a valuable tool for optimizing drug combinations.  For that reason we, at Gilead, have initiated a comprehensive virology program in support of the clinical development of adefovir.  Our results indicate that adefovir has a very favorable resistance profile, and our results also highlight the importance of adefovir for the treatment of nucleoside‑experienced patients.
[Slide]
In clinical practice resistance to drugs is becoming an increasing problem and a variety of mutations in different classes of drugs is commonly seen.  Shown here is the prevalence of resistance mutations in over 5000 clinical samples which were submitted to Virco for analysis during the period of August of 1998 and May of 1999.  As can be seen, there are a number of nucleoside reverse transcriptase inhibitor, non‑nucleoside reverse transcriptase inhibitor, and protease inhibitor mutations.
Among the nucleoside reverse transcriptase inhibitor mutations a change in position 215, which is associated with AZT resistance, occurs at almost 50 percent frequency.  A change in position 184, associated with 3TC resistance, was present in greater than 40 percent of all the samples.  This is followed by changes in positions 41 and 70, associated with AZT resistance, and changes in positions 69 and 74, associated with ddC and ddI resistance respectively.  Not shown on this slide but important to the discussion of adefovir is that the combination of the 215 mutation and the 184 mutation occurred in 25 percent of all the samples, and this is taken from greater than 10,000 clinical samples.
[Slide]
We have investigated the development of mutations which potentially give rise to development of resistance to adefovir.  Under the standard laboratory selection conditions, we were able to identify 2 mutations, the K65R and the K70E mutations which gives rise to about 12‑ to 16‑fold and 3‑ to 9‑fold reduced susceptibility to adefovir. The K65R mutation has previously been described as a ddI, ddC and 3TC resistance mutation.  The K70E mutation is unique to adefovir.  Both mutations are very rare.  In our own clinical studies in 219 patients who have been treated with adefovir for between 5 months and 1 year, we have never observed a K65R mutation, and in only 2 cases, which is less than 1 percent, did we observe the K70E mutation.
Looking at the recent Virco database of greater than 10,000 clinical samples, it is clear that these 2 mutations are, indeed, very rare.  The prevalence of the K65R mutation is 0.6 percent and the prevalence of the K70E mutation is 0.1 percent.
The fact that adefovir selects only for 2 relatively rare mutations indicated to us that it could also have a favorable resistance profile.  This was confirmed by analyzing a large number of clinical samples and recombinant viruses both by us and by outside collaborators.  The only viruses which reduced susceptibility to adefovir are viruses which are high‑level resistant to AZT and viruses which contain a multi‑nucleoside mutation and, as I mentioned already, the 2 viruses which express either the K65R or the K70E mutation.
However, unique to adefovir, all these mutations revert to close to wild type susceptibility to adefovir where the 3TC resistance mutation is present also.  So, viruses which are high‑level resistant to AZT in the presence of the 3TC resistance mutation, viruses which have the K65R insertion mutation in the presence of the 3TC resistance mutation, and viruses which have the K65R mutation in the presence of the 3TC resistance mutation all have wild type susceptibility to adefovir.
Moreover, adefovir also has activity against the multi‑nucleoside mutation Q151, and that makes adefovir unique among the nucleosides.  Further, it has activity against low‑level AZT resistant virus and virus which is resistant to either ddI or ddC due to mutations in positions 74 or 69.  If the 3TC resistance mutation occurs in wild type background, the resulting viruses are mildly hyper‑susceptible to adefovir.
[Slide]
This increased sensitization of viruses by the presence of the 3TC resistance mutation is shown here.  These were 4 individuals who, during the course of therapy, developed the 3TC resistance mutation.  Recombinant viruses were constructed at baseline and after development of the 3TC resistance mutation.  At baseline these viruses all had AZT associated mutations. However, after acquisition of the 3TC resistance mutation these viruses reverted to close to wild type susceptibility.
[Slide]
Similarly, the sensitivity of viruses containing the K65R mutation, dependent on the presence of the 3TC resistance mutation ‑‑ that is shown here.  These are 4 clinical isolates from the Virco database, which all expressed the K65R mutation, and they are between 4‑ to 6‑fold resistant to adefovir. [House audio system problems] ... and the 3TC resistance mutation, and they have close to wild type susceptibility for adefovir. This same phenomenon has also been demonstrated with the T69 insertion mutation.
[Slide]
This favorable resistance and cross‑resistant profile of adefovir in vitro also correlates with response to adefovir in vivo.  This we were able to show in a virology substudy in study 408 where, in a prospective and blinded manner, 191 patients were selected and their HIV reverse transcriptase was sequenced at baseline and at week 24.  During this study, HIV protease inhibitors became commercially available and treatment practices changed.  So we chose a set of early enrollees, patients 1 through 90, and a set of late enrollees, patients 252 through 352, to match the overall study population.  In the end, we had 180 evalauable plasma samples available.
[Slide]
Patients in study 408 had extensive prior treatment history, and the genotype analysis of this virology cohort confirms this.  Patients were grouped into 6 categories according to whether they had no mutations, or low‑level AZT resistance mutations, or high‑level AZT resistance mutations, both in the absence or the presence of the 3TC resistance mutation.  Low‑level AZT resistance mutations and high‑level AZT resistance mutations were defined as indicated on the slide.
As can be seen, by far the largest group of individuals, 43 percent, had both the high‑level AZT resistance mutation and the 3TC resistance mutation.  More than 70 percent of all the patients in this virology cohort had the 3TC resistance mutation present at baseline and only a relatively small part, 8 percent, had no mutation.
[Slide]
Based on the susceptibility of these AZT/3TC resistant viruses to adefovir, we speculated or we expected that patients in this genotypic group would respond to adefovir therapy and this is, indeed, what we found.  Of the 180 samples in the virology cohort, 24‑week HIV RNA data was available on 155 patients, and their response to adefovir or placebo is shown on this slide.
As you can see, all the patients who had the 3TC resistance mutation responded to adefovir therapy, with a mean change from baseline at week 24 ranging from minus 0.5 to minus 0.77.  This was highly statistically significant versus the patients receiving placebo in the same genotypic groups. Importantly, the patients who had 3TC resistance mutation and high‑level AZT resistance mutation responded to adefovir therapy also, with a mean change from baseline at week 24 of minus 0.5 logs, and this was again highly statistically significant versus patients in the same genotypic group receiving placebo.
This is important because it is well‑documented that patients in this genotypic group respond poorly to antiretroviral therapy, and it is also known that this genotype correlates with more rapid disease progression.  In contrast, and consistent with our in vitro data, patients in this group having high‑level AZT resistance mutation without the 3TC resistance mutation showed a response to adefovir which was not statistically significantly different from that of placebo.
What I showed you here is the analysis looking at mean change from baseline at week 24.  We have also carried out another analysis looking at DAVG, and the results of that analysis are consistent with this one in the sense that patients in this group, number 6, having 3TC resistance mutation and high‑level AZT resistance mutation showed a statistically significant treatment benefit versus placebo in the same genotypic group.
This was our genotypic analysis.  We have also carried out a phenotypic analysis where patients were grouped according to a phenotypic criterion.  That is, whether their virus was high‑level resistant to either AZT or 3TC, high level being defined as greater than 8‑fold resistant; low level being defined as less than 8‑fold, and this category obviously includes patients with wild type susceptible virus.
[Slide]
The results of this phenotypic analysis were consistent with our genotypic analysis, and they again showed that all the patients who had virus which was resistant to 3TC responded to adefovir therapy, with about a 0.6 lob change from baseline at week 24.  Importantly, this group, number 4, having virus which was high‑level resistant to AZT and resistant to 3TC ‑‑ as you can see here, these viruses were on average 14‑fold resistant to AZT; they were greater than 85‑fold resistant to 3TC but they responded to adefovir therapy, with a 0.66 log change from baseline at week 24.
Again consistent with the previous analysis and also consistent with our in vitro data, patients in this phenotypic group which had virus which was high‑level resistant to AZT without being resistant to 3TC showed a relatively poor response.
[Slide]
Consistent with our in vitro experience, we did not observe the development of resistance mutations to adefovir in this study but, rather, what we saw was a background of predominantly AZT‑associated mutations arising with similar frequency in the arm where adefovir was added on to background therapy versus the arm where placebo was added on to background therapy.  It was 35 percent in the adefovir arm, 42 percent in the placebo arm.  We did not observe either the K65R or K70E mutation emerging in this study and, importantly, all the patients in the adefovir arm who develop these background nucleoside mutations responded to therapy, with a mean change from baseline of minus 0.58 and this is statistically significant versus the placebo patients developing these background resistance mutations, which did not respond appreciably.
[Slide]
In summary, these clinical findings are consistent with our in vitro findings, and they point to the fact that adefovir has a favorable profile both with regard to lack of resistance development and with regard to lack of cross‑resistance.
Adefovir has shown activity against most nucleoside resistant viruses, including AZT, 3TC resistant viruses.  In vitro we make the observation that if the 3TC resistance mutation is added in we see increased sensitivity.  We see significant reductions in plasma HIV RNA in patients that have this 3TC resistance and, particularly importantly, in patients that have both 3TC resistance and high‑level AZT resistance we see continued HIV RNA suppression in patients developing background nucleoside resistance mutations. Finally, the development of adefovir‑specific mutations is rare.
With that, I would like to thank you and hand it over to Dr. Jaffe for discussion of the Phase IV plans and concluding remarks.
Phase IV Plans and Concluding Remarks
DR. JAFFE:  Drs. Toole and Bischofberger have described the results of our clinical and virology programs, demonstrating the anti‑HIV activity of the 120 mg dose and the equivalent activity and improved safety profile of the 60 mg dose.
[Slide]
To support traditional approval of the 60 mg dose, Gilead has worked with the FDA to develop 2 48‑week confirmatory studies.  Each is randomized and placebo‑controlled and currently enrolling patients.
Study 415 is an intensification protocol for patients with viral load of between 50 and 400 copies/mL.  Study 458 will utilize baseline genotype and phenotype to construct a new treatment regimen in patients who have failed their HART therapy.  Adefovir or placebo will then be added, as will 3TC, to each arm to select for the M184V mutation.  Time to virologic failure is the primary endpoint of each study.
As for the studies previously discussed, Gilead will conduct further resistance testing to further characterize the adefovir profile.
We will also study a 30 mg dose to see if anti‑HIV activity is maintained and kidney toxicity is further reduced, and we will continue our ongoing longitudinal study of patients receiving chronic adefovir and undergoing intensive renal function monitoring.  We will also conduct a long‑term postmarketing surveillance study in 2000 patients.
[Slide]
However, most important to maximizing the therapeutic index of adefovir dipivoxil is our risk management program.  This has been developed with important input from over 70 community members and HIV prescribing physicians.  Central to the program are education and access, access for all patients regardless of insurance status to monthly laboratory monitoring, and education about the risks of adefovir therapy for patients and their caregivers, including nurses, pharmacists and physicians.
We will build upon the foundation established in the clinical trial program and extend it within an expanded access wherein physicians responsible for 70 percent of the ART prescriptions in the U.S. participated.  The program will include a patient medication guide containing lay language regarding kidney toxicity.  Treatment and laboratory logs will simplify the tracking of monthly lab tests and required dose changes.  Labeling on pill bottles and reminders at the pharmacy and patient and physician registries will also increase awareness.  Preprinted prescription pads with limited refills will also be used.
Additionally, a black box in the package insert will emphasize the importance of baseline and monthly laboratory monitoring, and the contraindications of preexisting renal disease, hypophosphatemia and concomitant use of drugs with nephrotoxicity potential.
[Slide]
Now, turning to the rationale for the accelerated approval of adefovir dipivoxil, recent data from the CDC have documented that HART‑associated reductions in AIDS mortality are slowing.  This is due, no doubt, in part to the complicated and interrelated problems of viral resistance, drug toxicity and adherence difficulties.
While we all want drugs that are safe and effective for a lifetime of HIV therapy, it is the unfortunate reality that with each new treatment switch the time on that regimen decreases, and the number of viable treatment options declines accordingly.
Consistent with this urgent need for new options, approximately 400 new patients have enrolled on the adefovir expanded access program since its initiation.  Patients have taken adefovir because of the expectation of 0.3 to 0.4 log reduction, 50‑60 percent reduction, in their viral load.
[Slide]
Shown here are the results of a meta‑analysis conducted on data from ACTG studies which demonstrate the relationship between risk of disease progression and change in HIV RNA at week 24 following a change in treatment.  Compared to the risk associated with no change, a 0.3 log decline would be expected to reduce the risk of clinical disease progression by approximately 30 percent.
[Slide]
In conclusion, adefovir has anti‑HIV activity against the highly prevalent virus with combined AZT and 3TC resistance.  While other drugs retain some activity against these viruses, they too have important dose‑limiting toxicities.  The availability of adefovir will increase the options for constructing a nucleoside or nucleotide RT inhibitor backbone.  It has become extremely common practice today to use these backbones to help protect against the potential development of non‑nucleoside or protease inhibitor resistance mutations.  By the time a patient makes his or her way to a third or later regimen the number of viable RTI options for such a backbone have become severely limited.
Additionally, the simple dosing regimen of one tablet per day without dietary restriction will help facilitate adherence.  Finally, while dose‑limiting nephrotoxicity will limit the duration of adefovir therapy in many patients, it is extremely well characterized and easy to recognize.  Unlike the dose‑limiting toxicities of other antiretrovirals, the pattern of toxicity is not overlapping and, importantly, even when the toxicity does occur at a dose twice the dose sought for approval, it is reversible in over 95 percent of patients with drug discontinuation according to the Kaplan‑Meier estimates.
For these reasons, adefovir will make a valuable treatment option for HIV‑infected patients who have an urgent need for new therapeutic options.
Thank you for your attention.
DR. HAMMER:  Thank you very much.  I suspect that the committee is going to have a fair number of questions, and I think for efficiency's sake we should take a short break now, return for the FDA presentation and then open this up for discussion.  So, please, try to return at 10:20, no later than 10:25.  Thank you.
[Brief recess]
DR. HAMMER:  Please take your seats.  We are going to proceed with the agency's presentation and then we are going to open this up for committee discussion and questions.  The FDA presentation will commence with Dr. Kimberly Struble's discussion.
FDA Presentations
NDA and Clinical Development Overview and Summary
of Efficacy: Adefovir 120 mg
DR. STRUBLE:  Good morning.
[Slide]
The FDA presentation will provide an overview of the NDA submission and the clinical development history for adefovir, followed by the summary of efficacy results from 4 trials evaluating adefovir 120 mg.  Dr. Greg Soon will then provide the FDA summary of efficacy for study 417, which evaluated adefovir 60 mg versus 120 mg.  I will then discuss the safety issues which will solely focus on the development and resolution of nephrotoxicity.
[Slide]
Finally, an FDA summary of the virology substudy from study 408 will be presented, followed by overall safety and efficacy conclusions.
[Slide]
In June of this year, Gilead Sciences submitted an NDA application for adefovir 60 mg once daily for the treatment of patients with HIV infection with clinical, immunologic or virologic progression despite prior reverse transcriptase inhibitor therapy.
[Slide]
Notably, the majority of the Phase II/III development program focused on trials to evaluate the safety and efficacy of adefovir 120 mg.  The choice of this dose was based on 2 dose‑ranging trials evaluating doses of 125 mg, 150 mg and 500 mg daily.  All these doses showed similar antiviral activity without evidence of a dose response.  However, dose response was apparent for GI toxicities.  Therefore, Gilead chose to study adefovir 120 mg in Phase III trials.
[Slide]
During the conduct of study 408, which compared adefovir 120 mg to placebo, nephrotoxicity, associated with phosphate and bicarbonate wasting, was observed in a substantial portion of patients after 24 weeks of therapy.  The long‑term safety of adefovir 120 mg became a concern.  There was consensus at that time that the 120 mg dose had an unfavorable safety profile.  In response to feedback from investigators and the division, Gilead amended their ongoing protocols to require a dose reduction to 60 mg/day.  Therefore, the development plan for adefovir was refocused to evaluate the safety and efficacy of the previously unstudied 60 mg dose.
[Slide]
The NDA filing strategy for adefovir 60 mg is based on the following: 4 controlled trials to establish the activity of adefovir 120 mg; one bridging study to evaluate the relative efficacy and safety of 60 mg versus 120 mg; and an analysis evaluating the reversibility of adefovir‑associated nephrotoxicity.  Gilead contends that the 60 mg dose produces comparable activity to the more extensively studied 120 mg dose, but the onset of renal laboratory abnormalities is delayed with the 60 mg compared to the 120 mg.
[Slide]
Based on this, the division would like the committee to focus on 4 major regulatory issues today.  The first one, although the 120 mg dose is not the proposed dose for marketing, did the original adefovir development establish efficacy of the 120 mg dose in treatment experienced patients?
Two, with respect to efficacy, has Gilead demonstrated sufficient comparability between the proposed marketing dose of adefovir 60 mg and 120 mg, such that one can conclude that adefovir 60 mg is superior to placebo?
[Slide]
Three, does the 60 mg dose of adefovir provide a safer alternative to the 120 mg dose for chronic administration, and has the safety of the 60 mg dose been adequately characterized?
Finally, is adefovir‑associated nephrotoxicity reversible and clinically manageable?
[Slide]
As stated previously, the clinical development of adefovir primarily focused on the efficacy of the 120 mg dose.  This does was evaluated in 4 clinical trials.  First I will review the 4 trials conducted in treatment experience patients, studies 408, CPCRA 039 and ACTG 359.  I will then discuss the fourth trial which was conducted in treatment naive patients, which is study 411.  Please keep in mind that Gilead is seeking an indication for use of adefovir in patients with prior nucleoside experience.
[Slide]
For study 408, patients who received stable antiretroviral therapy for at least 4 weeks before study entry, with CD4 counts greater than 200 and HIV RNA greater than 2500 copies, were randomized to receive either adefovir 120 mg or placebo in addition to their background therapy.
The double‑blind, placebo‑controlled phase lasted for the first 24 weeks, followed by an open‑label rollover phase.  The primary efficacy endpoints were the treatment effects of HIV RNA and CD4 cell counts as measured by a time‑weighted average change from baseline over 24 weeks, or DAVG24.  It should be noted that this trial was initiated prior to the division's stated preference for evaluating HIV RNA changes by assessing proportions below an assay limit.
[Slide]
There were statistically significant differences favoring adefovir versus placebo for changes in HIV RNA as analyzed using DAVG24.  The mean reduction of 0.28 logs for the adefovir group compared to 0.06 logs for the placebo group was observed.  However, there were no statistically significant differences between the 2 groups for CD4 cell counts.  The mean increase was approximately 3 cells for the adefovir group compared to a decrease of approximately 5 cells for the placebo group.
[Slide]
This figure shows the distribution of HIV RNA reductions averaged over 24 weeks for patients in study 408.  The X axis indicates average HIV RNA reductions, with greater reductions toward the left.  RNA reductions for the adefovir groups are in red, and in white for the placebo group.
Overall, the distribution for the adefovir group is somewhat more skewed to the left, toward greater HIV RNA reductions.  However, both plots have considerable overlap.  There were no statistically significant differences between the adefovir and placebo groups with respect to proportion of patients with HIV RNA less than 400 at 24 weeks.  Overall, relatively few patients achieved RNA levels below 400 copies.
The design of this trial, in which patients with ongoing viral replication added a single drug to background therapy, does not always coincide with current standards of care.  Such designs may not be suitable for illustrating optimal use of an antiretroviral agent.
[Slide]
A second study, CPCRA 039 ‑‑ the design of this trial was similar to that of the 408 study, and treatment experienced patients were randomized to receive either adefovir 120 mg or placebo in addition to their background therapy.  This study was designed to evaluate differences in the rate of death and development of AIDS‑defining illnesses between the treatment groups.
Due to reductions in AIDS mortality and morbidity resulting from the general availability of active treatments, the DSMB determined that the study objectives would not be feasible unless enrollment exceeded 4000 patients.  Consequently, the study was prematurely terminated due to a projected inability to reach a sufficient number of clinical endpoints.  However, HIV RNA and CD4 cell counts were collected and analyzed for all patients enrolled.
The analysis plan did not provide predefined time points for analysis of HIV RNA and CD4.  It is also important to note that the executive summary was only submitted to the FDA for review, and we have not reviewed data from this trial in depth.
[Slide]
According to the CPCRA analysis, the mean change from baseline in HIV RNA at week 24 was a decrease of 0.02 logs for the placebo group compared to an increase of 0.9 logs for the adefovir group.  The mean change from baseline for CD4 cell count was an increase of 10 cells for the placebo group compared to 6 cells for the adefovir group.  Overall, there were no differences between adefovir and placebo with respect to changes in HIV RNA or CD4 cell counts.  However, there may be several factors that may have confounded the interpretability of these results, such as baseline imbalances in RNA and treatment changes.
[Slide]
Imbalances in baseline HIV RNA between treatment groups were observed.  The median RNA for the adefovir group was approximately 8000 copies compared to approximately 26,000 copies for the placebo group.  It is uncertain in which direction this imbalance would bias the comparison.  However, in several retrospective analyses of clinical trial data, lower baseline RNA has been associated with better treatment outcomes.  In an FDA analysis which adjusted for baseline RNA levels according to those seen in study 408, there were still no differences in the HIV RNA change from baseline for the 2 treatment groups.  In addition, there was a substantial proportion of patients with RNA less than 500 copies at baseline.  There were 29 percent in the adefovir group compared to 23 percent in the placebo group.  However, a CPCRA analysis excluding patients with RNA less than 500 also showed no differences in RNA change from baseline between treatment groups.
[Slide]
In addition, information was not collected on past antiretroviral agents, and there were also no protocol mandated restrictions on changes in background therapy.  The applicant states that at month 2 there were significantly more changes in therapy in the placebo group compared to the adefovir group.  Agents such as delavirdine, nelfinavir, and abacavir were classified as "other" and not included in the data analysis as a change in antiretroviral therapy.  As a result, data on changes in therapy may be underestimated in this trial.
[Slide]
The third study, ACTG 359, was a randomized, partially blinded trial in HIV‑infected subjects with at least 6 months prior indinavir use and with HIV RNA between 2000 copies and 200,000 copies.  Subjects had also been on a stable indinavir‑containing regimen for at least 4 weeks immediately prior to study entry and had taken less than 2 weeks of prior ritonavir or saquinavir.  Subjects were randomized to receive either the dual PI combination of saquinavir and ritonavir plus either delavirdine, adefovir 120 mg or the combination of adefovir and delavirdine, or patients received the dual PI combination of saquinavir and nelfinavir plus either delavirdine, adefovir 120 mg or delavirdine and adefovir.
The primary efficacy endpoints were proportion of patients with RNA less than 500 copies and changes in CD4 cell counts at week 16.  Only the executive summary from this trial was submitted to the agency, therefore, we have not reviewed this trial in depth.
[Slide]
For the three versus three drug factorial comparison, there were statistically significant differences favoring delavirdine over adefovir.  For the ritonavir‑saquinavir groups the proportion less than 500 for the adefovir group was 19 percent compared to 30 percent for the delavirdine group.  For the nelfinavir and saquinavir groups the proportion less than 500 was 16 percent for the adefovir group compared to 42 percent for the delavirdine group.  In the pooled PI comparison, the proportion less than 500 was 17 percent for the adefovir group compared to 36 percent for the delavirdine group.
This study demonstrated activity associated with the addition of delavirdine to dual PI regimens but was unable to demonstrate activity of adefovir in combination with PI‑based regimens in treatment experienced patients.
[Slide]
For the four versus three drug factorial comparison there were no differences between the dual PI regimens plus delavirdine compared to the four drug combination of dual PIs plus delavirdine and adefovir.  For the ritonavir‑saquinavir arms the proportion less than 500 for the adefovir plus delavirdine arms was 27 percent compared to 30 percent for the delavirdine group.  For the nelfinavir and saquinavir arms the proportion less than 500 was 33 percent for adefovir and delavirdine and 42 percent for delavirdine.  In the pooled PI comparison the proportion less than 500 was 30 percent for the adefovir and delavirdine arms and 36 percent for the delavirdine arms.
Again, there were no differences between the dual PI regimens plus delavirdine compared to the four drug combination of dual PIs plus delavirdine and adefovir.  This is important because this study has relevance for the interpretability of study 417, which you will hear about shortly from Dr. Greg Soon.  In addition, there were no significant differences noted for CD4 cell counts between any treatment groups.
[Slide]
There was a pharmacokinetic substudy conducted during this trial in a small number of patients.  The individual concentration data has not been submitted, nor reviewed, by the agency.  The results of this substudy have been presented previously at scientific meetings.  Results from the substudy suggest a drug interaction between adefovir 120 mg and delavirdine.  However, the mechanism of this interaction is unknown at this time.
In addition, saquinavir concentrations in this study were lower in the presence of adefovir.  Therefore, on the basis of the preliminary results of the substudy one cannot rule out a potential interaction between adefovir and saquinavir.  Further investigation is warranted regarding potential drug‑drug interactions with adefovir.
Gilead has conducted single‑dose drug interaction studies with adefovir 60 mg, and contends that there is no pharmacokinetic interaction between adefovir and saquinavir.  However, single‑dose studies may not be sufficient to assess interactions that may be arising from metabolic induction.
[Slide]
I will now review this study which evaluated adefovir 120 mg in treatment naive patients, which is study 411.
[Slide]
Any treatment naive patients with RNA greater than 5000 copies and CD4 cell counts greater than 100 were randomized into one of the following treatment groups in this open‑label trial: patients received either adefovir, indinavir, zidovudine or 3TC, or adefovir, indinavir and zidovudine, or adefovir, indinavir, 3TC, adefovir, indinavir and D4T or the control arm which was zidovudine, indinavir and 3TC.
When this protocol was submitted we informed Gilead that this trial was underpowered to serve as a registrational trial.  In response to our comments, Gilead increased enrollment in arms C and E, which are yellow on this slide, to enable assessment of comparability between these triple drug regimens.
[Slide]
This slide shows the HIV RNA status at week 20 for all treatment groups, and includes proportion of patients less than 400 and the percent patients with missing values at this time point.  In this study of treatment naive individuals the adefovir, indinavir and 3TC arm was comparable to that of the control arm at week 20 based on proportion of patients with HIV RNA less than 400 copies.
However, it should be noted that a substantial portion of patients had missing values, most of which had discontinued from study drug at week 20.  There were 23 percent in the adefovir, indinavir and 3TC arm versus 26 percent in the zidovudine, indinavir and 3TC arm.
It is noteworthy that arm C had a numerically higher proportion of patients with HIV RNA less than 400 copies compared to any of the other treatment arms, including arm A which consisted of a quadruple therapy of adefovir.  The quadruple therapy arm, which is arm A, was not superior to the control arm of zidovudine, indinavir and 3TC and was numerically inferior to treatment C.  However, differences between 3 and 4 drug regimens may be difficult to detect over relatively short time periods, particularly in underpowered studies.
[Slide]
I would now like to introduce Dr. Greg Soon who will present the FDA analysis of efficacy for adefovir 60 mg from study 417.
Statistical Review of Study 417:
Adefovir 60 mg vs 120 mg
DR. SOON:  My discussion will be on study 417, which is the only efficacy study for 60 mg with at least 20 weeks data.
[Slide]
First, I will review the study design.  Secondly, I will discuss the possible biological interaction of the background therapies with adefovir doses.  Then I will show how the interaction may influence the interpretation of the efficacy results.  Finally, I will discuss these results in light of the ICH guidance on equivalence trials.
[Slide]
Now, I will first review the trial design of study 417, and 214 protease inhibitor naive subjects were equally randomized to 3 combination groups.  The first group is the nelfinavir and saquinavir combination.  The second group is the nelfinavir and a nucleoside analog combination.  The third group is a saquinavir and a nucleoside combination.  Within each combination group subjects were further randomized to adefovir 60 mg or 120 mg.  The sample size for each treatment arm is listed in the third column.
In one of the protocol amendments, all subjects were required to stop using the 120 mg dose after the week 16 visit.  Even though most subjects already had the week 20 evaluation by the time of this amendment, the longer‑term comparison between the 2 doses will not be available.  The primary endpoint for this equivalence trial is the percent of subjects whose HIV RNA was below 400 copies/mL at week 20.
[Slide]
The original intent of study 417 was not to serve as a registrational trial.  It is important to note that study 417 was launched prior to the recognition of adefovir‑associated nephrotoxicity after 24 weeks of therapy.  Since the safety of long‑term dosing of 120 mg of adefovir became a concern, development of lower doses of adefovir assumed greater importance.
Issues with the design of this trial include the following: First, the 60 mg versus 120 mg comparison may be confounded by this complex combination regimen.
Secondly, determination of the relative contribution of 60 versus 120 in the context of potent combination therapy may not be possible within 20 weeks.
[Slide]
Now, I will describe the observed response of HIV RNA at week 20.  The numbers presented in the body of the table are the percentages of subjects in each treatment arm with various responses.  For example, in the combination group 1, adefovir 60 mg, 41 percent achieved HIV RNA below 400 copies/mL at week 20; 39 percent still had HIV RNA greater than 400, and 19 percent were missing.
This can be contrasted with the 120 mg arm in which 43 percent had HIV RNA less than 400; 26 percent were greater than 400; and 31 percent were missing.  Missing values almost always come from discontinuations due to factors such as intolerance or lost to follow‑up.
We see that for the combination group 1, the percent of subjects discontinued were higher for 120 mg, 31 percent versus 19 percent, but the percent of subjects less than 400 was similar, 42 percent versus 43 percent.
The second combination group can be similarly described.  However, percent with less than 400 was lower for both the 60 mg and the 120 mg arm than in the first combination group.
The third combination group appears to be very different from the other two combination groups.  For the 120 mg arm, only 20 percent of the subjects achieved the less than 400 status, much lower than the 60 mg arm and the 120 mg arm.  This occurred despite the percent discontinued being similar to other 120 mg arms.  It is 31 percent here versus 34 percent and 31 percent here.
[Slide]
The question here is, is there a statistical interaction between the combination regimen and adefovir doses.  The default assumption here is that there is an interaction.  The hope is that the trial will provide evidence to refute it.  A test of this statistical interaction using a logistic regression analysis yielded a p‑value of 0.15, suggesting that there is only a small probability of 15 percent that the seemingly different response patterns in the 3 combination groups were due to chance if, in fact, there is no statistical interaction.  This raises the possibility of biological interaction between the combination regimen and adefovir doses, which suggests that these 3 combination groups may not be described by a singled pooled analysis.
[Slide]
This table shows several possible analyses when missing values are treated as failures.  The red row indicates the pooled analysis for all the 3 combination groups.  This would be a proper analysis if the biological interaction does not exist.  Looking at the lower bound of the 95 percent confidence interval, this analysis suggests that the 60 mg dose is no more than 2.7 percent worse than the 120 mg dose.
The yellow rows pooled groups 1 and 2 together but analyzed group 3 separately.  In group 1 and 2, the point estimate of the treatment difference is 1.1 percent; in group 3, the treatment difference is 27.2 percent, both favoring 60 mg.
Examining the 95 percent confidence intervals, we see that in group 1 and 2 60 mg could be as much as 14.2 percent worse than 120 mg, while in group 3 60 mg appeared to be superior to 120 mg.  Separate analyses for groups 1 and 2 were not conducted because these 2 groups appeared to be similar.
[Slide]
In addition, analysis was done on subjects with week 20 HIV RNA measurements.  Essentially, this is an on‑treatment analysis where subjects who discontinued by week 20 were excluded.  Based on this analysis, in the first combination group the percent of less than 400 was 52 percent versus 63 percent favoring 120 mg.
In the second combination group the percents were 41 percent versus 43 percent, numerically very similar.  However, the third group still appears to be very different from the other 2 groups.  The percent of less than 400 was 51 percent versus 29 percent, this time favoring 60 mg.
[Slide]
When all 3 groups are combined, again looking at the lower bound of the 95 percent confidence intervals, the analysis suggests that 60 mg could be 11.3 percent worse than 120 mg in achieving the less than 400 status.  However, if we believe that there is a biological interaction, then this pooled analysis is not meaningful.  If we combine the first 2 groups, then the analysis indicates that 60 mg could be as much as 25.1 percent worse.  However, for the third combination group, it was shown that 60 mg is no more than 2.7 percent worse than 120 mg.
[Slide]
Because the case for efficacy of 60 mg is mostly based on this equivalence trial, the criteria for evaluating equivalence are very important.  Therefore, we will review the draft ICH guidance on this issue.
Based on this guidance, there are 2 minimum requirements for an equivalence claim.  First, the control arm for the equivalence trial should be an established therapy.  Second, the equivalence margin, sometimes called delta, should be less than the smallest effect size expected for the control versus placebo.
Based on these criteria, a minimum goal of an equivalence trial should be to establish the superiority of the new drug versus placebo without actually conducting a placebo‑controlled trial.
[Slide]
What these minimum requirements entail for study 417 is that in order to claim equivalence for 60 mg versus 120 mg, first, 120 mg has to be proven to be superior to placebo in treatment experienced patients.  Second, the equivalence margin used for this trial should be no more than the smallest effect size expected for the 120 mg versus placebo in treatment experience patients.
[Slide]
There are several limitations in assessing equivalence for study 417.  First, activity of 120 mg was not consistently demonstrated in treatment experience patients to serve as a well‑established control.  That is, only study 408 was supportive.
Second, it is difficult to choose an adequate equivalence margin for dose comparison for study 417 because of the small treatment differences observed with 120 mg versus placebo in study 408, and the lack of a placebo‑controlled study with 120 mg in a comparable population and similar background therapies as study 417.
[Slide]
Now Dr. Kim Struble will return to provide the overview of safety and summary conclusions.
Summary of Safety and Virology Substudy
and Overall Conclusions
[Slide]
DR. STRUBLE:  The overview of safety for ad 120 mg and 60 mg will solely focused on the development and resolution of nephrotoxicity.  This is not meant to minimize the fact that other toxicities were observed during clinical trials.  GI toxicities and increases in liver function tests and bilirubin were observed in patients receiving adefovir.  These events were similar to those observed for other nucleoside analogs.
[Slide]
The safety data base for the 120 mg dose is comprised of greater than 6000 patients who received adefovir 120 mg in the expanded access program.  It should be noted that all patients in the expanded access program required a heavy dose reduction to 60 mg.
The safety database also consists of 666 patients who received at least 1 dose of adefovir 120 mg in studies 408, 411 and 417.  The duration of treatment varies up to 150 weeks, followed by longer‑term follow‑up.  Study 408 provides important long‑term data on the development and resolution of nephrotoxicity.
Study CPCRA 039 and ACTG 359 were not included in this overview because these studies were not Gilead sponsored trials and we have not received all the individual laboratory data to review the safety information from these trials in depth.
[Slide]
I will now review the safety information for adefovir 120 mg from study 407.  Most of the safety data contained in the NDA is for the 120 mg dose of adefovir.  Nephrotoxicity is the most prominent treatment emergent advent associated with adefovir.  Severity, reversibility and management are important safety concerns for long‑term adefovir administration.  Only study 408 provides sufficient long‑term on the development and resolution of nephrotoxicity.
[Slide]
Adefovir‑associated nephrotoxicity generally occurs aft er 24 weeks of therapy, and is characterized by these laboratory abnormalities: serum creatinine greater than 0.5 increase from baseline; serum phosphate less than 2; bicarbonate less than 16; proteinuria greater than or equal to 2+; and glycosuria greater than or equal to 1+.  All the analyses that I will present focus on the onset and resolution of individual laboratory abnormalities.
[Slide]
Definitions for resolution of abnormalities in serum creatinine, phosphate and bicarbonate were based on the variability of these laboratory measurements in patients receiving placebo in study 408 during the first 24 weeks.  For each parameter, resolution within 2 standard deviations from baseline was evaluated.  The FDA analysis uses the last available laboratory value to determine resolution of laboratory abnormalities.  We believe that this analysis provides a conservative estimate of resolution at the end of study, and includes those patients who may have relapsed.
[Slide]
Overall, 61 percent of patients in this trial who received adefovir 120 mg developed at least one renal‑related laboratory abnormality.  Approximately 10‑29 percent of these patients did not have resolution at the last available value of individual renal laboratory abnormalities such as creatinine or phosphate.  It appears that in most cases renal abnormalities were reversible.  However, some patients will have some renal function impairment.  It is yet unknown if these abnormalities will resolve with longer follow‑up.
[Slide]
Gilead has proposed a clinical management program to reduce the risk of severe nephrotoxicity.  This program includes patient and physician education, monthly monitoring of serum chemistries and urinalysis, dose modification based on changes in creatinine or phosphate, and oral supplementation for deficiencies in electrolytes such as phosphate or bicarbonate.
[Slide]
However, we were concerned that some patients may develop significant renal injury despite monthly renal laboratory monitoring proposed by Gilead.  Our division conducted several analyses to determine the number of patients receiving adefovir 120 mg with significant changes in renal laboratory parameters.  These analyses focus on the development of significant changes in renal laboratory parameters by the next monthly study visit.
[Slide]
Overall, approximately 8 percent of patients who received adefovir 120 mg had a peak creatinine that was twice their baseline.  Two percent of patients had a doubling or more of creatinine by the next monthly study visit versus no patients in the placebo arm.  Six percent of patients experienced a shift of 3 toxicity grades for phosphate by the next study visit compared to no patients in the placebo group.  A shift of 3 toxicity grades was defined as a shift of normal phosphate which is greater than 2.4 to a grade 3 toxicity which includes phosphate levels between 1 and 1.4.
[Slide]
We were also concerned that sustained increases in serum creatinine could signify persistent and cumulative renal toxicity associated with long‑term use of adefovir 120 mg.  In the entire adefovir development program for the 120 mg dose, a total of 8 patients required dialysis.  Six patients who required dialysis were enrolled in the expanded access program, and 2 patients were enrolled in clinical trials, 1 in study 408 and 1 in CPCRA 039.
Also, continued phosphate wasting could put individuals at risk for bone toxicity.  To date, 6 cases describing a bone abnormality, such as osteopenia fracture, have been report ed among patients receiving adefovir 120 mg.  However, it is difficult to attribute these events to adefovir since the majority of reports document other potential etiologies, such as concomitant medications or traumatic injury.
[Slide]
I will now review the overview of safety information for adefovir 60 mg.  It is important to note that the safety data for the 60 mg dose predominantly comes from one controlled trial, study 417, in the expanded access program, and 108 patients received at least 1 dose of adefovir in study 408.  Of these 108 patients, 77 received adefovir 60 mg for 24‑48 weeks and 30 patients received adefovir for more than 48 weeks.
The first 1000 patients in the expanded access program were submitted to the division for review.  Of these 1000 patients, 561 patients received adefovir 60 mg for 24‑48 weeks and 43 patients received adefovir 60 mg for greater than 48 weeks.  Since the development of nephrotoxicity generally occurs after 20 weeks of therapy, it is critical to have a sufficient number of patients who have received adefovir for long periods of time, such as 48 weeks, to adequately assess the development and resolution of this toxicity.  However, there are only 73 patients who have received adefovir for greater than 48 weeks.  It is important to note that a substantial portion of patients who have received adefovir for more than 24 weeks solely comes from the expanded access trial.
[Slide]
Trial 417 provides information on the relative safety of adefovir 60 mg compared to 120 mg.  However, there are several limitations of this trial with respect to evaluating the safety of 60 mg versus 120 mg.  These limitations include, one, a large premature discontinuation rate.  Sixty‑nine percent of patients in the 60 mg group and 85 percent of patients in the 120 mg group prematurely discontinued adefovir by week 48.
Also, there is a lack of long‑term safety information for the 60 mg in this study.  After week 28 approximately 50 percent of patients prematurely discontinued adefovir due to either an adverse event, virologic failure or other reasons.  Only 30 patients had a week 48 study visit in the 60 mg group compared to 17 patients in the 120 mg group.  There are insufficient number of patients receiving adefovir 60 mg for more than 24 weeks in this trial to adequately characterize the onset and resolution of nephrotoxicity.
[Slide]
The discontinuation rate in this trial can be graphically displayed on this slide, which shows the proportion of patients still remaining on treatment over time.  The 60 mg dose is in red and the 120 mg dose is in white.  After study day 100 there is a dramatic increase in the proportion of patients discontinuing from therapy.  It appears that patients are discontinuing from the 60 mg arm at a slower rate compared to the 120 mg arm.  However, there are relatively few patients who remain on study at 1 year.
[Slide]
The data suggests that the time to onset for creatinine and phosphate abnormalities are delayed for the 60 mg group compared to the 120 mg group.  However, there were no statistically significant differences for the development of renal laboratory abnormalities and resolution of these abnormalities between doses.  However, numerically more patients in the 120 mg group compared to the 60 mg group developed renal laboratory abnormalities.  It is unknown if the incidence and time to resolution would be similar for both doses with longer‑term follow‑up and sufficient number of patients.
It is important to note that comparisons between the 60 mg and 120 mg with regard to resolution is difficult because there is a mandatory dose reduction to 60 mg for patients in the 120 mg group.
[Slide]
The overall safety conclusions from this trial with respect to nephrotoxicity are shown on this slide.  Due to a high discontinuation rate, an insufficient number of patients receiving adefovir 60 mg for greater than 24 weeks.  Given this limited safety database for the 60 mg dose, it is difficult to conclude whether the 60 mg dose is less nephrotoxic than the 120 mg dose.  We believe that longer‑term data is needed to fully characterize the time to onset, the frequency, and resolution of renal laboratory abnormalities for the 60 mg dose.
[Slide]
A safety update was submitted on October 5 of this year to the division for review.  This update contained limited safety analysis on the first 1000 patients enrolled in the expanded access program for adefovir 60 mg.
[Slide]
Gilead conducted an analysis on the development of creatinine and phosphate abnormalities for the first 1000 patients enrolled in the 120 mg arm compared to the first 1000 patients enrolled in the 60 mg arm.  FDA conducted an analysis on the development of significant renal events by next monthly visit.  Analysis regarding resolution of renal abnormalities is limited because it is often difficult to obtain follow‑up data once a patient discontinues from an expanded access program.
[Slide]
Overall, 18 percent of patients discontinued from adefovir 60 mg in the expanded access program due to an adverse event, of which 69 percent discontinued due to renal events.  Overall, 12 percent of patients discontinued for a renal‑related adverse event.
[Slide]
Gilead conducted analysis of time to creatinine and phosphate abnormalities for the 120 mg dose versus the 60 mg dose in the expanded access program.  The Kaplan‑Meier estimates showed that the time to creatinine increase of phosphate decrease is delayed for the 60 mg versus the 120 mg dose, and that this result was statistically significant.  From these Kaplan‑Meier estimates at 48 weeks, one can assess the proportion of patients who will develop creatinine or phosphate abnormalities.  Approximately 40 percent of patients in the 60 mg group compared to approximately 50 patients in the 120 mg group will develop these abnormalities by week 48.  However, there is a question whether these differences in the development of creatinine and phosphate abnormalities between the 60 mg and 120 mg are clinically meaningful such that one can conclude that adefovir 60 mg is a safer alternative to the 120 mg dose.
[Slide]
We conducted an analysis to determine the number of patients who would develop significant renal laboratory abnormalities.  Approximately 3 percent of patients had a peak creatinine that was twice their baseline.  Overall, approximately 1 percent of patients had a doubling or more of serum creatinine by the next monthly study visit; 2 percent of patients had a shift of 3 toxicity grades for phosphate by the next monthly study visit.
It is important to keep in mind that for this program a patient's next prescription was dependent on receiving renal laboratory measurements.  Despite this, approximately 1‑2 percent of patients will develop significant renal abnormalities such as doubling of creatinine or a shift of 3 toxicity grades for phosphate by the next monthly study visit.
[Slide]
For ad 60 mg there is also a concern that sustained increases in serum creatinine could signify persistent and cumulative toxicity associated with long‑term use.  During the expanded access program, 2 patients required dialysis.  Also, continued phosphate wasting could put individuals at risk for bone toxicities.  To date, only 3 cases describing a bone abnormality, such as osteoporosis, osteopenia or fracture, have been reported among patients receiving adefovir 60 mg.  The case of fracture in the expanded access program was due to a trauma from a fall, and additional information is still being collected for the cases of osteoporosis and osteopenia.
[Slide]
I will now briefly comment on the virology substudy from trial 408.  One hundred and ninety‑one patients were eligible for the virology substudy in trial 408.  Eligibility was based on 2 sets of consecutively enrolled patients to categorize early and late enrollees.  Both Gilead and FDA conducted analyses for the substudy.  The Gilead analysis included 155 patients who had a baseline genotype, baseline RNA as measured by bDNA, and a week 24 RNA measurement.  Their endpoint for this analysis was mean change at week 24, which was presented earlier this morning.
The FDA analysis included 180 patients who had a baseline genotype, baseline RNA as measured by PCR, and at least 1 post baseline RNA measurement.  The FDA endpoint for this analysis was the mean DAVG at week 24, which was the primary endpoint specified in the overall 408 trial.
[Slide]
All patients were grouped according to AZT and/or 3TC resistant mutations at baseline.  Low‑level AZT resistance was defined as RT mutations at positions 41, 67, 70 or 210, or any combination thereof.  High‑level AZT resistance was defined as RT mutation at position 215, with or without other low‑level AZT mutations, or greater than or equal to 3 low‑level AZT mutations.  Finally, 3TC resistance was defined as RT mutation at position 184.
[Slide]
Gilead has determined that in this substudy they have shown that adefovir retains activity against HIV strains that are both AZT and 3TC resistant and that the 184 mutation augments adefovir activity.  In the next several slides I will present the FDA analysis of this substudy.
[Slide]
In the FDA analysis of patients with high‑level AZT resistance that also had the 184 mutation, the mean DAVG for the adefovir group was minus 0.25 log compared to minus 0.67 log for the placebo group, which resulted in a treatment difference of minus 0.18 and an unadjusted p‑value of 0.032.  For patients with high‑level AZT resistance alone without the 184 mutation, the mean DAVG at 24 was minus 0.086 for the adefovir group compared to an increase of 0.09 log for the placebo group.  This also resulted in a treatment difference of minus 0.18 and a non‑significant p‑value.  Notably, the presence of absence of the 184 mutation did not affect the RNA treatment difference between adefovir and placebo.  Both were minus 0.18.  However, this was somewhat less than the overall difference for the substudy, which was 0.35.  Perhaps the clearest result from the substudy is that patients with high‑level AZT resistance alone will demonstrate cross‑resistance to adefovir.
[Slide]
The FDA conclusions from this substudy are summarized on the next two slides.  Exploratory subgroup analyses are useful for generating hypotheses that should be further evaluated in clinical trials.  For patients with dual AZT and 3TC resistance, the treatment difference between adefovir and placebo was less than the overall study population, which was minus 0.18 compared to minus 0.35 logs.
The presence or absence of the 184 mutation did not affect the treatment difference for adefovir compared to placebo in patients with high‑level AZT resistance.
[Slide]
In addition, the hypothesis that the 184 mutation augments adefovir activity requires further study.  Furthermore, data presented in the substudy was generated with the 120 mg dose.  It is unknown what impact adefovir 60 mg will have on reductions on HIV RNA in similar patient populations.
[Slide]
I will now finish my presentation with the following summary conclusions for both safety and efficacy of adefovir 60 mg for the treatment of HIV infection.
[Slide]
Efficacy of adefovir 120 mg has been evaluated in 4 trials.  Study 408 showed small but statistically significant differences in RNA over 24 weeks.  Two trials, the CPCRA 039 and ACTG 359, were not supportive of the efficacy of adefovir 120 mg.  The addition of adefovir to combination therapy in treatment experienced patients in studies CPCRA 039 and ACTG 359 did not improve treatment outcomes.
Although Gilead has requested approval of 60 mg for the treatment of nucleoside‑experience patients, the more compelling study results were found in the treatment naive patients, which was study 411.
[Slide]
The efficacy of 60 mg was evaluated in one 20‑week trial, which was study 417.  A second 4‑week monotherapy study comparing reductions in RNA of adefovir 60 mg versus placebo was conducted.  Since this study did not assess the activity and safety of adefovir beyond 4 weeks, it offers minimal support for approval for the 60 mg dose.
In order to determine if the 60 mg dose is equivalent to 120 mg dose, one needs to conclude that the 120 mg dose demonstrated any viral activity in treatment experienced patients.  However, the activity of the 120 mg dose was not consistently demonstrated in treatment experienced patients, therefore, making it difficult to assess equivalence of adefovir 60 mg compared to 120 mg in study 417.
[Slide]
Also for study 417, the pooled analysis which was presented by Dr. Greg Soon suggested comparability.  However, this equivalence comparison is problematic and complicated by a high discontinuation rate.  There appears to be a possible treatment interaction for group 3, which is the saquinavir and RTI group, in which 60 mg was superior to the 120 mg.  The results of group 3 had a disproportionate effect on the results of the pooled analysis, therefore, giving the appearance that the overall response rate is similar between doses.
[Slide]
Regarding safety, overall there is insufficient information on long‑term administration of adefovir 60 mg.  From the results in study 417, it appears that the time to onset for creatinine and phosphate abnormalities are delayed for the 60 mg compared to the 120 mg.  However, there were no statistically significant differences for the frequency or resolution of nephrotoxicity between these doses in study 417.  It is unknown if the incidence and time to resolution will favor the 60 mg dose with longer follow‑up and sufficient number of patients.
Also shown in the expanded access program the onset of creatinine and phosphate abnormalities appear delayed.  Approximately 40 percent of patients on the 60 mg arm compared to 50 percent of patients on the 120 mg arm will develop creatinine and phosphate abnormalities.  There is a question if this difference is clinically meaningful to conclude that adefovir 60 mg is less nephrotoxic than the 120 mg dose.
In addition, the resolution of nephrotoxicity from the 60 mg dose has not been fully characterized because there have been few patients and short duration of follow‑up in both the 417 and expanded access program to assess this.
[Slide]
In our review of the submitted data, there appear to be several unresolved issues with respect to the proposed adefovir 60 mg dose.  First, there is insufficient information available regarding the long‑term safety of adefovir 60 mg since relatively few patients have received the 60 mg dose for more than 24 weeks.
Second, there are limitations in the design of study 417 that cast doubt on a definitive conclusion that the 60 mg is an active dose.
Finally, it is difficult to determine at this point which patient population will be appropriate to receive adefovir treatment, given the risks of nephrotoxicity and the limitations of the efficacy data available for the 60 mg dose.
Gilead has proposed ongoing approval trials may provide sufficient information to adequately address these unresolved issues.  We look forward to your discussions today for these issues, and recommendations on the questions that are posed before you.
[Slide]
Before I end, I would like to acknowledge and thank the entire adefovir review team.  Thank you.
DR. HAMMER:  Thank you very much.  We are going to enter the committee discussion period now.  Questions for both the sponsor and the agency can be addressed during this period.  As I mentioned earlier, I think there will be a fair number of questions.  I would ask the committee members, in deference to their colleagues, on the first round here to prioritize your questions and ask only the two or three most pressing questions so we can get around the table.  After that, we will open it up further.  I will begin on my left with Dr. Bertino.
Committee Discussion
DR. BERTINO:  Could the sponsor present their pharmacokinetic drug interaction studies with delavirdine and saquinavir, please, if they have that data?
DR. HAMMER:  Please identify yourself for the transcriptionist.
DR. CUNDY:  I am Ken Cundy with Gilead Sciences.  Can I have slide 436, please?
[Slide]
I wanted to start off by just discussing a little bit more about study ACTG 359 in which an interaction was reported between adefovir dipivoxil and delavirdine and saquinavir.  As you can see from the design of this study, all patients received saquinavir and either ritonavir or nelfinavir.  In addition, they received delavirdine, adefovir or a combination of the two drugs.  The pharmacokinetics was evaluated in the 6 different cohorts in 7 patients per arm.
[Slide]
This slide illustrates how complex ACTG 359 was in terms of the background drug interactions between delavirdine and the protease inhibitors that were used.  As you can see, delavirdine has direct effects on the pharmacokinetics of saquinavir and ritonavir, and it also has effects on nelfinavir.  However, you can see that saquinavir itself has reverse effects on nelfinavir, and nelfinavir in turn has reverse effects on delavirdine.  So, in terms of this being the background in which adefovir was introduced, it makes things fairly difficult to interpret.
[Slide]
Our own studies in vitro have shown that adefovir dipivoxil was not a substrate for cytochrome P450, and, in fact, we looked at the ability of adefovir or adefovir dipivoxil to inhibit the metabolism of the known substrates of the major isoforms of cytochrome p450, including 1A2, 3A4, and 2DT, and we showed that neither compound was an inhibitor.  In addition, looking at the metabolism of adefovir dipivoxil in microsomes from rats that had been induced with various compounds inducing 1A2, 2B3A and 4A, there were no changes in the pharmacokinetics of adefovir.
We also looked at the potential for induction of P450 in rats using adefovir dipivoxil dosed orally, and we saw no induction of the major isoforms.  So, on the basis of this data, no pharmacokinetic interaction involving cytochrome p450 would have been expected.
[Slide]
This was the design of our own formal drug interaction study, looking at healthy volunteers in a single dose format.  We looked at 6 different drugs, including delavirdine and saquinavir, and they were studied in a random sequence and in a crossover design with 8 patients per arm.
[Slide]
This shows the effects of adefovir on the levels of saquinavir in our study.  This is within patients so it is a crossover design and is using the 60 mg dose of adefovir dipivoxil as opposed to 120 which was used in the ACTG study.  There was no significant change in the saquinavir levels.
[Slide]
This slide shows the change in AUC of delavirdine on addition of adefovir in our study.  Once again, there was no significant change in delavirdine levels.
[Slide]
One criticism that has been raised is that this is a single‑dose study as opposed to multiple dosing.  However, this study shows that the pharmacokinetics of adefovir dipivoxil were not changed on repeated dosing for 14 days in HIV‑infected patients, demonstrating that there was no induction of a metabolic clearance pathway for adefovir.
DR. BERTINO:  I guess one concern I have is that you did this in normal volunteers, not in HIV‑infected patients ‑‑ your previous slide.  Is that correct?
DR. CUNDY:  Yes, that is absolutely correct.  This study was conducted in healthy volunteers.  Our own studies in more than 70 patients, HIV‑infected, and more than 80 healthy normal volunteers haven't demonstrated a difference in the pharmacokinetics of adefovir dipivoxil.
DR. BERTINO:  I guess my point is that there is data now from Dave Flockhart's group at Georgetown and Angela Kashuba at UNC that shows that HIV patients may be different in terms of pharmacogenetic drug metabolism than normal volunteers.  I would also be concerned about the single‑dose studies with saquinavir and delavirdine because they are drugs that have dose‑dependent kinetics.  So, single dose may not be reflective of what steady state might be.
DR. HAMMER:  Thank you.  Dr. El‑Sadr?
DR. EL‑SADR:  I have a question for Dr. Struble regarding the safety data.  It looks like for the 60 mg dose, from your table on page 9, only 73 patients have received that dose for greater than 48 weeks.  Right?  Out of the 73, how many are still on drug?
DR. STRUBLE:  Maybe you should address that question to Gilead because I am not quite sure.
DR. EL‑SADR:  Because if you look at the discontinuation curves below that, it would suggest that ‑‑ I don't know ‑‑ very few even of those are still on drug after 48 weeks.
DR. STRUBLE:  Correct.  There were 73 patients that received it for more than 48 weeks at the time that I got the submission.  So, at this time I don't know how many more have received the drug for more than 48 weeks, or how many less have received the drug for 48 weeks.
DR. HAMMER:  Dr. Jaffe?
DR. JAFFE:  Thank you.  Just one point of clarification on the pharmacokinetics, we hope to have in the not too distant future, additional pharmacokinetic data on multiple dose from study ACTG 398 where HIV‑infected patients received saquinavir and adefovir in combination with other antiretrovirals.  We do not have that data, and look forward to having it to clarify some of the issues in the future.
As far as the 73 patients who were part of the NDA database at 60 mg for greater than or equal to 48 weeks, that is the data we have as of the last data cut‑off.  However, because of the ramp‑up of enrollment on the 60 mg arm on expanded access, we will be having approximately 75‑150 additional patients per month to add to the greater than 48‑week database.  So, each month that we cut the data, we will be having more of those patients available for review.
DR. HAMMER:  Thank you.  Dr. Stanley?
DR. STANLEY:  This is related to that also.  I guess I am confused about 417.  You show a chart on time to study drug discontinuation for both the 60 mg and 120 mg doses, but then at some point somebody said that at 20 weeks everybody transferred over to the 60 mg dose.
DR. JAFFE:  Yes, during the performance of study 417, and well after many patients had been randomized, with the unblinding of study 408 the extent of nephrotoxicity associated with 120 became evident.  With that information, our independent DSMB met to review the accumulating database and found that there was similar anti‑HIV activity between the two different dose groups.  However, there appeared to be more nephrotoxicity in one of the dose groups.  So, they felt it was important to have everybody who was presumably on the higher dose, dose reduce at week 16, with the rationale being that the drug appeared to be producing activity, anti‑HIV effect, and that more patients would be able to stay on the drug longer and benefit for a longer period of time.
DR. STANLEY:  But on this chart that you showed, even on the 60 mg dose you got a high rate of discontinuation.  I mean, only 30 patients lasted 48 weeks.
DR. JAFFE:  That is correct.
DR. HAMMER:  Dr. Feinberg?
DR. FEINBERG:  Thanks.  I was trying to get my thoughts together.  Let me mention a couple of questions that I have for the sponsor.  Study 408 is the only study that appears to be supportive of their proposed indication in treatment experienced patients, at least by statistical criteria by the p‑value.  It is not clear to me that the small difference in viral load change is a clinically meaningful change.
But I think another issue even in interpreting 408 is, as I recall from our meeting a year ago, patients were also permitted to change ‑‑ the protocol asked people to try to remain on stable background therapy but, in fact, patients did, indeed, change their background therapy before the specified clinical endpoint time of 24 weeks.  We didn't see any data about what proportion of patients did that, or what was the outcome of those individuals.
DR. JAFFE:  Sure.  Just one point of clarification, although not presented by FDA and we only presented the results of one study, there are 2 additional studies which have demonstrated anti‑HIV activity.  They are both short‑term in duration.  That is study 402 which enrolled treatment experienced patients and looked at the dose range of 125‑500 mg once a day for 2 weeks, and there were statistically significant differences between the placebo group and the active‑treated arms.  As previously presented, in study 403, patients were dosed 6 weeks during a blinded study and then had rollover to an additional 6 weeks monotherapy versus placebo, and there were clear statistically significant differences between the treatment arms in treatment experienced patients.
[Slide]
DR. TOOLE:  In study 408 patients were discouraged from changing their antiretroviral regimen for the first 24 weeks.  However, about 20 percent of patients did change and there was no difference between the 2 arms.
[Slide]
We also conducted an analysis where we excluded patients who added a new antiretroviral agent.  As shown here, for the active group during the first 24 weeks, for those that did not add an agent, there was still a decrease of about 0.3 logs after 24 weeks.  In addition, for those patients who were on the placebo arm and added adefovir during the open‑label phase, we also applied the same analysis and, again, a decrease of about 0.3 logs is observed after 24 weeks.
DR. FEINBERG:  I am sorry because that went by very quickly.  So, you are saying that this is the viral load change outcome?
DR. TOOLE:  This is excluding those patients ‑‑
DR. FEINBERG:  Excluding those who made a change in the first 24 weeks.
DR. TOOLE:  On adefovir, either after rolling over from placebo to the open‑label phase of adefovir, or during the blinded period.
DR. FEINBERG:  So, do you have a slide looking at that as an intent‑to‑treat?  In other words, the same analysis ‑‑ oh, no, it wouldn't be that.  I am sorry.
The next concern I have is kind of global.  I am not even sure how to phrase it.  I guess I am concerned that studies 402, 403 and 420 have never shown any evidence of a dose response with respect to the antiviral activity of adefovir.  In addition, at least by your Kaplan‑Meier estimates from expanded access, there doesn't seem to be any dose proportionality for nephrotoxicity either.
So, I guess I have questions about why not choose ‑‑ I mean, I am trying to figure out why 60 mg is the dose of choice, why that does might not be smaller than 60 mg?  I understand that the hepatitis B dose is 30 mg and, given everyone's concerns about nephrotoxicity, I wonder if you could tell us about the 30 mg database.  I understand it is a different disease and a different population but I would like to know is nephrotoxicity evidenced at 24 or 48 weeks of treatment for hepatitis B and, if so, is that onset later in time than you have shown us for 60 mg?  I understand we are talking about different indications.  My concern is what is it that this drug does, and why is 60 mg the right dose.
DR. TOOLE:  As part of our Phase IV commitments we will be investigating the 30 mg dose with regard to anti‑HIV activity and safety profile.  If I could have slide 62, please?
[Slide]
With regard to the difference between 60 mg and 120 mg observed in study 417, this slide looks at the Kaplan‑Meier analysis for the time to onset for serum creatinine increase.  In this case, we do see a significant difference, as shown by this p‑value, for the development of nephrotoxicity.  This is for creatinine increase.  We observed the same difference for hypophosphatemia.
DR. FEINBERG:  I might remark that on that slide the inflection point in terms of time for both doses, you know, appears to be happening between 24 and 28 weeks.
DR. TOOLE:  That is correct.  When we began the study we weren't certain whether what you would see is a 2‑fold delay before the development of nephrotoxicity at the lower dose.  It is clear that is not the case.  However, the apparent plateau does seem to be lower.  This plateau was also observed in study 408 even when there was a significant number of patients at risk for the development.
DR. HAMMER:  Have you done an analysis if you stratified for a different creatinine level?  I am sorry to interrupt, Judith, but if you did greater than 0.3 from baseline, for example, because the time of onset does look the same.  The cumulative proportion of patients with nephrotoxicity by that definition is different but I think the group might be interested to see if you used a lower threshold what those curves might look like.
DR. TOOLE:  We haven't done that primarily because if you look in study 408, the patients on the placebo arm who had a 0.3 rise is about 15 percent, and for a 0.2 increase it is about 40 percent.
DR. JAFFE:  I should also point out that in the expanded access program we were able to compare 1000 patients at 120 mg to 1000 patients at 60 mg with similar lengths of exposure, and while there is an incidence of about 40 percent according to the Kaplan‑Meier estimates at a year in the 60 mg group and 50 percent in the 120 mg group, according to the log rank test that is highly statistically significant.
Now, in terms of 30 mg and what we might expect to see, we have now treated about 25 chronically infected patients with HBV at 30 mg for about a year, and we can see at about 10‑11 months, now having precise knowledge of what to look for, small up‑ticks in creatinine, smaller than the 0.5, associated with minor decreases in phosphate.  So, we might expect to see nephrotoxicity associated with the 30 mg dose but at a much lower incidence and delayed onset as well.
DR. FEINBERG:  Those are co‑infected patients, chronic hep. B and HIV, or just chronic hep. B?
DR. JAFFE:  Those are chronic hep. B infected patients without HIV.  There have been studies that have looked at co‑infected patients as a subset of the CPCRA study 039.  About 10 percent of patients were co‑infected and, as part of the CPCRA's analysis it appeared that there was less incidence of renal toxicity.  Whether or not that is influenced by the small numbers we don't know.  As recently presented by the 039 study team, there was clear activity against hepatitis B infection in those patients compared to placebo.
DR. FEINBERG:  I have just a couple more sort of follow‑up questions, just chasing this issue of the nephrotoxicity.  One is that although we have been given a lot of laboratory data, other than one slide which said 6 patients or 1 percent had been reported as having a Fanconi‑like syndrome, we really haven't been shown anything about the clinical impact of this nephrotoxicity on patients, and I wonder if you have the data in that format to tell us something about the actual clinical manifestations.
DR. JAFFE:  Sure.  Much of the serious renal adverse events that were reported were early on in the program where knowledge of the precise manifestations of toxicity were unknown and may have led to hospitalization.  That is the slide that Jay presented earlier, which reflected not understanding the pattern of toxicity.
Now, at 60 mg we can say that in the 120 or so patients who came off study drug in the first 1000 patients at 60 mg, 5 of those events were considered to be serious; 2 of those patients underwent hemodialysis.  Both were extremely complicated patients with viral loads well above 100,000 copies at baseline, on multiple concomitant medications.
One of the patients had developed pancreatitis and hepatitis, and with a normal creatinine off adefovir was hospitalized and, while in hospital, received IV radiocontrast for an abdominal CT scan and developed renal failure while off adefovir.
The second patient also had a similar background history, developed pancreatitis and, while in hospital, not receiving IV radiocontrast, had multi‑organ failure.
[Slide]
I think it is important to put this a little bit in context.  The point of this slide is to show that renal failure can occur with adefovir.  This is at 120 mg, and this is one of the two patients from the controlled clinical trials who went on to dialysis.  He is a 55‑year old African American male who had multiple preexisting medical conditions and was on a slew of other drugs, who came off adefovir after an increase in his creatinine up to 2.4 mg/dL.  Over the next month, with evidence of wasting syndrome and a variety of other issues coming up, the patient was hospitalized with renal failure and underwent dialysis and also underwent biopsy.  In that biopsy, it was consistent with severe acute tubular necrosis as well as clear evidence of mesangial proliferation, consistent with HIV neuropathy.
The point of this slide though is to show you that while it is quite clear that adefovir is a nephrotoxin, in an advanced AIDS population there will be background noise with regard to renal failure.  And, this patient, in the placebo group, is a patient who was hospitalized for the treatment of pneumonia and in hospital received antibiotic therapy and ended up with renal failure.
So, we can state, I think fairly confidently based on the data, that adefovir is a mild nephrotoxin and that there is, however, background noise in the placebo group of patients who won't receive adefovir.  So, it is very difficult to sort out the actual contribution at times of adefovir to the patient's course.
DR. FEINBERG:  Thank you.  This last bit on nephrotoxicity is directed at the FDA, mindful of what Scott just asked about, looking for smaller increments in creatinine and understanding that creatinine is not an arithmetic test but represents a logarithmic function.  If I remember my internal medicine correctly, if you double your creatinine you lose 90 percent of your GFR.  So, have you done an analysis that looks at smaller decrements in renal function?  I guess what I am saying is I am concerned that a lot of what we have seen this morning, if I remember correctly, seems to be premised on this half milligram change, which is really an enormous, enormous change in the ability of your kidneys to function correctly.  I wonder if you have looked at anything less than that.
DR. STRUBLE:  No, we haven't.  We have only looked at 0.5 mg/dL increase from baseline for serum creatinine because that was the definition that was given to us for the development of this nephrotoxicity.
DR. HAMMER:  Thank you.  Dr. Mathews?
DR. MATHEWS:  I would like to ask two questions at this time.  One relates to the 30 mg dose that is possibly recommended for toxicity in the package insert.  The other is related to what is known about potential mitochondrial toxicity.
So, with regard to the 30 mg dose, the package insert has guidelines for dose reduction that include that dose, but I am wondering, since we haven't heard any data on the efficacy of that dose, whether there is a rationale for using it as opposed to withdrawing the drug altogether.
[Slide]
DR. TOOLE:  In studies 411 and 417 42 patients were dose reduced primarily for nephrotoxicity.  Looking at their median change from baseline following the dose reduction shows little evidence of rebound after 16 weeks.
DR. HAMMER:  Could I ask a follow up?  Do you have data when you stopped the drug completely, the same curve, either in this study or other studies?  When adefovir is stopped completely is there an RNA rebound?
DR. TOOLE:  We don't have data from this study for that, no.
DR. HAMMER:  Do you have any data, because I think it relates to Dr. Mathews' point?
DR. TOOLE:  In study 408 we have seen a return towards baseline in patients, but there are very few patients in that study who don't go onto other regimens after discontinuing adefovir so the numbers are small.  I am sorry, what was the second part of your question?
DR. MATHEWS:  To summarize, I mean, since these people were on background therapy we don't know, in fact, that failure to rebound is due to the fact that the 30 mg dose is active or that there is background activity in the regimen that they were on.  Is that correct?
DR. TOOLE:  That is true, but I think at least in study 411 the efficacy data are fairly convincing that the 3‑drug regimens with adefovir have activity which is comparable to the control.
DR. MATHEWS:  I understand that, but at this dose level, that is the question.  And, a lot of people would be exposed to that dose level in therapy.
The next question I have relates to whether in vitro studies have been done to assess the potential mitochondrial toxicity of this agent.  In particular, I think it is interesting because of the carnitine depletion that accompanies use of this agent.
DR. TOOLE:  Yes, we do have in vitro studies regarding inhibition of polymerase gamma.
DR. BISCHOFBERGER:  We don't have any evidence from preclinical studies, including animal studies and woodchuck studies, that there is any mitochondrial toxicity.
[Slide]
We have looked at inhibition of human polymerases, including the mitochondrial gamma polymerase.  Shown here is the kinetic substrate specificity.  So, in terms of the natural substrate, 100 percent would mean it is as efficient as a substrate as deoxy NTPs.  As you see here, the best substrate in this study was ddC with 25 percent deficiency.  The next one was ddA‑TP with 20 percent; the next one, D4T; then came adefovir diphosphate and then 3TC.  So, in summary, there is a substrate for gamma polymerases but at less efficiency than ddC, ddI, and D4T.
DR. HAMMER:  Can I just ask for a clarification to understand this, AZT triphosphate is a mitochondrial toxin but in this assay there is no incorporation?
DR. BISCHOFBERGER:  We did not see any incorporation in this assay, but if I can show slide 1143 ‑‑
[Slide]
What we have done here is we have just measured Ki's rather than efficiency of incorporation.  Here, AZT is included.  You see gamma polymerase.  It has a Ki of 18.  So, the higher the Ki, the lower the inhibitory ‑‑ so AZT is 18; adefovir phosphate, in this case, is 0.97; ddC is 0.034.  Dr. Hammer, does this answer your question?
DR. HAMMER:  Yes.
DR. BISCHOFBERGER:  Thank you.
DR. HAMMER:  Dr. Yogev?
DR. YOGEV:  Well, I have about 24 questions so let me start.
DR. HAMMER:  Stop with 3 and we will come back to the other 21 later.
DR. YOGEV:  The first question I have is basically for the team at the FDA.  Do we accept the 0.3 log as a real reduction?  Is 0.3 meaningful to even consider this drug as really an addition to the armamentarium?  Maybe I was spoiled with the NNRTI and protease inhibitors.  So, I wonder how my colleagues feel about it.
The question to the company is, ddI, I noticed, was one of the few which was 29 percent increase ‑‑ is ddI going to be excluded from the armamentarium?  Any recommendation for that because now many of us are using hydroxyurea which increases even more the intracellular ‑‑ are we going to see more pancreatitis because of combination with this drug?  Are there any data for the ddI accumulation?
DR. JAFFE:  I can't answer the first question for the FDA.  So, I would invite one of them to come up and deal with that if they would like, but in terms of ddI‑related side effects, we have long‑term placebo control from study 039, and the incidence of the primary ddI side effects, peripheral neuropathy and pancreatitis in both cases is higher in the placebo group compared to the active group, the adefovir‑containing group.  The use of ddI at baseline is roughly similar.  So, there is no data to suggest at this point in time that these minor elevations that we saw in the single‑dose study have any clinical relevance.
DR. YOGEV:  But those data are only for the first 20 weeks.
DR. JAFFE:  No, no, this was the long‑term placebo‑controlled trial where patients had a median follow‑up time of 11 months on study.
DR. YOGEV:  I am a pediatrician and I almost feel that I don't belong in this session because you didn't present any data on pediatrics and, yet, in the insert you are claiming that maybe it can be used between 4 months and 18 years.  Can we see a bit more data on that?
[Slide]
DR. TOOLE:  We conducted study 418, which was an open‑label, dose escalation study at 2 dose levels of adefovir, either 1.5 mg/kg or 3 mg/kg, in combination with other nucleosides and nelfinavir.  There were 25 patients in this study.  These were HIV‑infected children who were nelfinavir‑naive, with HIV RNA greater than 400 copies/mL.  The duration of the study was 16 weeks for the primary phase, followed by an open‑ended extension.  The endpoints of the study were PK, safety and HIV RNA changes.
[Slide]
The objectives of the study were to establish an appropriate dose of adefovir dipivoxil in children; to evaluate the pharmacokinetics, safety and tolerance of adefovir at 2 dose levels in combination with other antiretrovirals; to evaluate the antiretroviral response through 16 weeks of treatment, as well as to obtain preliminary information on the potential interaction of adefovir and nelfinavir.
[Slide]
The children received adefovir in a suspension formulation which was dissolved adefovir in combination with L‑carnitine in a sweetening suspending vehicle.
[Slide]
The baseline demographics show the mean age of the children to be about 6.5 years, primarily girls, with a mean HIV RNA of about 80,000 and a mean CD4 percent of about 25 percent.
[Slide]
Adefovir dipivoxil was well tolerated as all children completed 16 weeks of treatment.  Three patients discontinued for an adverse event and all three of these were due to hypophosphatemia which, again, developed in the extension phase, that is, beyond 16 weeks.
[Slide]
This slide summarizes the grade 3 or higher adverse events observed during the study.  There were no grade 4 adverse events.  There were 3 grade 3 adverse events, neutropenia, a congenital anomaly which was diagnosed during the study, and 2 case of hypophosphatemia at the higher dose level.
[Slide]
These children gained weight and height, as shown here.  This is looking at the mean change in weight and height at week 24.  However, when looking at the adjusted Z‑score, which is an instrument to take into account the patient's age and gender, the children were relatively underweight for their age with a Z‑score of minus 0.2.  However, it is important to note that these children came into the study with a Z‑score of minus 0.35.
[Slide]
The study was conducted with adefovir being added onto background therapy for a 1‑week lead‑in and then nelfinavir was added on day 8 and continued.  After week 1 for both dose levels we observe about a 0.2 log decrease, with a range of minus 0.5 to plus 0.4.  At week 16, after the addition of nelfinavir, there is a 0.5 decrease from baseline, with a range from minus 2 to plus 8.
[Slide]
So, to conclude, adefovir in combination with nelfinavir and other NRTIs has been well tolerated.  The median duration of adefovir for this study is 80 weeks.  Adefovir at the 1.5 mg/kg dose provides similar exposure to the 60 mg dose used in adults, and based on trough and peak levels of nelfinavir there is no apparent interaction.
DR. JAFFE:  Since we seemed to have skipped past the issue of the magnitude of the viral load change to pediatrics, I thought it would be useful to just take this opportunity and put a 0.3 log change into some proper context.  This is looking at monotherapy studies of other nucleoside reverse transcriptase inhibitors.  These are not our data.  They come from an ACTG study which has been presented publicly, and the Merck 033 study which may still be in their package insert.
[Slide]
This is a study in patients who had received AZT monotherapy.  It was a complicated study design which I believe had 4 arms associated with it, but 2 of the arms had patients rolling over to either D4T or ddI monotherapy.  As you can see, here the viral load declines over time, for D4T by week 24 probably about 0.125 and at the end of 48 weeks it is above baseline.  For ddI the activity is clearly greater, but at the end of 48 weeks approximates about 0.4 to 0.5.  That is in treatment experienced patients.
[Slide]
Now we are looking at treatment naive patients here.  This is the study design.  Treatment naive patients were randomized either to zidovudine alone, indinavir alone or zidovudine plus indinavir.
[Slide]
You can see that AZT in the treatment naive population through 24 weeks has about a 0.3 to 0.4 log decline.  So, I think it is important to put the changes we have seen with adefovir in context.  It is also important I think to understand how treatment effects may differ according to the treatment population that you look at.
For example, if we were to focus here on this treatment naive group and look at the combination of AZT and indinavir, which is about 1 log or 90 percent of the virus in your blood, if we were now to extrapolate to study 411 and look at the results that we see in the triple control, AZT, 3TC and indinavir, I think we can confidently say that 3TC is supplying about another 0.6 log decline.  The mean change at week 20 in that study is about minus 1.6.  However, if we feel confident in making that extrapolation, I think we also must acknowledge that given the results that we have seen with the triples including adefovir, that adefovir is supplying the same 0.6 treatment effect in that treatment naive population.
DR. YOGEV:  Well, the study you presented, it was from 1.9 to 12.9 age, yet you are claiming it to 0.4.  That supposes it can be used at less than 2 years of age.  We know from multiple studies that the pharmacokinetics in the younger ones is so much different that I was just wondering where you got the 4 months of age into that group, suggesting that it can work.
Also, it is interesting that the variation in that specific group that you are reporting, for the area under the curve the standard deviation from 1.29 is almost 0.3 mcg/mL, which is more than double what is in the adults, suggesting that there is going to be a huge variation in that population.  Shouldn't you just limit yourself to the 2 years and older unless you have a PK which you didn't show us to show the same?  Also, try and explain to me why you can go to 0.75 on toxicity.
DR. JAFFE:  There is very limited information in terms of dose reduction, and your comments regarding the age threshold are well taken.  Dr. Cundy will present some of the pharmacokinetic information.
[Slide]
DR. CUNDY:  This slide compares the pharmacokinetic data obtained in 10 HIV‑infected children, at the dose of 1.5 mg/kg of adefovir dipivoxil administered as a suspension of the tablets, with data for the 60 mg dose in HIV‑infected adults.
As you can see, the AUC and the Cmax under these conditions are almost identical.  This also demonstrates, however, that the apparent clearance of adefovir in children is somewhat greater than it is in adults.  But one would expect that a 1.5 mg/kg dose would administer a similar exposure of adefovir to a 60 mg dose in adults.
[Slide]
This is a graph that shows the effect of age in the cohort of HIV‑infected children on the apparent bioavailability of adefovir dipivoxil, and there is no demonstrated relationship with age, illustrating that we got very similar bioavailability across the range of 2‑10 years of age.
DR. YOGEV:  You just reconfirmed what I am asking for.  Less than 2 years of age, do you have any data?  I have no problems with 2 years and above.  I am talking about less than 2 because you are suggesting that it can be used in 6 months of age.
DR. CUNDY:  There was a previous study conduct ed, study 406, in HIV‑infected children where some pharmacokinetic data was generated at ages below the 2 year limit that was ‑‑
DR. YOGEV:  Sorry for interrupting, but that specific study was on 8 patients and the range was from 0.4 to 17 years of age.  One would like to know how many were really tested at less than 2 years to justify usage of this drug.
DR. CUNDY:  Yes, as far as the clinical outcome for 406, I will leave that up to Dr. Jaffe.
DR. JOLSON:  Scott, I wonder if I could just interject something as a point of clarification?
DR. HAMMER:  Sure.
DR. JOLSON:  I mean, as Dr. Yogev pointed out, normally we would have presented and commented on the pediatric information as part of this NDA, but as a point of clarification it is probably worth mentioning that the pediatric formulation has only recently been submitted.  It is part of a separate NDA, and that is why you are not hearing our commentary on it.  I think it has only been in‑house for about a month or so.  Gilead can correct me if that is incorrect.  So, we will take your comments under advisement, but that may be why you haven't heard a more proactive approach toward viewing the pediatric information from our side.
DR. YOGEV:  So, that suggests that in our discussion we are discussing we are only discussing potential approval, or advising for approval, for adults only, excluding pediatric?
DR. JOLSON:  That is correct.  The NDA that we are talking about today is for the adult indication.  The comments that you are making now will be relevant to the pediatric indication but that is not part of today's application.  They were separated in time by many months, about five months.
DR. YOGEV:  Does that also include pregnant women?
DR. JOLSON:  In terms of?  What would your question be?
DR. YOGEV:  Because now we are going to approve it for adults and I didn't see any data on pregnant women.  There was no discussion of that.  Are they going to be excluded?  Because the way it is written in the insert is in certain cases this drug can be used, and I am not sure we saw any data for safety pharmacokinetics to suggest 60 is right.
DR. JOLSON:  Well, I would ask the sponsor to respond to the experience in that population, but also it is probably worth mentioning that the draft insert that you see is what was submitted with the application.  Normally, by the time a product gets to market the insert has undergone substantial revisions.  So, anything is fair game for comments, but you shouldn't look at anything as though it is locked in.
Just getting back to the original question about the relevance of viral load, maybe Dr. Murray can just comment about our division's approach to that issue.
DR. MURRAY:  Well, it is true what you said for an individual for two separate HIV RNA measurements.  The variability could be 0.5 to 0.7 logs, but when you are looking at a large number of patients in a clinical trial smaller differences than the variability from one individual can be relevant.
I think two years ago we couldn't tease out what the lowest threshold would be for an HIV RNA reduction still having clinical benefit.  I mean, when we looked through a lot of the clinical endpoint studies, the majority of studies were an incremental 0.3 log or greater reduction seen was associated with clinical benefit.  It seemed like though that somewhere below 0.3 logs it was plus or minus.  In some studies clinical benefit followed and in others it didn't.  You have to remember that there is a lot of difficulty because what a drug can do as monotherapy might be very separate from what it does when it is being used in an active combination.  There probably is synergy, and it depends ‑‑ you know, some of the viral load reduction is all up front, if it is transient, all in the first 8 weeks ‑‑ you know, a viral load reduction even greater than that but  if it is not sustained would probably not give you clinical benefit.  So, it is a bit complicated question, but something below the inter‑subject variability probably ‑‑ the variability from one subject probably does confer clinical benefit.
DR. HAMMER:  Thank you.  Dr. Hamilton?
DR. HAMILTON:  Expanding somewhat on the topic we are talking around at this moment, I would like to tilt a little further toward that clinical windmill and inquire as to whether, in fact, the projection illustrated in this analysis of the relationship between the clinical disease progression and changes in HIV RNA have, in fact, been evaluated at all in the conduct of the course of the studies of what must be several thousand patients now.  Recognizing that clinical endpoints has not been, at the outset, the subject or the statistical focus of these studies, nonetheless, I would have hoped that some data might, in fact, have been collected.  I notice in the safety profile slide that Dr. Jaffe just showed that there were, in fact, 16 or 17 deaths in 2 treatment arms, only 1 of whom died apparently of renal failure.  I would kind of like to know what they did die of.  Are there morbidity, mortality, quality of life measures that we can use to help validate the putative benefits of this modest reduction in viral load?
DR. JAFFE:  By the way, we have not tested, nor have any information in pregnant women.
[Slide]
This looks at the mortality in 039 and, as Dr. Toole indicated earlier, the real value of this study is having a long‑term placebo control.  In the absence of a long‑term placebo control, 24‑week studies per se, particularly with patients who may have higher CD4 cell counts, it is very, very difficult to assess, because of the low event rate, what impact your drug may have.
The primary endpoint of this study was survival and, as you can see, there were 17 deaths in the adefovir group, 16 in the placebo group, and there are numerous different reasons.  I should point out that 1 patient who had an arrhythmia was on the adefovir arm but died 5 days into study, never having received study drug.  So, the distribution, or at least the numbers, is quite similar.
[Slide]
Looking at some of the other secondary endpoints, we can see that there is no difference with regard to death, 17 versus 16.  With regard to CMV disease, and because of the demonstration preclinically and to some degree in an early clinical study of anti‑CMV activity, this study actually had nested within it a CMV prophylaxis study.  So, patients were actually screened at baseline to make sure that they did not have CMV retinitis.  But similar to the changes in terms of mortality events, the decrease in CMV retinitis was also impacted by the changing background HIV therapies.  There were 5 patients on the adefovir arm compared to 10 on placebo that had CMV.
If we now look at progression of disease including death, there were 40 on the active arm compared to 48 and none of these achieved statistical significance.
[Slide]
Now, if we look a little more carefully at some of the clinical endpoints, these are data that have just recently been received by Gilead.  We have not had a chance to analyze them, nor has the FDA.  We are now looking at first occurrence of specific opportunistic disease, now looking at PCP, candidiasis, confirmed CMV, wasting syndrome, age‑related malignancies, other OIs, and in this grouping we are talking about herpes zoster, Microsparidia, a variety of other endpoints and AIDS dementia complex or PML, there are 39 first occurrences in the adefovir group compared to 62 in the placebo group, and this achieves statistical significance.  This is our p‑value.  This has not been done by the CPCRA, and it is an unadjusted analysis for baseline CD4 and RNA.  So, there is some degree of evidence of differences between the two groups.
DR. HAMMER:  Is that invasive esophageal candidiasis or is that oral candidiasis?
DR. JAFFE:  We don't have that information, but we have reasons to believe that it is oral, esophageal and perhaps even disseminated.
DR. HAMMER:  And, was prophylaxis comparable between the two groups, for example, for the PCP?
DR. JAFFE:  Yes, it was.
DR. HAMMER:  Those data are driven by PCP and candidiasis.  So, I think one has to really look at those two categories quite carefully.
DR. STANLEY:  Dr. Hammer, we should also point out that in this study there was no virologic benefit shown with adefovir.
DR. HAMMER:  Dr. Masur?
DR. MASUR:  In order to understand the nephrotoxicity a little bit better, could you elaborate on either preclinical or clinical data about what the mechanism might be, and also on the same issue, obviously you have looked at doses between 30 and 250 or 500.  What evidence do you have either preclinically or clinically that this nephrotoxicity is, in fact, dose related?
DR. TOOLE:  Preclinically, on histological examination we observed only a tubolopathy, glomerular changes.  The tubolopathy was not accompanied by any changes in serum chemistries of creatinine or phosphorus.  We did observe very minor changes of keriomegaly at doses as low as 1 mg/kg/day.
DR. MASUR:  That is pathology.  Do you have any indication of what the pathophysiology of this is?  Why is this unique to this particular class of compounds or this compound?
DR. TOOLE:  I was going to address the mechanism of nephrotoxicity.
[Slide]
We have recently cloned and expressed the human organic anion transporter from human kidney, and found adefovir to be a substrate.  The human organic anion transporter has been shown by immunohistochemistry to be localized to the proximal tubules.  Based on that, shown here is a model for a proximal tubule cell.  We believe that adefovir is transported to the proximal tubule cell by the organic anion transporter, and through an unknown mechanism is also secreted into the glomerular filtrate.  Over time, either adefovir or metabolite accumulates and through an unknown mechanism leads to cellular injury.  After injury, transport re‑uptake from the glomerular filtrate of glucose and phosphate is inhibited, resulting in glycosuria and hypophosphatemia.  Inhibition of protein uptake is inhibited, resulting in proteinuria, as well as inhibition of secretion of hydrogen ions which result in reduced serum bicarbonate.
DR. HAMMER:  Could I just ask what hydroxyurea does, does it potentiate the toxicity either clinically or at your basic mechanistic level?
DR. TOOLE:  We don't know in terms of a basic mechanistic level.  In our expanded access program we have done a preliminary analysis looking at patients who have received hydroxyurea.  There has been no increase in associated nephrotoxicity in those patients.
DR. BENDELE:  I am Ray  Bendele, Gilead Sciences.  We do see a dose‑related increase in nephrotoxicity in animals, in that in the rat, at approximately 100 mg/kg, we do begin to see increases in BUN and creatinine, as well as histologic changes.  As we increase the dose in monkeys orally, we have never seen increases in BUN and creatinine even at 75 mg/kg for 30 days, or 25 mg/kg for 3 months.  But if you give a high enough dose intravenously in the monkey you can produce proximal renal tubular necrosis.
DR. MASUR:  So, are you suggesting that there is a threshold at which you get toxicity?  Do you have any data suggesting that as you augment the dose you get earlier or more severe or less reversible toxicity?
DR. BENDELE:  No, as you increase the dose in the rat, for instance, at 37 mg/kg in some of the studies that we have run for up to a month, we don't see any evidence of increases in chemical chemistries, BUNs or creatinines, although we do see some histologic evidence of renal toxicity.  As we increase to 100 mg/kg we do see more severe renal toxicity with increases in BUN and creatinine.
In terms of the histologic effect, the longer the duration of treatment in the rat, for instance, the lower the dose at which you see the cytomegaly in the kidney, but it doesn't increase in severity as you increase the duration of exposure.  And, the effects are reversible.  In the monkey after 20 weeks at 25 mg/kg there were 7/8 animals at that had the histologic change of keriomegaly.  After a 1‑month recovery only 1/8 animals had any evidence of keriomegaly.  So, we do see recovery of the histologic lesion.  Although not totally, we do see recovery after 1 month in the monkey.
DR. HAMMER:  Dr. Lipsky?
DR. LIPSKY:  First a question on efficacy and then another one on kinetics.  In the expanded study you reported that by 9 months approximately 50 percent of the patients were off the drug.  Nephrotoxicity was only about 17 percent.  Why are people stopping the drug?  Is it efficacy? Toxicity?  What is going on?
DR. JAFFE:  In this patient population it, no doubt, is a combination of various factors.  In the expanded access program, in a setting where data are not audited, we are left with what the physician sends in, in the case report forms.  So, in terms of the 50 or so percent that have come off, about 20 percent come off for adverse events; about 10 percent come off for progression of AIDS; 2 percent have died; and then there are various other reasons, including non‑compliance, loss to follow‑up, etc.
DR. LIPSKY:  I see.  Thank you.  On the kinetics of the drug, when you did the dose reduction down to 60 mg, in the brochure that you presented, with an N of 6, you achieved a Cmax of around 0.1 mcg/mL, which appeared to be virtually identical to the Cmax at 120 in I think the 402 study, the one that you gave us, the reprint published in JID.  Is that because of a difference in assays or how does the concentration respond to the dose?
[Slide]
DR. CUNDY:  This is now looking at the data we have comparing short‑term dosing of adefovir dipivoxil with long‑term dosing in a limited number of patients.  Here we have comparisons of 12 patients that had long‑term dosing and 6 further patients that had been dose reduced for nephrotoxicity.  You can see here the apparent clearance of adefovir was reduced somewhat upon long‑term dosing in all patients.  However, it was further reduced by about 55 percent from control values in patients that had actually been dose reduced for nephrotoxicity.
DR. LIPSKY:  No, just classic pharmacokinetics with this drug ‑‑ what is the relationship between the dose you give and the level you get?
DR. CUNDY:  Oh, okay, I understand the question.
[Slide]
This slide demonstrates the dose proportionality of the Cmax of adefovir following oral dosing of the dose range from 60 mg up to 500 mg.
DR. LIPSKY:  And that was what?  Normals?
DR. CUNDY:  This is all HIV‑infected patients.
[Slide]
This is a similar graph for AUC values in HIV‑infected patients over the same dose range.
DR. LIPSKY:  Then, dose related to effect, the curves are very flat.  Is there any information about cellular uptake of this drug?
DR. CUNDY:  We don't currently have an analytical method that is capable of measuring intracellular levels of adefovir, although we are looking right now at finding a more sensitive method with the hope of being able to do that.
DR. LIPSKY:  In the information you gave you said intracellular levels had a half‑life of about 30 hours.
DR. CUNDY:  Those were actually based on studies in resting and activated human PBMCs using radiolabeled drug.
DR. LIPSKY:  I see.  Thank you.
DR. BISCHOFBERGER:  Can I clarify something very briefly?  We have actually carried out an analysis of intracellular levels in monkeys.  Could I have slide 1150?
[Slide]
This shows a study we have done with C14 labeled adefovir.  We have looked at plasma levels and intracellular levels of both adefovir and the antiretroviral active metabolite.  As you see, the plasma half‑life is on the order of 5‑7 hours, and the intracellular half‑life is very long.  It is on the order of 30 hours.  We don't have the corresponding data in humans, but this is in monkeys.
DR. HAMMER:  Is there a dose response in the diphosphate levels?  That would help us enormously, I think.
DR. BISCHOFBERGER:  Yes, we have actually gone from 15 mg/kg in the monkey up to 60 mg/kg and safety and efficacy see very nice dose proportionality, 4‑fold higher intracellular levels.  It correlates to the plasma AUC.
DR. LIPSKY:  What is your interpretation of the flat dose‑response curve?
DR. BISCHOFBERGER:  I am sorry, which flat dose‑response curve?
DR. LIPSKY:  In other words, regardless of what dose you have given, you seem to get the same response, whether it is 60 mg, 120 mg, 500 mg and you are proposing potentially 30 mg.  Do you have any explanation for that?
DR. BISCHOFBERGER:  No, I don't, but I do not think it would be the limitation in terms of intracellular active metabolites.  But, you know, one possibility could be we don't really know where these active metabolites are ‑‑ I mean, I am making it up obviously.
[Laughter]
DR. LIPSKY:  And, there doesn't appear to be any role for therapeutic monitoring for efficacy or toxicity in this drug?
DR. BISCHOFBERGER:  I am sorry, could you say that again?
DR. LIPSKY:  Is there any role ‑‑ there has been no presentation or any concern, is there any role for therapeutic monitoring for either efficacy or toxicity with this drug?
DR. CUNDY:  Actually, we are going to be looking at longitudinal changes in pharmacokinetics in our ongoing study 415, with the idea of seeing whether pharmacokinetics in any way indicate a patient might be predisposed to nephrotoxicity, but we don't currently have that data.
DR. HAMMER:  Thank you.  Dr. Pomerantz?
DR. POMERANTZ:  Yes, a couple of questions on some of the resistance data and the clinical virology.  First, maybe Dr. Bischofberger would be the person to talk about this, I am not sure.  But I am not sure how the definitions for phenotypic resistance were determined.  A variety of studies that I am somewhat familiar with that have been printed recently have had trouble determining what is phenotypic resistance.  And, at one point you talk about high‑level AZT resistance as being 8‑fold, increased over, I assume, over the non‑resistant control, as well as for the ADV in one study, a 4.5 versus a 1.5 was considered a significant increase.  Comments, and how you came up with this?
DR. BISCHOFBERGER:  Yes.  Could I have slide 978?
[Slide]
Shown here is our own data to justify the genotypic definition of low‑level and high‑level AZT resistance.  As you see, if you have single mutations, like 41, 67, 72, 219 or double combinations, 67/70, in general you see less than 8‑fold ‑‑
DR. POMERANTZ:  No, no, I understand that.  My question was why did you pick 8‑fold versus 10‑fold, as one group does, versus 3‑ or 4‑fold, which another group does to determine resistance?  Why 8‑fold?
DR. BISCHOFBERGER:  In the phenotypic analysis which I presented, the 8‑fold was actually picked by the company which carried out the analysis, which was Virologic.  They felt that 8‑fold was the cut‑off in their mind for low level or high level.
DR. POMERANTZ:  And, do you know, in their mind, how they determined that there was any clinical difference between 8‑fold or 7‑fold or 4‑fold or 10‑fold?
DR. BISCHOFBERGER:  I am not sure about that.  Maybe Brendon Larder can comment on that.
DR. HAMMER:  I don't know that Brendon wants to comment on the Virologic cut‑offs.  But let me just clarify, I don't think that is really Virologic's definition of high‑level resistance.  That is their definition of clear‑cut decrease in susceptibility from their control in vitro.  Between 2.5 and 8‑fold is a less clear‑cut range.  So, one can infer from that it is higher level resistance, but I think Virologic is stating that that is a more clear‑cut cut‑off in determining a change in susceptibility from the control.
DR. POMERANTZ:  Then, the second question is that one of your graphs shows that 1.45 versus 1.5 phenotypic difference in ADV resistance was considered significant.  Do you think that means anything if you are using 8‑fold for the AZT cut‑off?
DR. BISCHOFBERGER:  In which presentation was that?
DR. POMERANTZ:  I don't know the slide number but I have it here, in which high‑level AZT plus/minus 3TC ‑‑ you have a graph that shows ADV 4‑fold resistance versus high‑level AZT plus 3TC.
DR. BISCHOFBERGER:  Yes, I apologize.
[Slide]
So, these are Virco data, and what in general is observed if you do assays with XTD or NTT as the endpoint you get a bigger spread in the readout, whereas in assays that include light as the readout the thing is more compressed.
DR. POMERANTZ:  Right.
DR. BISCHOFBERGER:  So, this is statistically significantly different according to Virco.
DR. POMERANTZ:  Oh, so this was not Virologic?
DR. BISCHOFBERGER:  No, this is Virco data.  We have done statistical comparisons between these two and there is a statistically significant p‑value associated with the difference between these two.
DR. POMERANTZ:  Thank you.  That is helpful.  The other question I would have is that we have seen some data with less than 400 as a cut‑off.  Have you looked at any of these studies for less than 50 comparing the different trials with or without ADV?
DR. TOOLE:  We did that for both studies 411 and 417 retrospectively.  So, not all samples were available.
[Slide]
Shown here are the 3 different treatment groups for study 417.  They all have a comparable percentage of patients that were less than 50 using the ultrasensitive assay.
DR. POMERANTZ:  Right, and do you have it compared to one of your arms without ADV?  There was another study in which you compared it with AZT ‑‑
DR. TOOLE:  Study 411 ‑‑
DR. POMERANTZ:  Right.  Do you have that data?
DR. TOOLE:  Actually, no, we don't but the percentages were again similar for all treatment groups.
DR. POMERANTZ:  Similar at what level?
DR. TOOLE:  Around 60 percent.
DR. POMERANTZ:  Around 60 percent?  Wait a second, so you have 60 percent that are less than 50.  How many did you have in that trial that were less than 400?  They were almost all less than 50 then?
DR. TOOLE:  Oh, we do have it.
DR. POMERANTZ:  You do?
[Slide]
DR. TOOLE:  So, 60 percent is correct in some of the arms, but the control group is 73 percent.  The 3 adefovir‑containing groups range from 64‑71 percent, and the quadruple‑containing regimen is 64 percent.
DR. POMERANTZ:  And the less 400 put next to those is what?
[Slide]
DR. TOOLE:  So, using the intent‑to‑treat analysis, 59 percent and 50‑70 percent.
DR. HAMMER:  Is this because the samples ‑‑ you said for the other study not everything was available.  Is there a selection issue in the samples you had available for culture sensitive testing?
DR. TOOLE:  No, just because it was done retrospectively not every sample which was less than 400 was available for reanalysis.
DR. POMERANTZ:  All right.  I will leave it at that for the time being.
DR. HAMMER:  Thank you.  Dr. Wong?
DR. WONG:  I think we have gotten a pretty good ‑‑ you know, as we have listened to the questions and the answers I have gotten a pretty good handle on toxicity and virology.  But I guess in my mind the critical issue is still whether 60 mg of adefovir per day is as effective as 120 mg.  As I read the briefing book and the results, and then I heard the presentation by Dr. Soon, I had my doubts about using the equivalence design in which adefovir was added simultaneously with two other highly active drugs.  I guess I would like to hear the company's response to the criticism or to the concern about whether one can tease out the effect of the lower dose of adefovir when it is given simultaneously with two other highly active drugs, and whether this equivalence design might just be demonstrating the equivalence of no effect versus no effect.
DR. JAFFE:  First, we start with the premise that there is clear demonstration of antiviral activity for the 120 mg dose.  That is, study 402, 403, 408 all have very similar viral load curves when you give the patient as monotherapy either to no background therapy or to failing background therapy ‑‑ they are extremely consistent.
So, now we ask the question how do these results compare to other populations that have been treated?  Can we take a look at the results of 417 and understand or have confidence that this is what we would expect to see with three drugs used in a similar patient population?
Fortunately, because of groups like the ACTG and various other groups, there were contemporaneous studies being performed while we were doing 417 that had very similar study designs and treatment populations and, in particular, in protease inhibitor‑naive patients.
[Slide]
This is from ACTG 364, and what we are going to do here is focus in on a particular subgroup.  Many of you will be aware that this was a randomized comparison of the safety and efficacy of nelfinavir and/or efavirenz with 1 or 2 new NRTIs in NRTI treatment experienced patients.  So, it ended up being a 3‑arm study: nelfinavir, efavirenz and 2 nukes, efavirenz and 2 nukes and nelfinavir and 2 nukes.  Varied within this study is a subgroup that allows us to make cross‑study comparisons to 417, with the caveats that these patients may not have had the same treatment experience as the patients on 417.  We do not know the background of 364 virology to be able to make comments.  However, these were NRTI‑experienced patients, PI and NNRTI therapy naive, and they had viral load greater than 500.
On study 417 patients had to have had a viral load greater than 5000.  So we are going to limit the comparison to patients on 364 in the nelfinavir and 2 nuke arm to those patients who had viral loads of greater than 5000.  So, here are all of the patients, 66.  The baseline is 10,000 copies.  However, for the patients with greater than 5000 copies, 39, over half, the baseline is about 30,000.
[Slide]
Now looking at slide 25, this is an analysis done by Gilead, and we are thankful that the ACTG was able to share this data with us.  Looking at the patients with nelfinavir and 2 NRTIs, baseline greater than 5000, and looking at their viral load curve over time, you can see that there is an immediate drop with an apparent increase, with about a 1 log difference from baseline at week 24.
[Slide]
Now we are looking at the comparable groups in terms of nelfinavir as the protease inhibitor backbone, adefovir and one other nuke from study 417.  The 60 group is in violet; the 120 group is in light blue.  You can see, at the end of 20 weeks that the difference is about 1.2 logs.
Now, we have to be careful because we don't know the exact treatment backgrounds of patients on 364, but we can see from this, the difference being 1 log in 364 and 1.2 log in this study, that we are at the very least in the same ball park.
[Slide]
There are other data that we can look at as well.  These are data that appear in the in amprenavir, recently approved protease inhibitor.  It appears in the package insert, and this is study PROAB 3006.  So, we are simply providing data from the package insert.  We do not have any further data to look at.  This was a randomized, open‑label study.  Patients were randomized to amprenavir plus two nucleoside RTIs versus indinavir plus two nucleoside RTIs and, similar to the patients in 364, similar to the patients in 417, these were NRTI‑experienced patients who were PI naive.  There were 254 patients in the amprenavir arm.
[Slide]
The median age at baseline was 37 years, 80 percent male.  The median CD4 count is 399, so somewhat greater than the median cell count in the 417 study and, notably, the median RNA is slightly less than 10,000 copies.  The median viral load in the 417 study was, once again, 30,000 copies.
[Slide]
Now looking at a comparison of efficacy across these two studies, and mindful of the clear differences in baseline viral load between the two different groups, 4.5 versus 3.93, the percent less than 400 at week 20 for the relevant comparator arms from 417, adefovir 60 mg plus PI, either nelfinavir or saquinavir plus a nucleoside compared to amprenavir plus two nucleosides is 41 percent versus 43 percent.
So, the point of this is that between these different studies we can gain some degree of confidence that the results are similar from study to study, with the important caveats of not knowing the specific drug treatment histories, with the potential in 364 that they may have been somewhat more drug experienced, but the potential in the amprenavir study that they may have been somewhat less drug experienced.
DR. WONG:  But I guess we still don't see with and without adefovir.  So, the possibility that all or almost all the effect in the triple combination therapy was due to the other two drugs is still present in my mind.  What is your response to that possibility?
[Slide]
DR. TOOLE:  Getting back to the activity of the 60 mg dose, I would refer back to study 420 which was a randomized comparison with a placebo control, consistent with what we observed in our other studies, 402 and 403, we again see statistically significant activity, with about a 0.3 log increase after 4 weeks.  The DAVG4 was also minus 0.3 logs.  Based on the non‑overlap of the 95 percent confidence intervals, this is significant, again, demonstrating that the 60 mg dose does have activity.
In our earlier studies we also showed that the treatment effect was similar in treatment naive or treatment experienced patients.
DR. HAMMER:  Dr. Verter?
DR. VERTER:  I guess I should preface this by letting everyone know that of all the members of the panel, I am the least competent in HIV research, however, I think I have a fairly good knowledge of clinical trial research so I am going to limit my remarks to that, and I apologize if some of the comments are obvious to the rest of the members of the panel, and I will limit it to two of the many questions I have.
My concern comes in the design of the studies and how we can interpret them and, as a couple of other members of the panel have mentioned, the issue of some of the missing data.  From my perspective, there are two key trials, 408 and 417, and the comments I have are related to those.  This may be, again, obvious to most people but it isn't to me, that the key is if 408, which was the 120 placebo trial, is accepted as a given that in that type of cohort the effect that was seen is an acceptable effect for approval, although I know they are not asking for approval, that is an important issue.  It is almost clear to me that we have accepted that, but not absolutely.
However, even if that is true, the patients in 417 and the design in 417 seems to me to be totally different, and I don't know what impact that should have on our deliberations.  If we accept 408, does that mean that even though the entry criteria and the cohort risk level of the 417 patients is not as relevant?  For example, if I am interpreting all the slides I have seen today plus what was in the package correctly, in 408 at 24 weeks the percent of less than 400 copies was about 8 percent in ADV and 4 percent in placebo, whereas in 417, the 120 response rate was 31‑45 percent depending on which type of analyses you did, and with 60 it was 41‑48 percent which, to me, suggests that there is something different between those two cohorts and that may or may not impact on the comparison of 60 and 120.  So, that is my first issue on the risk level differences, including prior exposure to drugs, both the type and the length, as well as the RNA and CD4 differences.
Can I ask one more and then I will save the rest for later?
DR. HAMMER:  Oh, sure.
DR. VERTER:  Then, as important to me is the evaluation of the outcome.  I have seen at least three and maybe even more types of outcome evaluations and, again, it is not clear to me how we compare those across studies, such as the percent less than 400 copies, the change in CD4 count, the change in log RNA, the time‑weighted or unweighted averages.
Underlying all that is my next comment, which I will make brief, and that is the issue of missing data.  I feel that the term intention‑to‑treat in this presentation is a lot different than what I am used to calling intention‑to‑treat.  Although you are correct in trying to evaluate all randomized patients in an intention‑to‑treat analysis, if the outcome is at 24 weeks you don't have the data on all the patients at 24 weeks.  I have been involved in other studies where this is also a problem.  Fungal infection studies traditionally, for some reason, can't get the evaluations at the evaluation point.  I think it is very critical in a study where we are using a surrogate endpoint to know what the outcomes were at the defined point in time, assuming those patients are alive and if they are not alive you can make an appropriate adjustment there, but if they are alive, even if they are not on drug.  I will save the rest for later.
DR. TOOLE:  First of all, with regard to the comparison in study 408 for the percentage of patients that were less than 400, it is important to keep in mind that this patient population came in with a mean baseline of 30,000.  What you are looking at there is adding adefovir on top of a background regimen.  So you wouldn't expect to get many patients that go below 400 copies/mL in that type of study.  Whereas, in study 417 they were started on an entirely new regimen.
DR. VERTER:  If I could just comment on that, that is one of my points on how to treat the two studies.  I recognize there was a difference and I am having a little trouble in using 408 to evaluate 417.
[Slide]
DR. TOOLE:  The intent‑to‑treat analysis in study 417 was such that any missing observations were considered failure and because, as I showed earlier, there were more patients discontinuing at the higher dose group, that led us to look at an analysis where we use the last observation carried forward.
When we did that, there were 6 patients at the higher dose group who were now considered as less than 400 copies/mL at week 20, and there was 1 additional patient at the 60 mg dose who was now considered as less than 400 copies/mL at week 20.
So, that was our way of handling the missing data in that population.  In doing that, the lower boundary of the 95 percent confidence interval is still minus 0.73 and within the minus 12 percent that we set for equivalence.
DR. VERTER:  Can I follow‑up on that?  I guess that does highlight one my possible concerns.  I did see that data and I appreciate your showing it again.
The problem I have ‑‑ and I would have to go back to the survival curves ‑‑ is if 20 percent, 30 percent of the patients have not completed the 24 weeks the analysis could infer equivalence or mask equivalence, or even mask harm, depending on what happened to those 20 or 30 percent.  I appreciate the way you have done the analysis, and I think traditional clinical trial analyses by various authors suggest that is a good way to do it.  But oftentimes I think there is a fewer percentage missing the principal outcome, and I still have some concerns about that.
DR. TOOLE:  And it is hard to give a percentage less than 400 for any particular drug in a combination regimen.  However, in nucleoside‑experienced patients adefovir had demonstrated activity in study 408.  So, we assume that it is making a contribution in regards to changes from baseline viral load.
DR. VERTER:  One quick one, could you just tell the committee, of all the ones that didn't make it, don't have the week 25 evaluation, how many had died by week 24 in each group?
DR. TOOLE:  There were no deaths in the study.
DR. HAMMER:  Thank you.  Dr. Kopp?
DR. KOPP:  Thank you.  As a nephrologist, I have a number of concerns about nephrotoxicity but I think the central one has to do with the issue of reversibility, and I also have concerns about missing data.
First, I would like to ask in study 408, we have been told that 32 patients, that is 8 percent, at the time of last follow‑up still had serum creatinines of 0.5 or greater.  Also, the median follow‑up in those patients I believe was 6 weeks, which was shorter than in the other groups.  Do we have any further data on those 32 patients?
DR. TOOLE:  I am sorry, could you repeat the question?
DR. KOPP:  In study 408, the 32 patients, representing 8 percent of the total, at the time of last follow‑up had a median time of 6 weeks of follow‑up and had a creatinine elevation of at least 0.5.  Do we have any further follow‑up than what was presented?
DR. TOOLE:  That was up to our safety update submission.  That was part of the NDA.  There is no additional follow‑up in any of those patients.
DR. KOPP:  Is there the opportunity to contact these patients again in some fashion?
DR. TOOLE:  No, we have made significant efforts in trying to get these patients back.  I think another thing that might be instructive is to look at slide 812.
[Slide]
We have presented two analyses.  One was looking at the Kaplan‑Meier analysis which would account for patients who were dropping out for being followed to resolution.  Then there were 19 percent of patients that at last follow‑up had not achieved resolution.  However, many of those patients were not followed, as you stated, beyond 6 weeks.
We did an analysis looking for those patients for whom we had greater than 48 weeks of follow‑up, in this case looking for patients who had creatinine increases greater than 0.5 mg/dL, and in 168 patients there were 10 patients that had greater than 40 weeks of follow‑up and remained unresolved, so approximately 6 percent of the patients that had the abnormality.  So, this would be somewhere in between the estimate of 19 percent which remained unresolved with significant follow‑up.
DR. KOPP:  I guess a follow‑up question on that having to do with study 417, I believe it was 30 percent of patients on the lower dose of adefovir, 60 mg, who also experienced a creatinine elevation of 0.5 or greater.  What about resolution in those patients?  I don't think data was presented there.
DR. TOOLE:  There were 18 patients in study 417 that developed a creatinine abnormality of 0.5 or greater.  At the time of last follow‑up 12 had resolved.
[Slide]
Shown here are the data for those 6 patients who at last follow‑up had not resolved.  So, the interval of follow‑up ranges from none to 42 weeks.  Their last values range from 1.1 to 1.4 mg/dL.  Looking at their baseline, most of the patients are about 0.5 mg/dL fm baseline, so right at the cut‑off for resolution.
DR. KOPP:  Thank you.
DR. HAMMER:  Dr. Kimmel?
DR. KIMMEL:  I am also a nephrologist, and I wanted to pick up on what Dr. Feinberg was questioning.  For me to evaluate change of creatinine of 0.5 mg/dL, I need to know what the baseline was and I was very interested in finally seeing some baseline creatinine data on the slide that was just shown.  In all the slides where you have the virologic data, you never have baseline creatinines.  So, I would like to know what was the baseline creatinine in study 408, 417 and in the expanded access group because that will help us evaluate how severe the magnitude of the disorder is.
DR. TOOLE:  The mean baseline creatinine in all of our studies has been 0.9 mg/dL.
DR. KIMMEL:  So, you are using about a 30 percent loss of renal function.
DR. TOOLE:  That is correct, however ‑‑ can I get slide 842?
[Slide]
Again, it is important to put that in context to look at the placebo arm of study 408 and look at their variability from baseline.  When doing at ‑‑ and, again, this is the population at baseline of 0.9 ‑‑ 41 percent of patients in the placebo arm will have a 0.2 increase in creatinine during the 24 weeks; 13 percent will have a 0.3 mg/dL increase; and 4.4 and 1.4.  That is why we chose the 0.5 as being a more definitive marker of the development of nephrotoxicity.
DR. KIMMEL:  Thank you.  The second question I had is that as a nephrologist I am concerned about acute renal failure because it increases the mortality risk.  I am concerned about hypophosphatemia because it increases the risk of death from sepsis.  So, I would like to know in study 408 and the expanded access group ‑‑ I realize there was a very small number of deaths, but have you looked at the mortality risk conveyed by either hypophosphatemia, using your definition, an increase in creatinine of 0.5 mg/dL or the combination?
[Slide]
DR. JAFFE:  In terms of hypophosphatemia, other than the two patients on 120 mg who had renal failure, one with IV radiocontrast and the other setting I mentioned earlier from 039 who actually did not have hypophosphatemia but hyperphosphatemia, there is no apparent increase in mortality associated with hypophosphatemia.
[Slide]
In terms of deaths on the clinical studies, this is from the controlled clinical trials and there have been 6 deaths on the Gilead‑sponsored clinical trials.  Three expired 6 months to 2 years post the discontinuation of study drug, all from malignancies, and 3 others died while on adefovir, 1 for suicide and 2 multi‑organ failures with numerous risk factors.  One of the patients that I mentioned earlier that had the IV radiocontrast induced toxicity.  So, there is no evidence per se in patients who do not have evidence of acute renal failure that there is increased potential for mortality.
DR. KIMMEL:  But if you do a Kaplan‑Meier on patients who had an increase in creatinine versus those who didn't ‑‑ I am not talking about needing dialysis ‑‑ or if you do a Cox regression on those patients, have you done that?
DR. JAFFE:  Well, there were only 6 patients ‑‑
DR. KIMMEL:  I understand ‑‑
DR. JAFFE:  ‑‑ in over 1000 patients, and I believe of these 6 only 2 had evidence of renal toxicity.  So, I think it would be very difficult to show that there was, in fact, an impact of creatinine elevation.
DR. KIMMEL:  I realize there was a small number of events.  The last question I wanted to ask is I thought the data on the distribution of low bicarbonate levels and low phosphate levels was a little bit confusing because I couldn't really tease out how many of those patients were on phosphate supplements and how many were on bicarbonate supplements.  It is very different to have a phosphorus of 2 if you are taking 60 nutrophos a day or a bicarbonate of 16 if you are taking 16 tablets a day.  So, can you comment on the burden of therapy in those patients, the proportion of patients who were receiving supplementation?
DR. JAFFE:  In the 408 study, since toxicity was unexpected, we were not planning prospectively to have phosphate administration so there is a very small number, I believe about a dozen patients who got phosphate supplements.  In terms of bicarbonate supplementations, it is even smaller than that.  I believe it is 6 patients or so.
DR. KIMMEL:  And, that includes the data that we have seen on resolution figures?
DR. JAFFE:  That is correct.
DR. KIMMEL:  Thank you very much.
DR. HAMMER:  Mr. Schouten?
MR. SCHOUTEN:  I have one quick question for the FDA and then a little more detailed question for Gilead.  In Dr. Jolson's review that was prepared, on the bottom of page 4 it said there was no difference in HIV RNA values at week 24 in Gilead trial 408, but Gilead has shown us data that is different than that for the 24‑week HIV RNA data.
The other question is, I still would like to come back to this question about almost comparing apples and oranges by comparing 408 and 417.  To get some sense of how comparable these patient population were, and they don't sound all that comparable, can you tell us how many people were PI naive in 408, and do you have any resistance data in 417, like we saw the virology subset in 408, to get a sense of how treatment experienced the 417 patients were who were PI naive coming into that trial to make some sense of comparing these two very different patient populations?
DR. HAMMER:  Dr. Jolson, did you want to respond or clarify that first point?
DR. JOLSON:  Yes, I wonder if you could just clarify your question, the first question that was addressed to us?
MR. SCHOUTEN:  In your review on 408, it was said there was no statistically significant difference with respect to proportion of patients with HIV RNAs less than 400 at 24 weeks, but we saw different data presented here this morning.
DR. JOLSON:  That is correct.  I think what you are referring to is that we did say there was a statistically significant difference for the DAVG at 24 weeks but there were no differences for the proportion less than 400.
DR. HAMMER:  Is that a point of controversy or consent?  The proportion below 400 copies at 24 weeks.
DR. JAFFE:  In study 408?  That is true according to the PCR technique.  According to the bDNA technique, which was used for screening patients into study and was actually the assay that was to be used prospectively, there was about 19 percent of patients at 24 weeks who were below the cut‑off of that Chiron assay and about 4 percent on placebo, and that was statistically significant I believe at 0.002.
DR. HAMMER:  Is that the version 2 assay?
DR. JAFFE:  Yes, it is.
DR. HAMMER:  Thank you.
[Slide]
DR. JAFFE:  So, there was a bunch of questions, but getting to the first one in terms of protease inhibitor therapy, this will show the distribution of patients at baseline on protease inhibitors, and one must be mindful that this study began in 1996, shortly after indinavir and ritonavir were approved.  So, there were changes in the background therapies for patients enrolling on this study, whether they were there at the beginning of the study or at the end.  So, there was more protease inhibitor use in patients who had enrolled late in the study.  About 40 percent, 39 percent and 38 percent of the patients were on protease inhibitors at the time of enrollment.
I think Dr. Toole mentioned this earlier, we looked at the presence or absence of PI within a regimen at baseline, and compared to placebo the differences were statistically significant.  If you were on a PI‑containing regimen and you had adefovir added to your regimen, the mean change at week 24 was 0.33 compared to essentially no change on placebo, and that had a p‑value of 0.016.  If you were not on a PI at baseline and added adefovir or placebo, the mean change at week 24 was minus 0.43 compared to essentially no change in placebo patients, and that had a highly statistically significant p‑value of about 0.001.
Your question then led into how does this compare with the 417 patients.  I think the first thing to do is refresh memory of the baseline genotypes from study 408.
[Slide]
This will show you in that particular study that 43 percent of patients had high‑level AZT and 3TC resistance at baseline.  An additional 15 percent had high‑level AZT resistance in the absence of the 184.  So, fully 58 percent had high‑level AZT resistance at baseline.  Only 8 percent of patients had no evidence of an RT mutation directed against AZT or 3TC.
[Slide]
The point of this slide is to show you what the background genotypes were in patients on 417.  I think one important point is to note that these are less treatment experienced patients so one would fully expect, since the level of high‑level AZT resistance at baseline is only 9 percent, that the group at large would certainly have ‑‑ we would have high expectations that they would respond to adefovir therapy, and consistent with the notion that they were less treatment experienced, 43 percent of the patients had no AZT or 3TC mutations.
MR. SCHOUTEN:  I guess that answered my question and points out that the 364 nelfinavir comparison arm isn't a very fair comparison because that is a very, very different patient population.
DR. HAMMER:  Dr. Verter?
DR. VERTER:  I would just like to follow‑up on your comment.  I think what you said is correct and it also highlights the confusion I was having on my comment earlier.  In the FDA analysis that was presented, you are, indeed, correct.  The percent less than 400 was not significant.  However, in the analysis presented by the company today, they used DAVG, which was somewhat of a different outcome, and that highlights exactly the point I was making earlier.  There are many different ways of cutting this data and we need to understand which ones, how well they correlated, and what the implications are for each of them.
DR. HAMMER:  Dr. Feinberg?
DR. FEINBERG:  I wanted to follow up, Jeff, on your comment and the slides we just saw about genotype at baseline because in the company's presentation of the 408 virology substudy it was puzzling to me that adefovir had no statistically significant different impact on mean change in viral load from placebo in patients that had no NRTI mutations at baseline, and in patients who had low‑level AZT resistance at baseline.  I am trying to make that story fit together.  If I look at the slide set ‑‑ I don't have the numbers.
[Slide]
Yes, that is the one.  You know, in light of what you just showed in terms of the question about baseline genotypes, it is disturbing to me that in the patients who are genotypically wild type there is no statistically significant impact of adefovir versus placebo.
DR. BISCHOFBERGER:  As you may recall, the largest group of people, 71, belong to this group, number 6, and really the other groups are so small in patient numbers that that doesn't make a statistically meaningful comparison possible.  You have to remember that these 11 patients ‑‑ about half of them are on adefovir and half of them are on placebo, and so you are really comparing 6 on one to 5 on the other, and that makes a statistically significant p‑value not possible.  That is the only reason.
DR. HAMMER:  Thank you.  I have a few questions also but in the interest of quality of life I am going to suggest that we break for lunch.  We will come back and have a few more minutes for questions.  We will return in one hour, at 2:10.  Thank you.
[Whereupon, at 1:10 p.m., the proceedings were recessed, to resume at 2:10 p.m.]

AFTERNOON PROCEEDINGS
DR. HAMMER:  Before we start the next session, Dr. Jolson has a point of clarification she would like to make.
DR. JOLSON:  Dr. Hammer, I just wanted to clarify some of the earlier discussion that we had about pediatric use and the pediatric formulation, just so that the committee can take this into account as they consider the data.
I mentioned this to Dr. Yogev at lunch so even if he is not sitting there, he has heard what the issue is.  The data that was presented was pharmacokinetic and safety data in pediatrics.  Then there was some discussion about whether or not there was enough data to support dosing in very young children.  At that time, I made a comment to point out that the pediatric formulation, which is being considered under a different NDA, is not the subject of today's discussion because, in fact, it was only recently submitted as a different formulation.
However, in the committee's deliberation today, remembering that we are considering a solid formulation of adefovir, they can consider what ages it is appropriate for including young children who are able to swallow a tablet formulation and, therefore, can take into account and consider the adequacy of both the safety and pharmacokinetic data to support use in children who can swallow a tablet formulation.  I didn't mean to imply that we were only considering use in adults.  I was speaking more to formulation, and I just wanted to clarify that so that the committee can take that into consideration.
DR. HAMMER:  Thank you.  Do any of the committee members have a question about that?  If not, we are going to take, hopefully, no more than 30 minutes for additional points of clarification and questions from the committee to the sponsor or the agency.
I didn't get a chance in the round to ask any questions and I am going to just make a few targeted points and ask for rather rapid responses from the sponsor, if possible, that hopefully will help us in our deliberations this afternoon.
The first question is about CD4 responses.  We saw the CD4 results for study 408 and I think one other study.  I think as part of a marker of response, it would be help for the committee to get perhaps a better overview picture of what CD4 responses are like with adefovir at the 60 mg dose, the dose we are being asked to consider today.  So, are there additional data beyond the 408 study that the sponsor would like to quickly present?
[Slide]
DR. TOOLE:  Shown here are the mean change from baseline with 95 percent confidence intervals from study 417 comparing the 2 dose levels from baseline out to week 20.  As shown here, they are very similar.  At week 20 there is an 86 cell increase at the 60 mg dose compared to a 76 cell increase at the 120 mg dose.
DR. HAMMER:  Thank you, but that again raises the issue of the background therapy versus teasing out what adefovir is doing.  So, are there any data that help us tease that out?  For example, it may be in the packet, but in the 420 1‑month monotherapy study?
DR. TOOLE:  In the 420 study we looked at DAVG.  For the active group it was plus 5 cells and for the placebo it was minus 40 cells but that did not reach significance.
DR. HAMMER:  Thank you.  One other quick question and, again, this relates to trying to tease out activity of adefovir when used in other combinations, would you like to comment on study 411 in the 4‑drug arm versus the 3‑drug control arm?  Specifically when adefovir is added to indinavir, ZDV and 3TC there seemed to be no difference compared to indinavir, ZDV and 3TC alone.  Is that impression correct, and would you please comment on that?
DR. TOOLE:  That is correct.
[Slide]
That is true.  Looking at the quad arm with the addition of adefovir to the control arm showed no additional benefit.
DR. HAMMER:  And how do you interpret that?
DR. TOOLE:  However, if one compares these two arms, you could also interpret that as saying that the addition of AZT to this arm also provided no significant additional benefit, or the addition of 3TC to this arm also provided no additional benefit.
DR. HAMMER:  Yes, Dr. Yogev?
DR. YOGEV:  Just in continuation to that, we just completed a study in the ACTG using a protease inhibitor with one NRTI versus two NRTIs and at week 24 we didn't find any difference while a difference that is showing up at 36 to 48 weeks.  So I think part of the way to look at this drug ‑‑ maybe the time is too short to see if this drug is adding to what is there.
DR. HAMMER:  Thank you.  A virologic question, one issue that comes up in selection of resistance is that adefovir may not be selecting for mutations identified in the in vitro studies, but there is a continued evolution of nucleoside mutations, both in adefovir and control arms.  Is there any evidence for increase or decrease, or is it similar as far as other nucleoside analog mutations?  I ask this question because of the increasing amount of data that certain nucleosides can engender resistance not to themselves but to typical mutational patterns to other nucleosides.
DR. BISCHOFBERGER:  We have seen in study 408 that the resistance mutations that come up in the adefovir‑treated arm are mostly 67 and 70 and those, either alone or together, do not impart any reduced sensitivity to adefovir.  That is why we call them AZT‑associated mutations.
DR. HAMMER:  And those are in arms that also do not contain AZT?
DR. BISCHOFBERGER:  Some of those arms do and some of the arms contain D4T.  So, there is a background of nucleosides and it is not readily apparent where those mutations come from.  The best example is probably in 417 in the double protease arm.  At the 60 mg dose we had one 167 mutation come up, and that has to be due to adefovir.  That is one of the few arms where we had adefovir as the only nucleoside.
DR. HAMMER:  Then I would like to ask the sponsor if you would like to comment on the FDA analysis of study 417, specifically regimen 3 and the saquinavir arm that seemed to under‑perform in the presence of adefovir at 120 mg being somewhat of an outlier in response, and whether there is an interpretation to that.  Is that a fluke or is that more likely to be something real, again raising the specter of a drug interaction?  We heard from the FDA presentation that at least by a statistical test the probability was that that was not a fluke, but what is the sponsor's response to that?  I think it is important to hear your views.
[Slide]
DR. JAFFE:  First, we will start by just looking once again at a slide you have already seen.  This is to better understand the plausibility of an interaction between the 120 mg dose and saquinavir.  I might also point out with regard to pharmacokinetics, if you look at exposure for patients receiving 60 mg and at patients receiving 120 mg, because of inter‑patient variability, there is actually overlap.
Now, looking specifically at the idea that there may be a dose‑specific interaction between 120 mg and saquinavir, we see no evidence to that effect.  When we look at the other saquinavir‑containing arm, nelfinavir plus saquinavir 60 mg, the intent‑to‑treat is 42 percent and 120 mg it is 44 percent.
Within protocol defined methods, we have tried to deduce or understand the homogeneity of response and whether or not this is a chance outcome, and I will ask Jim Esinhart from Pharma Research, the contract research organization involved with the performance of this study, to review those data.
DR. ESINHART:  Dr. Soon presented the results of the logistic model.  We defined, as part of the original planning of the analysis, Braeslow‑Day test and I am going to try to present this without a slide.
The resulting p‑value from the Braeslow‑Day test, which is analogous to the logistic regression, was 0.449.  So, it is basically equivalent to a flip of a coin.  We believe this p‑value is large enough to exclude a clinically meaningful interaction.
In addition, this test was repeated at week 12 and the resulting p‑value is 0.82, which supports the conclusions that these data are consistent with no interactions.
DR. HAMMER:  And lack of interaction you are defining here as?
DR. ESINHART:  The lack of interaction?
DR. HAMMER:  There are at least two potential interactions here, dose and response, saquinavir‑adefovir interaction.  Which interaction are you excluding by this analysis?
DR. ESINHART:  This was an overall test looking at overall interaction across the three groups, which is the protease‑containing groups as well as the other dose levels.
DR. HAMMER:  Dr. Verter?
DR. VERTER:  I would just be curious, in looking at the tables, at the potential for looking at one or more of the interactions, there are only 35 or so patients in each cell, and there are what appear to be some observable numeric differences, let's say because of the small numbers, and they don't go in the same directions across the groups.  So, I am wondering if you did either any simulations or any other studies to detect ‑‑ you know, what ability did you have to detect an interaction, at what level?
DR. ESINHART:  We did not do any further analyses.
DR. HAMMER:  Thank you.  I have one last question, and it relates to the ongoing studies for traditional approval because part of our charge today is to think about those studies in relation to our decision‑making and the advice that we are asked to give.  So, I would ask about the status of the two studies for durability that are planned, the target and where the enrollment stands, and when it started.  I would also ask, as a corollary question, in the intensification study using adefovir, which has a high incidence even at 60 mg of nephrotoxicity at the 6‑month or more mark, about the probability that patients will stay on that regimen through the 48‑week time point.  So, I think it is really where those studies stand for enrollment; when the target enrollment will be finished; and the issue of feasibility of actually getting the answer that you desire.
DR. JAFFE:  With regard to study 415, that is a study that began, and was actually finalized with FDA input, in May of this year.  We began enrollment at the end of May.  The target sample size is 390 patients, which will be enrolled at approximately 60 study sites around the world, with about half of the study site ex‑U.S.  We have currently enrolled approximately 100 patients on that study.
Study 458 ‑‑ we have only recently finalized that protocol with some input with FDA, and that protocol, which is being performed at a similar number of sites, about 50 with two‑thirds of those sites ex‑U.S., has just begun enrolling and randomized its first patient last week.
Now getting back to your question about the feasibility of looking at 60 mg long‑term in study 415, when we have conducted placebo‑controlled trials where patients do not have knowledge as to whether they are on active or placebo as opposed to dose‑blinded studies, we have not had difficulty in keeping patients on drug for a long period of time.  In particular, I would once again point to 039 where 38 percent of patients came off after about a year on active versus 32 percent on placebo.
DR. HAMMER:  Thank you.  I will now open this up for any last questions from the committee members on a random basis.  Dr. Bertino?
DR. BERTINO:  Yes, a kinetics question and a patient management question.  It was disappointing not to see any data on sex or ethnic differences.  I think it said not enough to draw conclusions.  Given that one of the nephrotoxicity risk factors that appeared to be protective was non‑Caucasian, are you planning on doing any male/female studies and looking at ethnic differences pharmacokinetically?
DR. CUNDY:  Yes.
[Slide]
We have actually looked at the effect of gender in our larger studies in the healthy, normal volunteers, and this was in 81 patients, 46 females and 35 males.  All of these subjects were studied with a single dose of adefovir dipivoxil at 60 mg, and we used the FDA‑recommended comparison, the 1‑sided T‑test, and under these conditions the PK of adefovir dipivoxil was equivalent in males and females.
I could actually address the second question, which I believe was effect on race.  If I could have slide 1114?
[Slide]
Most of our data from HIV‑infected patients, more than 70 patients ‑‑ approximately 75 percent of that data was generated in African Americans.  From our healthy volunteer data we have approximately 72 Caucasians, 3 native Americans, 3 Asians, 1 African American and 2 Hispanics and across this entire database there doesn't appear to be any effect of race on the pharmacokinetics of adefovir dipivoxil.
DR. BERTINO:  Thanks.  Can I ask a question on a patient management issue?
DR. HAMMER:  Sure.
DR. BERTINO:  Looking at the flow‑diagram in the briefing book, the question I have is what happens if a patient doesn't show up for his laboratory monitoring on a monthly basis?  Are they not dispensed the drug?
DR. JAFFE:  The language within the package insert, and it will certainly be emphasized within all of the educational materials associated with this product, is that you need to have monthly monitoring.  In fact, we are going to take the step of having preprinted prescription pads that limit refills to only be provided if you have monthly laboratory monitoring.
DR. BERTINO:  So, the answer is you don't get a refill if you don't have your monthly monitoring?
DR. JAFFE:  That is the intention, yes.
DR. BERTINO:  Okay.  I see kind of a rock and a hard place issue here.
DR. HAMMER:  Although I think it should be stated that if a physician doesn't use that prescription that is pre‑prepared anything can be written.  Dr. Feinberg?
DR. FEINBERG:  I have a couple of questions here.  One is a follow‑up of what Joe Bertino just asked, but I want to ask it not from a pharmacokinetic standpoint but from concerns about long‑term toxicity.  I actually thought it was striking that non‑Caucasian race was protective.  At best, less than 20 percent of all the people in the studies, including expanded access, appear to be African American in terms of race and ethnicity.  Intuitively, since there is a greater risk of HIV nephropathy and possibly a higher incidence of just hypertension and other things that aren't good for your kidneys in that population, one of the crucial things that needs to be done for this drug is to have long‑term clinical follow‑up of people.  I am curious as to why everybody was lumped together as non‑Caucasian for that analysis.  I would have certainly thought that looking at the African American patients separately would have been important, and it may be like some of the other questions I raised before, that the N here is too small to generate an answer.  But when we met last summer, you know, a lot of our stated concerns were that we have adequate duration of follow‑up of the nephrotoxicity both in general and then in specific populations.
DR. JAFFE:  With regard to the multivariate analysis, non‑Caucasians incorporated both Hispanics and African Americans.  However, if you look at African Americans by themselves there is, according to the Cox regression model, a statistically significant reduction in risk.
If we look at study 408 and focus in on African Americans, the incidence of renal toxicity, as defined by the creatinine elevation, was 23 percent compared to 41 percent in Caucasians.
DR. HAMMER:  Dr. Hamilton?
DR. HAMILTON:  Looking at that from the other side of the coin, is there any reason to think that this drug has any special benefits for those with HIV nephropathy?
DR. JAFFE:  Well, it very well may based on accumulated knowledge on HIV nephropathy and active replication in sensitive cells.  However, we do not have specific knowledge of how the drug may perform in that patient population, although we do have plans at some New York City sites to actually answer that question in a formal randomized study in the future.
DR. HAMMER:  Mr. Schouten?
MR. SCHOUTEN:  Yes, a quick comment on the no lab, no drug.  You know, for my antiretrovirals I save a significant amount of money if I mail order for 90‑day supplies.  So, one‑month limitations would cost me a significant amount of money in added co‑pays.
Two other things, in following up on the resistance question I asked earlier, because I think your proposed indication is targeting people who have failed reverse transcriptase inhibitors in the past and your data set in 408 was too small to address the wild type group but in 417 you have a much larger group of wild type.  Have you looked at a subset analysis of response in the two dose arms based on background resistance in your 417 database?
DR. JAFFE:  Yes, we have and consistent with the overall result of the study, there really is no difference between the two different dose groups with regard to background genotypic mutation at baseline.
DR. HAMMER:  Dr. Lipsky?
DR. LIPSKY:  I have a question for the agency.  In the presentation there was a slide on study issues in 417, and the very first item was "not intended as a registrational trial," and then a group of agency concerns.  Was that at the beginning when this study was proposed?  Can you put that in some sort of context?  Because when we left here a year ago, August, there was talk about an induction phase at 120, lowering the dose to 60.  It was unclear where we were going.  From the agency's perspective, what was the evolution of your concerns of 417 and what happened?
DR. STRUBLE:  I think that study 417 was submitted like a Phase II trial where they were assessing 60 mg versus 120 mg.  All along, the sponsor was evaluating the 120 mg for registration.  One the toxicity in 408 became a concern, then that study which was never intended to serve as a registrational trial gained much greater importance because there had been a dose reduction.  So, that is what we were faced with, with a trial that had already started to enroll.  The intention was never to be a registrational trial, and then subsequently the focus shifted for the 60 mg.
At the time of the closed session last year we had talked about other strategies ‑‑ you know, 120 mg for 16‑week induction followed by a dose reduction to 60 mg, and after further consideration it was decided that the 60 mg up front would be studied all along.
DR. LIPSKY:  And when were the concerns about powering the study, confounding issues of the multiple therapies ‑‑ I am a little confused.  This was ongoing or did this ‑‑ I mean, you raised these issues and nothing happened, or what?
DR. STRUBLE:  Well, we raised the issues that, now since the 60 mg was going to be the dose that they were choosing to market, we had issues with the 417 trial: the complex treatment regimens, the 20‑week time point.  We had given advice about how to increase the sample size and maybe pick other comparisons, and this is what we were left with at the end of the day.
DR. LIPSKY:  I see, and was there ever consideration of having a placebo group?
DR. STRUBLE:  No, not at the time.
DR. HAMMER:  Dr. Yogev?
DR. YOGEV:  Can the company explain to me, in study 408 versus 417, the percentage of patients in the 120 mg group who had onset of serum creatinine increase at week 28 is 20 percent versus 40 percent, and for the phosphatase it is almost zero versus close to 40 percent.  Why is there a discrepancy?
DR. JAFFE:  Sorry, your specific question is looking at the Kaplan‑Meier plots?
DR. YOGEV:  Correct.
DR. JAFFE:  So, why there is a small increase in patients who had creatinine elevations in 417 earlier on than in study 408?
DR. YOGEV:  If you take week 28, does that suggest the populations are so different?  In one study you have 40 percent and in the other one you have almost zero for the phosphatase toxicity.  Is that part of a different population and we need to pay attention when we predict when toxicity can come out?
DR. JAFFE:  We do not have an explanation for that.
DR. KOPP:  I noticed that in your proposed treatment guidelines or toxicity management guidelines that if patients have a creatinine elevation of 0.3 to 0.4 they be dose reduced from 60 to 30.  I know earlier you said you had 42 patients in 411 and 417 treated with that dose of 30.  Can you comment about what happens to toxicity?  My concern here is that if we know we have a patient with significant renal toxicity, what happens from continuing to give a nephrotoxin, albeit at a lower dose?
DR. JAFFE:  The best data that deal with the issue of continuing drug exposure in the setting of toxicity actually come from study 408 where we have longer‑term follow‑up.  In the patients who developed creatinine elevations, 70 percent had their resolution when they came off study drug.  However, about 30 percent of the patients actually went down to 60 mg and had resolution of their creatinine toxicity, and a full about 5 percent of patients actually stayed on full dose, 120 mg, and had resolution.  So, in terms of going from 60 to 30, we would expect that something similar would occur.  However, we are being very, very cautious in terms of the management guidelines and we are recommending that patients came off the drug if they have a further increase.  The patients that Dr. Toole showed with the mean change, were patients were continued on 30 mg for about 4 or 5 months and we expect to have more data in the not too distant future without continuous increase in creatinine.
DR. KIMMEL:  I have another question about the dosing guidelines, which refers to stopping treatment and then restarting treatment over what seems to me a variable period of time, depending on the resolution.  Are you concerned about resistance in those patients?
DR. JAFFE:  We have not seen anything to suggest that we would develop resistance.  In those patients that we have dosed at very low doses for short periods of time we have not seen anything to suggest that resistance will develop.  However, as part of the Phase IV program we certainly will be following patients closely to see if that, in fact, occurs.
DR. HAMMER:  Dr. Mathews and then Dr. Feinberg and then Dr. El‑Sadr.
DR. MATHEWS:  In a number of your trials you monitored serum carnitine levels, and the proposed supplementation ‑‑ I didn't see anything calling for monitoring of carnitine levels.  In your background you said using 500 mg of carnitine maintained the level in the normal range in the vast majority of patients but not all, and I know some patients have been supplemented with more than 500.  So, what is the actual data on carnitine depletion and the adequacy of the 500 mg dose?
[Slide]
DR. JAFFE:  What we have here are longitudinal data from study 417, the dose comparison study.  You are looking at mean free carnitine concentrations in the serum.  At the 120 mg dose with supplementation of 500 mg of carnitine, you can see that there is a decrease to a nadir of about 75 percent, 80 percent which, by week 48, is now about 80 percent.  For 60 mg, a similar pattern but by week 48 it is about 95 percent of baseline.  We rarely see patients who have gone below the lower limit of normal with patients on 60 or even 120, and when that does happen we believe it is because of an effect on the renal tubular cells, not being able to reabsorb filtered carnitine.
In terms of what this means clinically, there are many examples of other drugs that are administered chronically, and perhaps the best studied one, although the mechanism may be somewhat different but, nonetheless, it leads to decreases in serum carnitine to about 40‑50 percent of baseline levels, is the anti‑epileptic drug valproic acid which is used chronically, and I believe it is the most widely prescribed anti‑seizure medication in kids, and supplementation with carnitine is not used in that patient population because there is no evidence that there are any symptoms or clinical sequelae related to carnitine deficiency.  That, in fact, is the case in our clinical studies as well.  We have not seen anything to suggest that decreased levels of carnitine have any clinical sequelae.
DR. MATHEWS:  This may be a different situation.  For example, zidovudine myopathy has been associated with carnitine depletion, and it is going to be used concomitantly with adefovir.  So, I am not so comfortable without monitoring in some way carnitine depletion.
DR. JAFFE:  Well, we understand your concern.  This drug has been dosed in combination with AZT in, I am sure, thousands of patients without any evidence that there is an increased incidence of myopathy or neuropathy.  Perhaps one of our consultants, Dr. Charles Stanely, could come up and comment on the significance of the types of levels of free serum carnitine that we are seeing.
Dr. Stanely, by way of introduction, is in the Department of Pediatric Endocrinology at the Children's Hospital of Philadelphia, and I think it is fair to say that Charlie has spent a good deal of his professional career looking at primary and secondary deficiency states for carnitine.
DR. STANLEY:  Maybe the simplest way to talk about the issue of carnitine depletion is the one clinical situation we know of where carnitine depletion causes clinical symptoms is in the genetic defect of the carnitine transporter.  Those children have muscle carnitine levels and serum carnitine levels that are reduced about one or two percent of normal, and treatment with carnitine that gets their muscle levels back to five percent of normal eliminates their clinical symptoms.  So, a small reduction in carnitine levels that have been seen with this drug are not very significant.
In terms of the myopathy with AZT, that seems to be a mitochondrial DNA depletion problem, and a secondary carnitine deficiency associated with blocks in mitochondrial metabolism is a quite frequent occurrence.  But carnitine deficiency in that situation is a consequence of a metabolic block rather than a cause.
DR. HAMMER:  Dr. Feinberg?
DR. FEINBERG:  I have I guess an editorial comment and then a question.  My editorial comment is that with regard to the resistance profile for this drug, I guess all I want to say is that it seems to me a bit sanguine to say that resistance development isn't very much anticipated.  The likelihood that it may require multiple mutations to create solid resistance to this drug is quite real.  The K70E only gives you 3‑ to 9‑fold reduced susceptibility.  I remember that it wasn't until the second year of AZT monotherapy that we saw the clinical impact of resistance development, and not very many people have taken this drug for an extended period of time.  So, I am not so sure we are there yet.
My question to the sponsor is there are three trials in experienced patients, one that has statistically significant favorable outcome and two that do not.  The two that do not were the federally funded trials, the ACTG and CPCRA studies.  In our briefing documents, apparently the FDA had only the executive summaries for those, and so I would like to understand why the agency didn't have access to those data sets, if someone could explain that, please?
DR. MURRAY:  I think that the 359 results were still quite preliminary at the time when the NDA was submitted.  I don't know if I have an answer for the CPCRA 039 study.  Gilead did do some of their own analyses and so, you know, I guess it was probably a little bit more than just an executive summary.  We did have a little bit less for 359.  You know, by the regulations though if there are studies that are out there that are relevant or, you know, could even cast doubt or speak to efficacy or safety, they need to at least be mentioned with the caveat that we are not able to, you know, review all data.  Sometimes, you know, these studies get finished at kind of inopportune times, and I think that that was at least part of the problem.
DR. HAMMER:  But there were some FDA analyses of 039 for looking at some of the baseline covariates for RNA and other things ‑‑
DR. MURRAY:  Exactly, yes.
DR. HAMMER:  ‑‑ and those were presented this morning.  So, you did have access to some data sets to allow you to make those analyses.
DR. MURRAY:  Right, right.
DR. HAMMER:  Dr. El‑Sadr, do you have a question?
DR. EL‑SADR:  Actually, I have a couple of questions.  I guess when you were doing 408, at that point we really didn't know about the nephrotoxicity yet and the patients were not getting the monthly monitoring.  In that study, in 408, about 40 percent of the patients, by week 48, developed the serum creatinine increase.  Now, in contradistinction, I think in 417, where you were doing the monthly monitoring for the serum creatinine, exactly the same percentage of patients developed the elevations in creatinine by week 48 also.
So, are you saying that if we monitor these patients carefully every month that we are going to somehow prevent this from happening?  Because it seems to me that it didn't make a difference in the percentage of people who actually had the exact same abnormality.
DR. JAFFE:  One, I think you decrease the incidence when you go from 120 mg to 60 mg.  So that is one important point.  But in terms of the management strategies and the following of patients with monthly laboratory monitoring, the important point there is that we limit the potential of increasing the renal toxicity so that patients would either dose reduce or come off drug.
I think an analysis that the FDA has done, one that we have both done and I think agree with the results, is that in study 408 70 percent of patients would have had an antecedent smaller increase in their creatinine that would have led to a dose reduction ahead of a potential doubling of their creatinine.  If we had known about the utility of the monthly monitoring, many patients would have had less of an increase in their creatinine.  And, we expect that the same would apply at least as much in the 60 mg dose.  That is why when you look at the graded toxicity in 417 you see that there are no patients who have gone above creatinine 2.0 mg/dL or grade 3 toxicity on the 60 mg arm.
DR. EL‑SADR:  You had no difference in the proportion of people.  Another question I have, and maybe I am confused about this, this morning one of the very early slides that Dr. Jolson showed was about the requirements for accelerated approval.  They indicated two studies with at least 24 weeks of data.  So, which studies are we considering?  One is 408 and the other one is for accelerated approval?  Because the other study, 417, only has 20‑week follow‑up, not 24.  Right?
DR. JAFFE:  I mean, we would have to ask the FDA to comment as well.  I think they showed a draft guidance for industry slide.  However, at the time the program began, and we made reference to this earlier in the day, at our end of Phase II meeting, in April of 1996, we discussed one study, study 408.  As correctly pointed out by Dr. Struble, at that time we didn't even discuss studies 411 or 417.  They were intended principally when they first began as studies that would help round out the safety database, and took on more importance as we became aware of the dose‑limiting nephrotoxicity at 120 mg.
DR. EL‑SADR:  Which are the two major studies for accelerate approval that are being proposed?
DR. JAFFE:  Well, I think we would have to say 408 and 417.
DR. HAMMER:  Dr. Pomerantz, and this will be the last question before we move on.
DR. POMERANTZ:  I agree.
[Laughter]
I forgot one from this morning though, sorry.  I was interested in the things to come in the future and the "intensification" study that was labeled 415 in which ADV is going to be added to some regimen.  Now, I would be interested to know, this is a single addition of ADV to intensify people who are failing therapy, who have gone to 400 but not 50, and do you really think a 0.3 as a single drug is going to be a good intensification step?
DR. JAFFE:  It is intended for patients with viral load at baseline of between 50 and 400 copies, and the idea is to add on 60 mg or placebo, and the primary endpoint is not driving patients below 50 copies but time to virologic failure.  So, the hypothesis is that patients would stay below 400 for a longer period of time with the added benefit of adefovir therapy.
DR. POMERANTZ:  So, you look at below 50 as a secondary endpoint?
DR. JAFFE:  Yes, that is correct.
DR. POMERANTZ:  Thanks.
DR. HAMMER:  Thank you.  Dr. Jolson?
DR. JOLSON:  Maybe I could just get back to Dr. El‑Sadr's comment about what are the two studies.  There certainly are more than two studies in this application.  Probably when we say two studies here, we would consider one of the two studies to initially support the safety and efficacy of 120 mg, and that would probably be the 408 study and the 411 study, even though 411 is in a population that they are not seeking an indication for.  Then 417 would be looked at as trying to make the bridge between 120 mg and 60 mg.  The exact length of the duration is probably more relevant to consider in terms of safety considerations for the drug than necessarily conforming exactly to what the guidance document says.  That is a general recommendation.  So, the duration should be really whatever duration you all have considered to be the minimum necessary to characterize the safety and activity of the 60 mg dose.  So, hopefully, that clarifies how we would look at the application.
The other studies that we talked about, the CPCRA study and the ACTG 359, would then be looked at additionally as studies that would have to be taken into account in the entire equation as you evaluate the package.
DR. EL‑SADR:  So, from you perspective, from the agency, you do not require two studies with 60 mg since that is the dose we are being asked to approve.
DR. JOLSON:  No, if you will recall the slide that I showed this morning, what we would usually require is a bridging strategy and that would be whenever there is a significant change, in this case dose, or if there were a change in regimen or a substantial change in formulation such that the pharmacokinetics are different.  Usually, once the initial safety and efficacy is established, we then require usually a single study to make that bridge such that you can basically say that there is a connection between what is known about the initial product and what is the known about the proposed product, the to be marketed product.  In most cases, it is usually a single study.  That is why that 417 study becomes really critical in your discussion in terms of whether or not that study makes an adequate link.
DR. HAMMER:  Thank you.  We need to move on now to the open public hearing.  There is a substantial number of people who have signed up in advance.  There are a couple of preliminary comments.  One, if you have not signed up in advance but wish to make a comment you will be permitted to at the end of the list of individuals who have signed up.  Because of the numbers who have signed up, I would ask people to please try to limit your comments to three minutes in fairness to everyone else and so that we can move through the afternoon.  Also, when you come to the microphone please identify yourself and the organization you represent.  Please also disclose any financial interest in the product at hand today, and also any travel support to this meeting.  If you have specifically no financial interest to report, please so state for the record.
The first individual who has signed up on our list is Dr. Sandra Burchett, from Harvard Medical School and Children's Hospital.
Open Public Hearing
DR. BURCHETT:  Hi. I did have travel support to come today.  I am at Children's Hospital in Boston, and there I am clinical director of a program that follows about 130 HIV‑infected children.  We have had opportunity, because most of the children who are infected have perinatal infection and are, therefore, infected for a long period of time and are long‑time treated patients, to look at children with advanced disease who have undergone multiple levels of therapy.
We have had 10 subjects enrolled to the expanded access protocol with adefovir, and of those, 7 children have received adefovir longer than 4 months in my clinic.  They range in age between 9 and 15, and the duration of therapy is between 16 weeks and 40 weeks.  Of those subjects, if they started out with greater than 200 CD4 cells, they had a substantial increase in their CD4 count.  One example is rising from 800 to 1200, with a fall in viral load from 500,000 copies/mL by the Amplicor assay to less than 40 within 1 month.  That child maintains his non‑detectable viral load and is doing well on therapy.
There are two children in that group.  There are five children in the other group that began with fewer than 200 CD4 cells, and in that regard all children had an increase in their CD4 count.  Another example would be something like 75 to 300, with a fall in their viral load.  Examples include 750,000 down to 200,000, or down to 5000.
These children also received at the same time additional agents that are included, as many as 8 drugs or at least 4 drugs were also given, and all children received at least 2 new agents in their combination.
The subjects in this group then have done well on adefovir combination therapy, except for one child who did develop Fanconi renal syndrome at about 20 weeks on therapy.  The children and the nurses in our clinic like this agent because it is once a day, because it is also available in liquid formulation that is also palatable.  If you have tasted it, it doesn't taste so terrible.  And, the kids are in school so that this is helpful for them, to be able to take something that is once a day and they can take at bedtime.  Thank you.
DR. HAMMER:  Thank you.  The next speaker is Dr. James Jones.
DR. JONES:  Good afternoon.  My name is Dr. James Jones and I did have travel support to get here this afternoon.  I am in private practice, mostly HIV medicine.  The majority of my practice has been HIV for the past ten years.  I am Board certified in internal medicine.  I am associated attending in medicine at St. Luke's Roosevelt Hospital Center, in New York, assistant clinical professor of medicine at Columbia University College of Physicians and Surgeons.
To date, I have had 24 patients enrolled in the adefovir expanded access program.  The majority of these patients were going on their third regimen and, besides being protease inhibitor experienced, were heavily nucleoside reverse transcriptase inhibitor experienced.  Out of these 24 patients, 16 remain on drug at this date, with a range of 4‑18 months on adefovir.  Four patients have discontinued adefovir secondary to nephrotoxicity.  The earliest incidence of nephrotoxicity occurred at 8 months.  All of these 4 patients resolved their renal insufficiency with discontinuation of drug.  One out of 24 patients discontinued secondary to non‑compliance with his antiretroviral regimen, and 3 patients out of 24 expired secondary to complications of HIV, 2 cases of PML and 1 case of fulminant hepatic failure due to hepatitis B.
In these patients there were very few early adverse events, mostly mild and nausea which resolved without a change in therapy.  While in the setting of a salvage regimen where numerous agents were changed in an attempt to improve the outcome it is impossible to judge the efficacy of one agent, I can say that in the 4 patients who stopped their adefovir due to nephrotoxicity, adefovir was the only agent that was stopped and there was a rebound in viral load in those patients.
My feeling is, with my experience with adefovir, that this agent offers a significant option for salvage therapy with convenient dosing and very few early side effects, and I feel that the nephrotoxicity observed with this agent can be easily managed with proper and timely monitoring.  Thank you.
DR. HAMMER:  Thank you very much.  The next speaker ‑‑ my apologies in advance if I mispronounce the name ‑‑ is Dr. Paul Cimoch.
DR. CIMOCH:  Mr. Chairman, advisory members, as a matter of background, I did receive travel support to come to this meeting.  I am Medical Director of the Center for Special Immunology where I do primary care and clinical research exclusively for patients with immune disorders.  After University of Miami in the early '80s, I have managed and evaluated well over 1500 patients with this disease.  I am also a clinical assistant professor of medicine at USC, and Board certified in internal medicine.
Like many HIV specialists, over the past two decades I have witnessed patients struggling from one small HIV scientific advance to another.  In recent years though, through the use of HART cocktails, we have seen patients literally go from bed‑bound to back to work.  Yet, despite these advances too many patients continue to fail our currently antiretroviral treatments and many patients are exhausting the regimens.
In this context, I was delighted to be part of the adefovir expanded access program.  Please note that all of my patients enrolled in this program are highly treatment experienced, on the average treated with at least five prior antiretroviral agents and usually on their third or fourth antiretroviral regimen.  Sixty‑two patients were enrolled although 6 never received any doses of adefovir.  Therefore, out of the 56 patients receiving adefovir, 11 of these 56, or 20 percent, were permanently discontinued, 5 for deaths unrelated to this drug; 4 moved from the area; and 2 did have severe toxicities on the 120 mg dose.  Thirty‑six of the 56 patients, or 64 percent, have had either their Preveon held or their antiretrovirals on hold.  Eleven of the patients, 20 percent of this total, are on hold due to side effects and may not start the drug again.  Twenty‑two patients, or 39 percent of the total, have had nephrotoxicity by lab criteria and, hopefully, will await resolution and restart the drug in the near future.  Three patients have stopped the drug due to other complicating illnesses.  Nine patients currently remain on study, 10 percent of the 56 patients, and are still on therapy as a salvage regimen.
The salvage regimen, as a backbone, had abacavir, aprenavir, either D4T AZT, and all were on 3TC.  They range anywhere from 4 weeks to 68 weeks on therapy.  All of these 9 patients have had a greater than 1 log drop in viral load, and 2 out of the 9, or 22 percent of the patients, have viral loads of less than 50 copies by the bDNA assay.  One patient has been on treatment now for 68 weeks.  It is of note, however, that 5 of the 9 patients are now on therapy with the 30 mg a day dose, and appear to have sustained undetectable viral load.
With regards to the side effects and toxicities, you heard about them earlier.  They seem to be reasonably tolerated.  The nephrotoxicity was extensively discussed. It is easily identifiable through meticulous monitoring, and is usually amenable to electrolyte replacement and/or dose reduction of adefovir.  It is my hope that many of these patients will also be able to resume their adefovir once their laboratory parameters improve.
So, in summary, based upon the accelerated approval criteria presented this morning by Dr. Jolson, I encourage this committee to approve adefovir based upon the following:
Number one, it offers convenient once a day dosing in general, and is well tolerated with some mild side effects.
Number two, it has a different toxicity profile than the currently available antiretrovirals, with nephrotoxicity as the AE being easily identified, managed, and appears to be largely reversible.
Number three, for many patients who have already failed multiple antiretroviral regimens, it may provide them with a unique resistance profile to combine with other antiretroviral agents.  Even if these patients only get 6‑12 months of benefit from this drug, it may, in fact, bridge the gap for many patients until the next wave of antiretroviral drugs become available, presumably effective against multi‑drug resistant HIV.
Finally, something that has not been discussed today is that adefovir may provide additional antiretroviral benefits against other viruses commonly co‑infecting HIV, including hepatitis B and CMV.  Thank you.
DR. HAMMER:  Thank you very much.  The next speaker is Dr. Charles Farthing.
DR. FARTHING:  Good afternoon, Mr. Chairman.  My name is Charles Farthing.  I am a Board certified ID physician.  I am medical director of AIDS Healthcare Foundation in Los Angeles, and a clinical assistant professor of medicine at UCLA.  I have been an investigator on several adefovir studies, and on the HIV advisory board for Gilead.  I did receive travel support to come to DC today, but I didn't want to come to DC today.
[Laughter]
At AIDS Healthcare Foundation we care for some 4000 HIV patients, and I supervise some 16 primary care providers, and we have had about 130 patients on expanded access with adefovir.
At the beginning of today's proceedings we were told there were two reasons why a drug might receive accelerated approval.  One is it is more potent than other agents.  That clearly does not apply to adefovir.  The other was that it works when HIV is resistant to other medications, and this, in my mind, does constitute a reason for approval of this drug.  In my interpretation of the data, adefovir definitely does have a unique resistance profile.
As a clinician, I am concerned that there are many patients now highly resistant to nucleosides and PIs, and many of these patients may not survive the probable two years until other agents, such as DPC961, AG1574, tenofovir and AG17176, that will hopefully salvage them, become available.
Also, many of our currently failing patients are highly nucleoside and PI exposed but still NNRTI naive, and I feel we need to protect that NNRTI and using adefovir as part of a cocktail is one way that we may be able to do that, and these are the ways that I am currently using adefovir in the clinic.
In two years the need for adefovir in HIV treatment may not be great as we will by then probably have the new drugs I have mentioned.  Also, we will probably have tenofovir which seems likely to fulfill its promise of being a better than adefovir with the same favorable resistance profile, three times the potency and, hopefully, without the nephrotoxicity but this is at least two years away.
Therefore, the need for adefovir is now, not later, and I would ask the committee not to delay approval.  It would be sad if you delayed approval and then approved the drug in two years time perhaps when we may not need it.
Leaving it just on expanded access is not a very good option in my mind either as many cannot access expanded access programs, and even in sites where expanded access programs are running the physician may well choose not to use it just because of the extra work and hassle it involves for him to provide it for the patient.
Finally, I would like to add that we didn't find toxicity management particularly difficult with our 130 patients on expanded access.  We had no serious nephrotoxicity leading to dialysis, and I found it reasonably easy to instruct our 16 providers on how to monitor their patients, supplement their patients and discontinue when necessary.  Thank you.
DR. HAMMER:  Thank you very much.  Dr. Howard Grossman?
DR. GROSSMAN:  I am an internist from Manhattan and like Dr. Jones, I am on staff at St. Luke's Roosevelt Hospital and an assistant clinical professor of medicine at Columbia.  I am here also to speak in favor of approval for adefovir dipivoxil.  I did get transportation support.  I am an investigator on the ATHART trial, the GS415 trial that was described earlier, the intensification trial, and we have extensive experience with expanded access.
My clinic employs three doctors and a physician's assistant.  We follow a little over 700 patients at this time.  We are running about 22 clinical trials, mostly Phase III and IV pharmaceutical‑sponsored trials, and we also have our own trials that we have been pursuing.
We were involved from the beginning in the adefovir expanded access, since January, 1998, and we have had 64 patients registered; 56 started the drug; 20 are still on therapy today and a couple of them are actually here today and will speak to you.  For all the patients treated with adefovir, the mean time on drug was approximately 9 months, which is the same as what the company reported.  For the 20 patients who are still on drug at this time, their mean time on drug is 11 months.  The shortest time on drug was 2 months for a patient who had to discontinue in order to take another nephrotoxic drug, cidofovir for CMV disease, and 2 patients were on for 3 months.  One of whom was lost to follow‑up and one of whom chose to go off all drugs.
In the rest of the cohort, the major reason we did stop was nephrotoxicity, the protocol designated cut‑offs for those patients.  A number of these patients had creatinine increases greater than 0.5 mg/dL from baseline.  Most of the patients had some proximal renal tubular dysfunction and needed replacement of phosphates and bicarbonate, and handled that very well.  In every case where we stopped the drug the creatinine returned to baseline in anywhere from 2 weeks to 2 months.  We had nobody who had continued renal dysfunction.
For the most part, I have used adefovir in a multi‑drug salvage regimen, the so‑called megaHART.  There have been a number of cohorts that have been described extensively at meetings.  We reported on our cohort at the salvage therapy meeting in Toronto last May, and all of these patients were on adefovir.  There were 33 patients and they had a mean antiretroviral experience of 73 months, ranging from 36 to 120.  They had taken a mean of 9 drugs, ranging from 5 to 11 drugs.  All were failing their previous HART therapy.  They had mean plasma viral loads of about 21,000 copies/mL and a mean CD4 of 153, which was an elevated CD4 for most of those people from where they had started antiretroviral therapy.
Patients were started on regimens of 2‑3 NRTIs, 1 NNRTI, 2 PIs, hydroxyurea and adefovir.  They had been treated with almost every drug class at that point except nucleotide analogs.  There was 1 patient who developed pancytopenia within 2 weeks which we thought was due to hydroxyurea, and we didn't follow him after that.
Seventy percent of these patients achieved plasma viral loads less than 500 copies on 2 or more readings.  Just to speed up, almost 40 percent of patients had undetectable plasma viral loads for 7 months or more at the time that I reported this trial.  One patient was undetectable for 10 months at that time, and now has been undetectable for 18 months.  Most of the patients actually tolerated these regimens really well despite what you have heard from some people, and some of that may have to do with the fact that these are highly motivated patients who were self‑selected because they thought they could stick to a regimen like this and they were people who were desperate.
I think our results are better than some of the other cohorts because we have actually been following these people so closely.  But in every instance when we stopped adefovir we had some increase in viral load, and that is what convinced me that this drug does have some efficacy because across the board every single patient had some rebound, not to baseline but it was a significant change from where they had been at the nadir.
Most of these patients thought adefovir was actually the most tolerable drug that they were taking.  I think from the patient's perspective it is a very tolerable drug.  I think where the challenge is, is for physicians because of the need for close follow‑up but, like Charles, I think that we do not really have a lot of problem convincing people that they needed to take electrolyte replacement.  If they didn't want to take it, that they shouldn't be on the drug.  If it was too complicated to come in monthly, they didn't take the drug.  And, I think that is something that I have heard from other people.  It is fairly easy to talk to patients about.
There have been a number of people who have voiced concern about the ability of doctors in the community to administer this drug properly.  I think it is time we all realized that all the drugs we are giving are as toxic and as difficult as cancer chemotherapy ‑‑ and my brother, the oncologist, says "we like chemotherapy."  And, we have a lot of responsibility when we are giving these drugs to know what we are doing.  I think we can feel fairly protected by some of the things that the company has expressed that they are willing to do.  I think that that will make a big difference as far as the educational campaign.
Finally, I think that conditional approval is appropriate here.  I think that this drug has proven its efficacy in my patients.  I think that it is well tolerated by them.  It is certainly not a home run for treatment but we have more and more patients, as Charles mentioned, who have failed everything, who need the bridge to the next set of approvals.  We won't have access to a lot of new drugs until maybe the middle of 2000 or 2001.  I think if we can get 8‑10 months out of using effective regimens that have adefovir in them that that will help bridge that gap for a lot of patients.  Thank you.
DR. HAMMER:  Thank you very much.  The next speaker is Dr. David Hardy.
DR. HARDY:  My name is David Hardy.  I am from two places.  I practice medicine at the Pacific Oaks Medical Group in Los Angeles, a large private practice specialized in the care of HIV‑positive persons, and also has a clinical research component with it, and I also do research at UCLA School of Medicine.
I am here today to give my testimony in favor of the accelerated approval for adefovir dipivoxil for the treatment of HIV infection in nucleoside‑experienced patients.  My experience with adefovir stems from 1996 when I was a local PI for the GS408 study.  We enrolled 52 patients at our site, had one of the largest enrollments in the study, and continued to follow the patients throughout the majority of the study duration through 1998, when all patients went off.
It was surprising to me that 408 actually showed something important, primarily because of the fact the study was being carried out during a time when antiretroviral therapy was in great flux, between 1996 and 998.  Many of the patients were in reality failing their therapy when they came into the study and had very, very poorly suppressed viral loads and were put on the trial as a sort of last‑ditch effort.  The therapy for many patients was really suffering from a learning curve.  Many physicians were trying to learn how to use antiretroviral agents, and I was surprised there was any kind of cumulative effect at all seen in that trial because of its design flaw of adding one single agent to a failing regimen.  But, in fact, it did show something important which I think we can all learn from now.
I also participated in the GS4150 study, the intensification trial.  As an investigator with that study, trying to bring viral load down below 400 in those who were between 50 and 400, and also the private practice I work with has enrolled over 85 patients in the expanded access study among 13 physicians in our private practice group in West Hollywood, Los Angeles, and we still have over 43 of the 85 patients still on the drug, with a median follow‑up of around 6‑7 months.  We have seen no severe or irreversible toxicities among any of those patients.
I think it is important today to focus on the patient population for whom this drug is being considered and the currently available options for this patient population specifically.  I am not certain of this, but my recollection is that this is the first time this advisory panel has ever considered an investigational antiretroviral agent to be specifically used in treatment experienced patients, those who have proven nucleoside resistance, at least AZT and 3TC and this is, hopefully, the beginning of a new era in the continued evolution of antiretroviral therapy and we are considering patients who have few options as opposed to those who have lots of options with being naive to antiretroviral therapy.
For those of you around the table who treat HIV‑infected patients, I ask you to honestly think about the data upon which you make your decisions when constructing antiretroviral regimens for your patients who have genotypically or phenotypically proven AZT‑3TC or 3TC resistant virus.  How many agents do you know of that have proven efficacy with clinical data for this kind of genotypic analysis at baseline?
I believe the data we saw this morning starts to create some of these guidelines about how to treat patients with resistant virus.  We haven't actually had any kind of data before to use in terms of creating therapies for these patients.  The niche that adefovir dipivoxil is starting to fill is the previously avoided patient population, those who have resistant virus by genotypic proof or phenotypic proof due to prior drug failure.  It is reassuring to me today to see that both Gilead and the FDA demonstrated that the M184V mutation did, in fact, increase the sensitivity of AZT resistance virus with a significant decrease in viral load at 24 weeks.
Why and how adefovir causes this phenomenon with AZT resistant viruses is not entirely clear, but it does seem to work better here than it does in wild type virus.  I think this is precisely where the new drugs are needed in the future, treating patients with resistant virus not those for whom we already have lots of available agents, such as wild type viruses.
On thing that I think seems very clear is that this medication does seem to be used with an agent concomitantly that causes and maintains an M184V mutation to optimize the efficacy of adefovir like 3TC, abacavir and perhaps FTC in the future.
As far as toxicity goes, one of the very first cases of clear‑cut Fanconi syndrome occurred at our site in 1997 in a patient who fell in the cracks between week 24 and week 32.  This patient was, in fact, hospitalized because of his Fanconi syndrome, had a creatinine peaking over 5 mg/dL, a phosphate that plunged to 0.7, and was in the hospital for over 2 weeks but did, in fact, survive.
Based upon this, and the occurrence of this same kind of problem in subsequent patients, it was, in fact, I think important to note that physicians and the persons who help take care of their patients can, in fact, learn from incidences about toxicity to better follow their patients with appropriate follow‑up care.  I think an important point to say is that adefovir can be used safely in patient populations which need that kind of alternative therapy.  Thanks.
DR. HAMMER:  Thank you very much.  The next speaker is Dr. Philip Kaiser.
DR. MARGOLIS:  Well, I am not Philip Kaiser.  I am David Margolis.  I am an associate professor at Texas Southwestern. Like a previous speaker, I didn't really want to be here today either but, since I was the only one from our group that could attend and I thought there were some important points to be shared, I thought I would share that expanded access experience at the Parkland Hospital with you.
I won't go over points made by the previous speakers because many of the ones that I would make are similar.  But the Parkland HIV Clinic is a typical urban clinic and follows more than 3500 patients of a wide variety of backgrounds.  The success we have had with the adefovir expanded access program I think should be pointed out.
There have been 82 patients treated in the expanded access program, and 20 of them have left the program, 4 because of reasons unrelated to adefovir at the patient's request.  Interestingly, 7 left because they either had no response or disease progression or genotype testing became available that suggested other agents might be more useful for them.  Then, there were 9 adverse events, of which only 5 were renal related: 1 proteinuria, 1 hematuria, and 3 rises in creatinine, 1 in the setting of lymphoma.  There were no adverse events that were severe or irreversible.
That leaves 61 patients that remain on therapy and I don't have the detailed virological data but there are 62 patients that are at a very advanced stage of disease, on the average have used 8 antiretrovirals in the past, and those 62 patients have been on therapy for an average of 20 weeks, 8 of them for more than 36 weeks.
So, I think this just illustrates the point that in a very busy, demanding clinical situation, perhaps exactly the setting where you would think that management of this drug would be difficult and that provision of benefit using this drug would be difficult for patients, that is not necessarily the case.  Thank you.
[Dr. Margolis noted off record that he had received Gilead travel support]
DR. HAMMER:  Thank you.  Dr. Joseph McGowan?
DR. MCGOWAN:  Thank you.  I would like to thank the committee for giving me the opportunity to speak briefly about my clinical experience with adefovir.  I have also received travel support to be here today.
My name is Dr. Joseph McGowan.  I am an infectious diseases specialist at Bronx Lebanon Hospital Center in New York.  I am assistant professor of medicine at Albert Einstein College of Medicine as well.  I am the director of HIV ambulatory care for our hospital's AIDS program.  Many patients infected with HIV in the community that I serve are highly antiretroviral experienced, and issues of drug resistance and salvage therapy have been paramount since the introduction of highly active combination therapy.
My use of adefovir dipivoxil has been exclusively as an agent available in expanded access.  At my site, we have enrolled a total of 68 patients for expanded access for adefovir since January of 1998, and 67 individuals actually began treatment and 37 remain on treatment.  Before the initiation of an adefovir‑containing combination, the average number of prior regimens used had been 6.4, with an average of 4.4 prior nucleoside analog reverse transcriptase inhibitors and 3.3 prior protease inhibitors, and one‑third had prior NNRTI use as well. Salvage combinations contain a mean of 5.3 drugs and only 13 percent were able to add a new nucleoside analog and 40 percent a new PI.  However, due to inter‑class cross‑resistance full activity was not expected from these agents, and we do not have access to either genotypic or phenotypic resistance testing in planning new therapies.
The average time on adefovir overall has been a mean of 164 days, ranging from 15 up to 603.  For those who discontinued drug, it was 186 days, and for those continuing on drug 146 days.  I have tried to always combine adefovir with 3TC when feasible in order to sustain the M184V mutation which may enhance the activity of adefovir, as we have seen.  Most of the combinations used have included a non‑nucleoside since our patients are relatively less exposed to this class of drug, and generally consisted of triple class salvage therapy with the addition of adefovir.
Initial responses to combinations that have included adefovir and efavirenz were impressive, with 87 percent of patients having a decrease in viral load of at least a log and 43 percent achieving a viral load under 400 copies by 13 weeks.
The reasons for permanent discontinuation of adefovir were progression of HIV disease in 9 individuals, loss to follow‑up of 8, patient requested to discontinue combination therapy in 6, and concurrent use of foscarnet in 1.  We had 2 patients who permanently discontinued for adverse events, a combination of proteinuria, hypophosphatemia, increased blood pressure in 1 patient, and 1 who had blurred vision and dizziness.  I have seen proximal renal tubular dysfunction commonly and somewhat predictably, however, only one patient, as I mentioned, required permanent discontinuation as a result.  No patient has had permanent renal failure, and most have returned to a baseline renal function by 2‑4 months with either holding or dose reduction of adefovir.
I have been fairly aggressive in repleting phosphorus and potassium if needed.  If I see a downward trend in phosphorus in from the monthly labs I will begin repletion early, even when phosphorus levels are above 2.5.  I can't be sure, but I believe that this has prolonged usefulness of the drug.  I will hold combination therapy with adefovir in patients who are responding if the phosphorus drops below 2, aggressively replete phosphorus, push all hydration, monitor urinalysis and chemistries during the period off drug, and often prompt attention will lessen the time off drug, a correction of 2‑8 weeks in most cases, at which time combination therapy can be reinstituted with continued phosphorus supplementation, which I continue giving them even when they are back.  I have successfully been able to regain viral suppression in this way in some patients.  I have one patient in particular who initially had to discontinue drug after 6 months for proximal renal tubular dysfunction and increased creatinine and has had 10 months of viral suppression after restarting combination therapy including adefovir.
Overall, I feel having adefovir dipivoxil available will benefit patients living with HIV infection in need of options for salvage therapy.  As mentioned, it will not be an agent for initial therapy due to its adverse events profile, however, I do envisage that with proper monitoring by experienced practitioners long‑term therapy is possible with this agent in patients whose HIV drug options are severely limited.
DR. HAMMER:  Thank you very much.  Next speaker is Peter Hale.
MR. HALE:  Thank  you.  My name is Peter Hale.  I am from Los Angeles.  I am editor of a new treatment publication, being launched next year by AIDS Healthcare Foundation.  I am very pleased to be here today because I think this drug should be approved.
I realize that we have all seen a lot of data this afternoon.  Some of it would seem to go in different directions and some of it sometimes would seem to be conflicting, and certainly there was a lot of background clutter with different antiretroviral regimens as backdrop with drugs being added and changed and different doses involved but, certainly, I am not an expert but if I were I would find it very difficult to make sense of all the data I have seen today.
My own experience has been much more simple.  I took adefovir as part of the expanded access program, and I thought that I did really well on the drug, even better than expected.  I believe there are many other people in the same situation as myself who had a good experience on the drug.  I had not failed virologically any combination regimen but I had failed protease inhibitors.  Certainly my doctor felt that way.  After two months of starting a protease inhibitor my glucose went through the ceiling and I ended up in the hospital.  I became fully insulin dependent, and over a period of two years I had to increase that insulin from 30 units a day to over 120 units of insulin a day.
Earlier last year my lipids were out of control, and even with cholesterol lowering drugs my doctor started to worry about running into coronary heart problems.  Hypertension developed just at the beginning of last summer so suddenly I was on medicine to lower my blood pressure.
So, the plan was to get off indinavir specifically, and the plan was to go to a non‑PI‑containing regimen, with sustiva efavirenz anchoring that new regimen.  I am very highly AZT‑3TC experienced, so I was coming off AZT, 3TC and crixivan and was very surprised that that regimen was holding up.  I was undetectable.  Anyhow, we stopped the crixivan and we started first with adefovir, and we also planned to intensify with abacavir.  So we did that. We started with adefovir and abacavir.  Four weeks later, or six weeks later when we were worried about the hypersensitive reaction to abacavir ‑‑ we were looking for that ‑‑ we added sustiva.  I could not start sustiva.  We tried on three separate occasions two weeks apart to start sustiva, and the nightmares and CNS side effects were just simply ‑‑ they were extreme.  So, I was stuck with three nuke and one nucleotide combination without a PI and without a non‑nuke, and I stayed undetectable on that combination for six months.
We all know that adefovir is very easy for patients to take.  I didn't feel anything.  My lab values stayed over the normal ranges for the first five of those months.  I had no elevation in creatinine.  On the fifth month my phosphate dropped to 2.1 which, I understand, is not super low.  We had the nutraphos right there so we supplemented with that straightaway.  There was a trace of protein in my urea half way through the fifth month, if I remember.  I was being monitored monthly, not just blood draws but also with urine analysis.  There were no abnormalities, other than that trace of protein on the fifth month.
So, I have to believe that there is some antiretroviral efficacy if someone who is as experienced as I am on AZT and 3TC can stay undetectable for six months on AZT, 3TC, abacavir and adefovir, without a non‑nucleoside and without a protease.  We switched off that regimen, if only because the data on aprenavir, as it was coming through, suggested that for me, with my background on protease inhibitors, it was worth a try.  So, we made that switch.  The reason I came off the drug had nothing to do with nephrotoxicity.  We were very aware of kidney problems and at the first hint of any trouble we would have dropped the drug.
I forgot to mention that not only was I able to stay undetectable during that period, but my lipid levels returned to normal within six weeks of starting that combination and they have remained normal since.  I take no cholesterol lowering drugs.  I was able to stop my meds for high blood pressure within two months, and my blood pressure is normal also.
So, I think there is a niche.  Whether it is for people failing a combination regimen in the conventional sense of virologic failure and breakthrough of viral load, or somebody like me who wants to simply get off and get onto some other combination to avoid the toxicities, which are very real and not imagined, caused by other agents.
I hope very much that this committee will approve this drug on the basis proposed, conditional approval with good monthly monitoring of laboratory values.  Because the toxicity is such an obvious one ‑‑ it stands out like a sore thumb ‑‑ I believe it is very easily managed, and with the education that Gilead is proposing the physicians and other healthcare providers will be aware of it.  Thank you.
DR. HAMMER:  Thank you very much.  The next speaker is William Bahlman.
MR. BAHLMAN:  I always like to do something a little different.  I want to salute the doctors who took the time to come down here for this hearing today.  I think it is very important to have doctors, who are on the front‑line using the expanded access programs, here, at the FDA hearings.  It is very important.  I want to thank Peter Hale for his comments.  I agree with all the comments that have been made so far very, very strongly.  I have known Peter for some ten years and, thankfully, he is still around to be with us and advocate for this drug here, today.
I also received a sponsorship from Gilead to attend this meeting, against my lover's demand that I stay in New York to celebrate Halloween with him.  It has been four years that we have been together and we haven't had one Halloween together, which is his favorite holiday.  So, I am here under protest.
My name is Bill Bahlman.  I am a founding member of Act Up New York, and I have served on the committee advisory board of New York University Bellevue Hospital's AIDS program for several years, and I am an officer on that advisory board.  I am also a 14‑year survivor of AIDS.
Act Up New York, along with Project Inform and a couple of other organizations, helped craft the expanded access and accelerated approval programs that we have talked about so much here today.  So, I feel a very close part of all of these discussions here, as we have worked so hard to put those programs in place.
I am not a doctor.  Unlike some other community advocates, I do not play one at this podium nor anywhere else, for that matter, and I have continually fought for the right of doctors and people with AIDS to make their own choices about how to treat this disease.
I just got back from the European AIDS conference in Lisbon where, I am happy to say, according to the Euro‑SIDA study most all of people with AIDS are currently being treated with three or four antiretroviral drugs as part of a HART regimen.
On the disturbing side, one prominent British researcher argued that antiretroviral therapy should not begin until a patient's CD4's fall below 180.  Fortunately, this same researcher granted that when one starts therapy should be a matter of personal choice.
That is what I am arguing here for today ‑‑ patient choice and a doctor's right to use the drugs he or she feels are needed to maintain the health and life of their patients.  It appears as if this is a controversial accelerated approval hearing.  I hope I am preaching to the choir here that this drug should be granted accelerated approval.  I hope that is the case.  You know the data and I need not dwell on it, except to say that I believe there is clear activity of this drug against the virus, and that the modest but real impact of a new anti‑HIV drug can be difficult to show beyond all doubt, particularly in patients who have been heavily pretreated, but that doesn't deny the drug's effect.
The question before you today is do we still need drugs with a modest but real impact against the virus.  I firmly believe we do.  You have before you a community consensus statement and two position papers, one from Project Inform and another one from Ron Baker's HIV and hepatitis web newsletter.  He was formerly the editor of BETA, which was from the San Francisco AIDS foundation.  So, he is a very prominent writer in our community.
I agree with these statements and their support of accelerated approval.  In the debate among community advocates in the last couple of weeks, I heard one community advocate say, "I wouldn't give adefovir to my cat."  I wouldn't give any of my AIDS drugs to my cat.  I have heard it said, "I wouldn't want to ever take adefovir."  I don't want to take any of the four drugs that I am currently on but I do.  I want to stay alive, and I am 100 percent adherent to my regimen.  I haven't missed a single dose in the 23 months that I have been on HART regimens of two protease inhibitors and two nucleoside analogs.  My viral load has been below 50 by both bDNA and PCR every monthly time period for the last 20 months.  My CD4s are over 700 even though my baseline viral load was 143,000.
The entire HIV advocacy community pushed Gilead very hard to establish an expanded access program.  About nine thousand people have gained access to adefovir through this program.  This alone clearly shows a need for this particular drug.  When I say we pushed Gilead very hard, I want to say that establishing expanded access programs does not happen by accident.  It does not happen by regulation in terms of a company saying, "okay, we've reached Phase II, we're going into Phase III, now the program's going to begin for expanded access."  It never happened that way in the past.  It doesn't happen that way now.  It is not going to happen that way in the future.  It takes very, very hard work by a coalition of AIDS advocates to get the drug company to agree to do these programs and to get them up and running, and to see that they are maintained well.  It does not happen easily.  My concerns are if this drug doesn't get approved today, what kind of message does that send to the industry about running a program that reaches as many as nine thousand people with AIDS?
Expanded access offers a unique opportunity to educate doctors on how to use and monitor for toxic effects of a new drug.  Over 2000 physicians, representing over 70 percent of HIV prescriptions in this country, have participated in the expanded access program.  I argue that these same doctors, already educated in the use and monitoring of adefovir, will probably represent over 90 percent of prescriptions postmarketing.
As a side note, amprenavir, which was approved by the FDA about six months ago, has to this date been used by significantly less people with AIDS than adefovir has.  A recent study has shown worse adherence to amprenavir than indinavir.
My position is to strongly support accelerated approval.  It clearly shows activity.  Adefovir is a novel compound with a novel resistance profile.  People with AIDS who have been heavily pretreated have shown that there is a profound need for this drug.  This advisory panel has done a very good job over the last years.  You have supported the approval of abacavir and other drugs even with a minority of community opinion being opposed to approval.  Every drug you have recommended approval for has remained a vital life and health saving option for people with AIDS.  Not a single drug has had to go off the market; not a single drug has not shown that it is continually needed by people with AIDS to save alive.
The market, doctors and people with AIDS continue to make more intelligent decisions about treatment as well.  You have done the right thing in the past.  I urge you to continue with your legacy, you can justly be proud of.  Thank you very much.
DR. HAMMER:  Thank you very much.  The next speaker is Max Delgato.
MR. DELGATO:  Good afternoon, everyone.  My name is Max Delgato.  I live in Baltimore.  I work for the federal government as a translator.  I received support for transportation to get here.
I tested HIV positive in September 1989.  I did not receive any treatment until July of 1998.  At that time, my viral load was 120,000 to 127,000.  After four weeks of treatment my viral load went down to 858 and after 12 weeks I am undetectable.  I am still undetectable.  My CD4 count was 346 when I started, or 21.7, and at the present my CD4 count is 571.  Due to my treatment's compliance I experienced no side effects.  I gained weight, 10 lb, believe it or not, and I look forward to this medication on the market.  I will appreciate it.  Thank you.
DR. HAMMER:  Thank you very much.  The next speaker is Timothy Christy.
MR. CHRISTY:  Good afternoon, ladies and gentlemen.  I have been on the regimen for about 11 months now ‑‑ over a hear and a half, and when I first started ‑‑ well, before that, about 10 years ago I was on AZT and it never bothered me ‑‑ just a little bit.  Then I have been on some of the other drugs and some bothered me and some didn't, but the worse one was Viracept, and I had to get off that.  Then my physician told me about the clinical program that was being offered by Gilead Sciences and I told him, sure, I would be willing to go on that program, and that was a year and a half ago.  My viral load I think was about 24,000 and my CD count, whatever it is, the blood count, I think 192.  And, I have been undetectable.  Well, the first month after that my viral load went down to 400 and now it has been undetectable ever since, and my last checkup was 4 weeks ago, and my blood count was over 500, and before that it was 400‑and some odd.  My blood pressure has been normal for years, even before I found out that I was HIV positive, about ten years ago.
With the newer drugs, I have had no bad effects at all, only the first time when I took the sustiva, it made me very dizzy the following morning.  It was like being hit by Dan Marino and Steve Young and Jesse Ventura all at one time.  But after that it was fine.  So, I have no problems at all.  In fact, I have very, very little reactions and I keep to a very strict regimen with that, every 12 hours, and I make sure I take that at a certain time, between 8:30 and 9:00 in the morning and 8:30 and 9:00 in the evening, right after eating I take these.
I want to thank Dr. Howard Grossman for his help.   He has really been an angel of peace and a faithful guide to me since I have been with him.  I want to give heart‑felt thanks and my gratitude to the people at Gilead Sciences for coming up with this drug.  I feel that you should approve it.  I mean, I don't think many of us would be alive today if it weren't for these new drugs that have come about.  As I said, I have had no repercussions from these drugs at all.  I don't know any of these technical terms.  I am not a medical doctor, I am not acquainted with all these.  I just go every four to five weeks for my checkup.  I listen to what the doctor has.  You know, I am one of these people who go through the "white coat syndrome" when I go to my doctor and I follow whatever he says, and his advice and that is it.  So, I hope very much that you approve this drug and all these new drugs to help people who are HIV infected.  And, that is all I think I have to say.
On a lighter note, I just want to congratulate the people in Washington for the victory of the Washington Redskins, and my condolence to the supporters of the Oakland Raiders on their loss to a superior team.
[Laughter]
DR. HAMMER:  Thank you very much.  Our next speaker is Hosam Chreim.
MR. CHREIM:  My name is Hosam Chreim.  I am from New York City.  I received travel support today to get here.  I am 34 years old.  I contracted HIV 13 years ago.  Since then, I have been on almost every drug to fight this disease.  The virus was building resistance to the drugs that I was taking, and adefovir was a different type of drug.  My doctor put me on adefovir along with two other antiretrovirals and a protease inhibitor a year and a half ago.  Since then, on the new combination my T‑cells have been rising from below 200 to above 400, and my viral load, that once was over a million copies, now is between 2000‑4000 copies.
I have had very little side effects, but overall I feel very good.  Every time I feel that I am at the end of the rope, a new drug comes and prolongs my life.  To many of us who have been fighting this disease for a long time, this may be an additional treatment until a cure for AIDS is found.  Thank you.
DR. HAMMER:  Thank you very much.  Amy Sullivan?
MS. SULLIVAN:  Good afternoon.  I have received travel support to be here today, but no financial interest in the company, and out of respect for the panel I will try not to picture you in your underwear since I am a little bit nervous.
[Laughter]
DR. HAMMER:  That is a unique comment for this committee hearing but it does create humility on our side.  Thank you.
MS. SULLIVAN:  I am the director of clinical research for Pacific Reiser Medical Group in San Francisco.  We are a group of healthcare providers who treat over 800 HIV‑positive men and women in the Bay area.  We are also very active in clinical research for ART drugs to treat HIV, and currently participate in a dozen or so such trials.
We had the opportunity to be an investigative site for adefovir dipivoxil expanded access program.  I was the coordinator and primary patient contact at our site since the program's inception in early 1998.
I would like to share with you some insight I have gained about this drug and its impact on our patients.  We had a total of 27 patients on study.  Those of you in industry know that when a drug is put on expanded access it is the sickest people that enroll first, the patients who have burned through almost every other drug available.
I spend a lot of time with each patient when putting them on a new regimen.  It is vital to patient compliance and comfort to thoroughly explain both how to take the drug, including dosing and nutritional requirements, and also what to expect.  This became especially important with adefovir.  There has been no lack of discussion today of this drug's unique toxicity profile, but from a treater's standpoint, the effort to educate patients about adefovir treatment should really be no different than any other new antiretroviral therapy that the patient is prescribed.
We explain to patients up front the possibility that they may begin to experience lab toxicities around the fifth month of treatment, and that they will be monitored closely for these changes.  Because we are working with patients that don't have many more treatment options, this risk has never been a deference to them.
The adverse effects of adefovir are not a mystery.  They are predictable and easily monitored.  As we gained more experience with this drug, we became more comfortable with monitoring and managing toxicity.  In the course of the adefovir expanded access program, two things about this drug have impressed me and the patients that we treat.
First, the simplicity of dosing ‑‑ one pill once a day, no nutritional requirements.  Patients are generally incredulous when I review dosing with this drug.
Secondly, the absence of side effects.  The few patients we eventually took off study for toxicity reasons were virtually clinically asymptomatic.  The rest of the group had very few, if any, side effects attributable to adefovir.
These two aspects of the drug have a profound positive impact on quality of life for people living with HIV, which is one of the main goals of HIV therapy in my eyes.  Let me remind those of you that don't lay hands on patients on a daily basis that people are still dying from AIDS.  Let's not lose sight of the fact that we have the opportunity to make this drug available to many more people battling HIV.  If we can extend their lives and increase their quality of life by any degree, I feel we have a responsibility to do so and, therefore, support this NDA.  Thank you.
DR. HAMMER:  Thank you very much.  Juaquin Sanchez?  Is Juaquin Sanchez here?
PARTICIPANT:  Juaquin wasn't able to make it.  He is in Los Angeles.
DR. HAMMER:  Thank you. The next speaker is Francois Ouliez.
MR. OULIEZ:  Mr. Chairman, my name is Francois Ouliez.  I am one of the directors of the European AIDS Treatment Group, and co‑chair of the European community advisory board.  Today we don't call it Halloween in Europe but All Saints Day, where we celebrate the memory of all those who died in the past.  So, the question I am wondering about today is whether or not this product could have made a difference for the people who have recently died of AIDS, or those who are expecting new options to avoid death in the following months.
I received travel support from Gilead Sciences.  I was wondering about the lack of real CD4 response in the trials that we saw this morning.  Since, in a heavily treated population the CD4 response is a strong predictor of progression to AIDS, when we discussed this point with my colleagues last week in Lisbon, we were really wondering if this drug could be of any benefit to patients with AIDS.
Soon we will have to express our opinion to the European Medicinal Evaluation Agency on this new compound.  Allow me to summarize what this opinion could be if this review by the EMEA would take place in November, 1999.
First, one crucial question, what do people need today for their treatments?  More potent treatments; more potent regimens, with a longer duration of viral replication control, and treatments that respect the quality of life; treatments that are efficient in heavily pretreated patients; and treatments that have limited toxicity, or at least that don't add any toxicity to the available products.
The question is, has adefovir one of these added values compared to available options?  If yes, if only one out of five of these values is met, then approval should be considered.
First potency, potency in experienced patients.  There are some trends, some indications that adefovir could be very active in these trends harboring the M184V mutations.  This was assessed in a substudy, and so far a trial design to evaluate this benefit in terms of viral load has not been conducted properly.  This potent synergy between adefovir and the M184V mutation has not been properly evaluated.  As I say, the CD4 response has not been very impressive.  Nevertheless, the need for immune restoration is crucial in NRTI pretreated patients.
Second, duration ‑‑ one pill a day for modest activity.  Maybe this is the minus 0.3 log that could make the difference in order to maintain HIV RNA below 50 copies for a long time.  Has this been shown in clinical studies?  Not yet.  Long‑term studies like the other trial in Europe could not conclude, mainly because of the new context in HART.  But the sustained antiretroviral activity is balanced by the discontinuation rate, 40‑50 percent at week 48.
Quality of life ‑‑ one pill a day, whenever you want, with no food effect.  That seemed okay.  Many people can support that.  People are so afraid to stop all treatments even if all treatments failed, and one pill a day is still something most reluctant patients regarding treatment can stand.  But quality of life is also a matter of tolerance and safety.  What about monthly monitoring when you are on holidays?  What about monthly monitoring in summertime when all settings are closed in Europe, for instance?
Toxicity, grade 3 or 4 serous adverse events were, at minimum, 5 percent across all trials.  New products, new PIs, even maybe EPMPA may suffer from renal toxicity with adefovir.  We don't want to jeopardize the use of future PIs which will be limited through renal filtration.  After the blood, after the bone marrow, after the liver, after the pancreas, after the CNS, after the endocrine system, after the cardiovascular system, and now the kidneys.  We would prefer to keep our future options open.
Many questions were raised.  What about monthly monitoring?  What about long‑term toxicity?  What about mitochondrial toxicity related to adefovir?  Is the carnitine supplementation accurate?  Does it really correct the depletion?  What is the impact of this depletion?  We don't have a clear idea.
For these reasons, we would recommend approval for adefovir if the activity in 3TC or abacavir pretreated patients will have been demonstrated in a prospective manner with a true viral load benefit.  If 60 mg daily would definitely prevent the risk of high grade renal toxicity.  And, what about 30 mg?  What about 10 mg?  If a longer‑term toxicity profile could exclude any other toxicity.  Adefovir mitochondrial toxicity should be better evaluated.  If we could have the certitude that doctors would be properly informed about the guidelines to monitor the toxicity and respect them.
Because of the late submission of the application to the EMEA, we may revise our opinion when Phase III trial results will become available and when the EMEA will evaluate this product later next year.  But, as of today, November 1, 1999, we would not recommend approval.  Thank you.
DR. HAMMER:  Thank you.  The next speaker is Michael Marco.
MR. MARCO:  Hello, there.  I figure that I can take the podium since I am the only person here who has received no financial support.  I at least deserve this since I had to use my travel budget, which is very small, in Treatment Action Group.
Treatment Action Group has a position paper that we have out on the table, and I know that the committee members have seen it.  I promise the committee members that I will not read the whole thing for you because it is eight pages, but it has great references at the back.  What I will ask you to do is just look at the TAG position on page one, and then on page five there is an excellent discussion.
Now, basically after you read it, I would also like you to look at the summary slides that Dr. Struble had in her presentation.  The FDA's analysis was excellent and I feel that my tax dollars were hard at work, and I appreciate that.  I also want to let Dr. Struble know that TAG has a job opening ‑‑
[Laughter]
‑‑ if you would want to move to New York, we would have you.  It is much safer now and we are a fun group of guys.
In the TAG position, it is unfortunate but as current data has shown, especially for the dose of 60 mg, we cannot support the approval.  We do not believe it is effective nor safe for what it has been indicated.
There are just five major points to consider.  The five major points to consider are truly in the questions that Dr. Hammer will be asking you shortly.  Although 120 mg is not proposed for marketing, did the original adefovir development establish efficacy of 120 mg QD dose for the treatment of experienced patients?  I think the answer is no.  As we saw in the FDA's analysis, study 408 did not show a difference statistically from placebo.  It did not show a difference in the CPCRA study, nor in the ACTG study.  I am one that believes that federally funded studies usually yield fairer results than industry‑sponsored studies.
If you look at the subset analysis, that does look encouraging and we do want to see some further information about adefovir's activity in people with 3TC resistance.  But you must understand this was a subset analysis, and to quote the FDA slide, exploratory subset analyses are only useful for generating a hypothesis, not for approval.
The two 60 mg studies plus the expanded access group are riddled with dropouts.  The dropout rate, the discontinuation rate is huge.  If you note, in the 60 mg dose only 73 patients ‑‑ I repeat, 73 patients have had more than 48 weeks of drug.  That is not enough.  I cannot go back to my community and tell people that this is safe when we only know that 73 patients have had this drug for 48 weeks.
I also appreciated Dr. Wong's concern during the question period when he was trying to tease out the 60 mg versus 120 mg in study 417 that was looking at it in combination with other antiretrovirals.  As he said, was it no effect versus no effect?  These are issues that you will want to weigh.
I must say that I am very excited about adefovir for hepatitis B, and I am actually on the ACTG protocol team looking at this drug at lower doses, at 10 mg and at 30 mg.  I hope that I can be back here in, say, 18 months to ask you to approve the drug if it does show activity and safety for hepatitis B.  But today Treatment Action Group says that at this dose it is not effective nor safe for approval.  Thank you.
DR. HAMMER:  Thank you very much.  The next speaker is Jules Levin.  Jules yields.  That is the end of the list of signed up speakers in advance.  Is there anyone here who would like to make a statement as part of the open public hearing?  If so, please come forward.  If not, the open public hearing is closed.
What I would like to do is take a ten‑minute stretch break.  I would ask people not to leave the room unless it is mandatory.  We are going to restart in ten minutes on the dot.
[Brief recess]
Questions to the Committee and Discussion
DR. HAMMER:  I would like to call the committee back into session.  This is now the point at which we consider the questions to the advisory committee.
A couple of points in advance, I am going to, as we should, allow each member of the committee to comment on each question.  Because of the number of questions and the length of discussion that we have had antecedently, I would ask that comments be targeted.
The fourth question on the list is the voting question today.  The questions are designed for the audience and the committee to really reflect and parallel the developmental strategy of this agent which, as we have heard several times today, is a bit unique because it started at the 120 mg dose and then changed in midstream because of the nephrotoxicity.  So, the efficacy and toxicity at 120 mg and the bridging strategy to 60 mg is reflected in the nature of the questions and in their sequence.
I would also mention that Drs. El‑Sadr and Feinberg need to leave early.  So, I am going to ask them to comment on question number one first, and also to make comments, if they wish, on the other three questions.  But for the other committee members, I would say let's reserve discussion for each question in turn.
With that introduction, I will read the first question for the record.  Although the 120 mg dose is not proposed for marketing, did the original adefovir development establish efficacy of the 120 mg QD dose for treatment experienced patients?
If yes, then with respect to efficacy, has the applicant demonstrated sufficient comparability between the proposed marketing dose of adefovir 60 mg and the 120 mg dose such that one can conclude that the 60 mg dose is superior to placebo?
If no, what additional data are necessary to characterize the efficacy of the 60 mg dose of adefovir?
I will not read the other three questions at this time but, again, if Drs. Feinberg and El‑Sadr wish to comment on them before they have to leave, they are invited to do so.  So, let me turn to Dr. Feinberg.
DR. FEINBERG:  All right, well, I will bite this bullet right away.  I think the answer to question number one is no.  I think that Gilead's 408 study, although it had a statistically significant difference, that difference strikes me as being, at best, sort of marginally clinically significant.  Two federally funded studies were negative.  Study 417 I think is beset by design problems that were well elucidated by the FDA folks, not to mention that close to a third of the data for the 120 mg dose in 417 were missing.  So, that is my response to question number one.
So, I am obligated then to speak to question 1B about what additional data are needed to characterize the efficacy of 60 mg.  I would start by saying that not only does the 60 mg but probably the 30 mg dose needs to be studied carefully in order to generate these data.  Since there is already a recommendation in the proposed label that people would be dose reduced to 30 mg, rather than get caught up in this problem once again of not knowing what the drug does at lower doses, it really should be tackled head on.
And, I think the only way this can be done is in appropriately controlled and double‑blind fashion.  I think there are a number of different ways to go about it.  For example, other companies have recently shown that it is feasible and ethical to do a lead‑in of a couple of weeks, two to four weeks of monotherapy dosing, especially with agents where there is reasonable data in hand that resistance doesn't develop rapidly, in a placebo‑controlled fashion to sort of really see what does this drug at different doses ‑‑ I would say at 30 mg and 60 mg ‑‑ do on their own.  It is incontrovertible to me that you need to know what bang you are getting for this buck, especially since this buck is going to buy you potentially a lot of nephrotoxicity.
I know a lot of people spoke from personal experience, both the physicians and patients, but I too have given this drug to a lot of people, both in controlled clinical trials as well as in expanded access, and my experience is not quite as cheerful, and I was almost starting to believe that the six patients with clinically significant problems ‑‑ that maybe half of them were mine.  You know, it is not an inconsiderable kind of toxicity, and it is not an inconsiderable thing for people to be taking replacement phosphate and magnesium for months after months after months.  I have not seen ready reversibility so I am certainly concerned that we know that these drugs work if we are going to be offering them to patients with the potential that there is very real possibility of harm.
So, given that that is my answer to question 1 and 1B, I would just make some other comments for the other pieces of it.  I do not think the safety profile is adequately characterized.  It was frightening to me to see that the number of patients on the 60 mg dose of adefovir for 48 weeks totaled 73 people, 30 in a randomized trial and 43 out of the first 1000 in expanded access.  I was very anxious about how thin that data set was.  I do not think that the data indicate that reversibility has been definitively demonstrated for any dose of adefovir.  I think it would be really critical to try to understand who belongs to that subset of patients for whom the toxicity is not going to be reversible.  It would be wonderful if there were some way to identify the people at highest risk up front and avoid giving them the drug.  It may be that time to onset becomes somewhat more prolonged with lower doses, but it does not necessarily follow that there is some absolutely clean dose.  I don't know that we know that there is a clean dose of this drug.
That leads into this monthly monitoring issue.  I think that it is clear from the FDA presentation that there is a subset of patients for whom monthly monitoring of electrolytes is going to be inadequate.  So, my concern would be to want to, again, have some data to make a reasonable guess on the part of clinicians to know which patients are going to need closer monitoring than monthly because I think there are definitely some patients like that.  In fact, as we learned more and more about this and started intervening in patients as soon as their phosphate levels started dropping, you could not always necessarily ameliorate the problem by repleting phosphate and taking people off the drug, or lowering their dose right away.  Some people seemed to slide into a more prolonged period of difficulty regardless of your moving quickly.  So, I think it is important to do that.
My concerns about the proposed monitoring scheme, the management scheme, is that in the real world of treatment feasibility of providing drug on a monthly basis dependent on patients showing up for lab ‑‑ I don't think that is going to play well in all situations.  There are a lot of patients for whom compliance is an issue.  Maybe that means up front those are the patients who shouldn't be given this drug.
Then, that goes to question four, is 60 mg safe and effective?  Do the provided data establish this?  I think the answer to that is no.  I think, therefore, my answer to 4A, what other data should be provided before reconsideration of this application, as I stated really in my answer to 1B, I think we need to know that 30 mg and 60 mg work.  We need to know that unequivocally.  I think, in addition to knowing that unequivocally, it is going to be critical to study a large enough number of patients.  The actual numbers of patients in the controlled trials is really very small.  So, when the presentation said over 5000 patients treated, we are really talking primarily about the expanded access.  The total number of people in the controlled trials was, I believe from a sort of seat of the pants feel for it, less than 1000 patients.  So, I think we need to see this drug studied in a large enough number of patients for an extended period.
In my mind, as I said last summer when we had the closed session, 48 weeks is the minimum duration of observation that you would want for this drug, especially if it turns out that the onset of nephrotoxicity is even a little more slow with 30 mg than with 60 mg.  You just have to know that.  That kind of decision‑making up front on the part of patients and physicians is crucial.
I also think that it would be critical that future study populations be more diverse both by gender and race.  This was primarily men and primarily not minority populations.  As I mentioned before, I am concerned about nephrotoxicity in particular subsets, although I know that the analysis the company did runs opposite to my feeling about that.
Then, what additional recommendations?  I actually think it would be very important to study this drug in hepatitis B, HIV co‑infected patients.  That may be clearly a niche population for this drug.
I think other little bits and pieces will evolve with the rest of the conversation.  I think that formally assessing viral load rebound in patients who have to discontinue the drug for toxicity in some standardized manner would be valuable.  In other words, people who stop the drug for toxicity get a viral load at 1 week, 2 weeks and X weeks after that, and you get a series of standardized time points that you could look over a large population.  That is kind of a backwards way of assessing the contribution of this drug to multiple drug regimens.  I will yield there to Wafaa.
DR. HAMMER:  Dr. El‑Sadr?
DR. EL‑SADR:  This is difficult.  I will start with the first question.  I think the sponsor essentially is asking for proposed marketing for this drug for treatment experienced patients, and I think the three relevant studies for treatment experienced patients with the 120 mg dose are the Gilead 408, the CPCRA 039 and the ACTG 359.
Based on using the preferred HIV RNA viral endpoint the FDA has recommended, the less than 400 HIV RNA suppression, there doesn't appear to be a benefit of adefovir at 120 mg in any of these studies, the three studies, and certainly there was no evidence of benefit on CD4 cell counts, which I think is a very valuable surrogate marker.  Even if we take the sponsor's analysis of the 408 data, it is the only one that showed a positive effect with the 120 mg dose in treatment experienced patients.
So, I guess I am saying to number one that I do not think that the data support that 120 mg has established efficacy for the treatment experienced patients.
I do think though, in relation to 1B, that there is really a dire need for more data on the 60 mg dose of adefovir.  I think there is a lot of interest in getting the data, and I think it is very important to get the data on the 60 mg dose, and I think the way to get the data is to compare 60 mg to placebo.  The two studies that are being proposed by Gilead I think are the right studies to do.  It will be very interesting to look at those results, both in terms of using the 60 mg in an intensification type of study, as well as also in "salvage" type of design in 458.  So, 415 and 458.
I don't think the duration of follow‑up in 417, as we discussed today earlier, demonstrates either the efficacy or the safety of 60 mg of adefovir.  I think it is too short to demonstrate safety and it is too short to demonstrate efficacy.  I think the follow‑up is too short.
To move on, I think I sort of answered number two.  I feel like a minimum follow‑up of 48 weeks is needed at least for the 60 mg dose.  I think we always sort of look at the data from expanded access, but we all know the limitations of expanded access data.  People who stop taking the drug in expanded access programs are really lost to follow‑up most of the time because they remain in follow‑up mainly because they are getting the drug.  Once they are not getting the drug, often the company and the sponsor don't have data on those patients.  So, I think it is going to be very difficult to get safety data or efficacy data from expanded access because there is always going to be a selection bias.  You are following the people who have done well in expanded access, and I think, unfortunately, that is the nature of expanded access.
Therefore, I think the way to get at the data with 60 mg is going to be through clinical trials rather than expanded access, and it is going to be through studies like 415 and 456 and others so that we can really learn about the efficacy and the safety of this dose.
As for the renal management, toxicity management, I really don't know whether there is any other option, other than monthly follow‑up.  I guess, by monthly electrolyte monitoring we are at least trying to identify early those who are developing some abnormality before it becomes very severe.  It would be very helpful to try to identify risk factors for developing this syndrome.  I know other people have tried, but maybe as we accumulate larger numbers of patients we can actually come up with a profile of the patient who is either at high risk or at low risk so we know, when we start a patient on whatever dose we are going to start them on, what the likelihood is of nephrotoxicity and, therefore, we can tailor the intensity of the follow‑up.
I think it would be very interesting to pursue a little further the racial difference that was identified.  I think it is fascinating, and probably the nephrologist can comment on that later on.  I don't know why African Americans would be at less risk but I think it is very interesting and probably needs further pursuit.
I also think the management ‑‑ the whole idea of dose reduction is interesting although, on the other hand, we don't know that the lower dose is of any value.  We don't know whether it is better to stop.  Could we possibly be generating resistant virus by using suboptimal doses like 30 mg?  I don't know the answer to that, but I think that can be easily studied within the context of these trials, once a decision has been made to reduce or stop the current dose, to either stop the dose or to dose reduce, so that we can find essentially which is the better strategy.
In relation to question number four, again, I think the paucity of data on the safety and efficacy of 60 mg is quite obvious to all of us here today, and we need longer‑term data.  It is funny to think of longer term being 48 weeks but I think that is the minimum of longer‑term data.
I think also there has been a lot of confusion today about sort of where the niche for the drug is.  A lot of the patients who have been studied with adefovir have been not truly "salvage" patients.  At least based on the context of the clinical trials, they have been primarily PI naive and antiretroviral naive, or some PI experience and mainly NNRTI naive, while most of the use, I am hearing, in the expanded access program has been in very experienced patients.  So, there is sort of very broad populations that are being exposed to the medication, and I think the two studies that have been designed are probably going to be answering different questions for each of the populations that are very relevant ‑‑ the patients who are going to be sort of in an intensification mode and the patients who are going to be more treatment experienced and more of a "salvage" mode.
I think there is a need to look at this drug and do drug‑drug interactions.  There are a lot of drugs used in HIV care that I don't think have been looked at ‑‑ I don't know if methadone has been looked at, or oral contraceptives, or trimethoprim sulfur, or NNRTIs, or all the other drugs in terms of the new proposed dose, the 60 mg dose, and that should really be done as we learning more about the dose.
I guess in the end, this is a very, very tough decision but I can't truly, in my heart, be convinced that there are enough data to support the safety or the efficacy of 60 mg.  It is unfortunate because I think somehow this NDA was maybe prematurely submitted.  The data is going to come and the sponsor is conducting and planning the right studies but I don't think we are there yet.  Thank you.
DR. HAMMER:  Thank you very much.  I would like to turn to the other committee members.  In turn, I would also like the committee members to just focus on question number one, the 120 mg dose efficacy issues.  I will start on my right with Mr. Schouten.
MR. SCHOUTEN:  With regard to the efficacy of the 120 mg dose, I can't ignore the CPCRA nor the ACTG trial either, and I think that given our standard criteria for efficacy being percent less than 400 or less than 50, I just don't see the data given with the composite of all the studies at 120 to say that I can convincingly say that there is efficacy, given our standard criteria for efficacy.  But, clearly, this drug does have some antiretroviral activity.  So, I am torn.  And, clearly, this drug is suppressing HIV to some degree but it is not meeting our standard efficacy criteria.
Regarding whether or not there has been efficacy of the 60 mg and 120 mg dose, I just think the design of 408 and 417 and the patient population is so different I just don't see how I can look at those two studies and saying that it has shown efficacy.  I would like to see a very different trial design than 417.  I would like to see a placebo arm, and that be the main variable comparing the 60 mg to the 120 mg, and have placebo or have more consistency in the patient population than there was on the 120 in the 408 trial.
DR. HAMMER:  Thank you.  Dr. Kimmel?
DR. KIMMEL:  The question of efficacy is I think outside my area of expertise so I would prefer to pass.
DR. HAMMER:  Thank  you.  Dr. Kopp?
DR. KOPP:  I actually feel the same way.  I will also pass.
DR. HAMMER:  Thank you.  Dr. Verter?
DR. VERTER:  I probably should pass because it is somewhat outside, but I will speak to it from a statistical perspective because I have a thing about 1B.  Repeating somewhat what I said before, there were multiple ways of analyzing the data.  I agree with ‑‑ she just left, but she said there were three studies in total and the data, just the data from those studies don't seem to suggest statistical efficacy.  There does seem to be some viral activity but not statistical efficacy.
I am also somewhat troubled by the lack of one consistent measure of efficacy ‑‑ differences between medians, mean change between two time points, DAVG analyses and I think RNA and CD4.  So, I urge Gilead, the FDA and whoever else presents data to this committee, whether I am on it or not in the future, to try to come up with some consistent measure, something that the community can accept, that the industry can accept and the FDA can accept.  It will make everyone's job a lot easier.
With respect to 1B, I agree with the comment that I think the ideal stud ‑‑ semi‑ideal ‑‑ would be a placebo‑controlled 60 mg dose, but within that context I urge, if they are going to do it, or any other studies that are done, that as much as possible you get complete data on everybody.
DR. HAMMER:  Thank you.  Dr. Wong?
DR. WONG:  I am going to disagree partially with those who have spoken before.  I am convinced that the data show that the 120 mg dose was effective, was efficacious.  I understand that there were some conflicting results between the different studies but the 408 study convinced me.
I should comment that holding any investigator to a fixed criterion, such as the proportion of patients who achieve 400 or fewer copies of HIV RNA per milliliter of blood is probably ‑‑ I mean, it is certainly a reasonable criterion but it shouldn't be considered to be the only criterion.  The HIV concentrations and the DAVG24 results that Gilead showed were convincing to me.
On the other hand, I think that the comparability of the 60 mg dose was not shown for the reasons that we discussed earlier.  The design of the study was really such that it probably could not have been shown because of the multiple confounding factors, the small samples, etc.  That is my answer to question one.
DR. HAMMER:  Thank you.  Dr. Pomerantz?
DR. POMERANTZ:  Yes, I don't think that, unfortunately, I was convinced that 120 mg dose is efficacious for marketing, even though it wasn't put forward for that at this time.
There were a number of things, in deference to Dr. Wong, that I did take quite seriously, and I thought that the FDA's presentation actually took me from a borderline case to over the edge because I do think that getting below 400 copies is a very reasonable thing to look at nowadays.  I think that there are drugs where it becomes somewhat more complex.  The PIs have been shown in certain cases to have a clear effect on morbidity and mortality, not directly correlated in all patients to decreases in RNA levels, and that is an interesting concept, whether there is a change in the fitness of the virus and, therefore, that is different, but there is no data for that here.  And, with that not there, I still would hold until someone shows that this drug has something comparable with the de‑synchrony that has been shown in certain PIs that the 400 level be something that should be a reasonable earmark at least for the 120.
I also was really taken back by the amount of the missing data, and Dr. Feinberg has flown the coop, but I agree with her.  I thought that 22‑32 percent was surprising in relatively small studies, and I don't know where those people went but that is problematic when you have so few studies.
Again, this is a drug that has some strength to it, but a 0.3 log change has to have more than it showed for effects and still have problems with the data sets for me to go forward and say yes.
So, that being no, I agree that some type of placebo‑controlled trial, certainly with other drugs, at 60 mg and, as Dr. Feinberg said, at 30 mg would be quite reasonable to get at what they are asking for.
Just to go to number two, Scott, because it is related to it, I don't see that 60 mg has been shown either.  There were very few patients over 40 weeks.  There just wasn't enough to convince me that with the adverse effects that we have data here.
I want to make one last comment, and that is there is no doubt that the word "niche" is a good word for this drug in certain cases, and the sort of parade of very important anecdotal remarks that were made is interesting.  There may be holes in the armamentarium where this will fit in for a particular patient, but dissecting that out in trials is sometimes hard, and I think the company has to decide what they want from this drug.  Do they want an up‑front drug that is used by many patients who are naive?  Do they want it to be for people in their first salvage?  Or, do they want to try to find a niche where certain patients will get help with a drug when all else has failed?  I think they have to decide where they position this.
DR. HAMMER:  Thank you.  Dr. Jolson?
DR. JOLSON:  I am sorry to interrupt.  I just think it might be worth clarifying something about the endpoint issue so that there isn't a misunderstanding in terms of percent undetectable versus DAVG.  Hopefully, they are all measuring the same thing, which is viral suppression, but I don't want people to leave the meeting thinking there is only one way that the agency is willing to look at viral suppression.
In fairness to the sponsor, this study was designed several years ago, started several years ago, really before there was consensus on the goal of therapy, which is reducing virus to below ‑‑ what it is 400 or 50, what our current standards would be now.  That is what our current guidance reflects.  But I think this study was probably designed in 1996, something about that.
Also, even if it were started today, by design the study would really be unlikely to show, because of the way it was added as a single drug, percent undetectable.  So, hopefully, when you are all considering this, you will just sort of factor that in terms of the time element and the study design.  Hopefully, you will see that it is not that it doesn't meet FDA's current endpoint.  We would ask you all to evaluate it as evidence in and of itself of viral suppression.
DR. HAMMER:  It might also be worth commenting that the intrinsic potency of the agent and also the population in which it is being targeted make it difficult to use proportion below 50 copies as really the clear‑cut endpoint.  One has to use a mix of virologic endpoints here and change in RNA or DAVG have to be co‑equally looked at, just as an aside here, but thank you for the clarification.  Dr. Lipsky?
DR. LIPSKY:  In answer to question one on the 120 mg dose, I would say that there is suggestive evidence for some degree of viral suppression.  I should respond a bit to the comment, "well, what about the 60 mg dose?"  I think there is much less suggestive evidence on that.
What I would do is, if feasible, go back to basics here and wonder where did the 60 mg dose come from, except that it was half of 120 mg, and we are hearing about 30 mg and possibly lower ‑‑ if one could go back, if it is feasible, to their 402 type study and look at basic dose‑response relationships and see how low you can get.  I think they were using p24 in that study.  One can be a bit more sophisticated these days, but to see how low one can get because, gee, what if 10 works the same way as the other, it would be unfortunate to have to, thus, go with a higher dose.
It seems like in a situation where there is a therapeutic index question, one would want to know very clearly the dose‑response relationship of toxicity and the dose‑response relationship of efficacy so as to maximize the therapeutic index.
DR. HAMMER:  Thank you.  Dr. Masur?
DR. MASUR:  I think there is a lot to recommend this drug.  As has been emphasized, it is a different class of drugs.  It is once daily and, in many ways, it is convenient to take.  So, I think the company should be applauded for developing this.  But I would agree with most of the previous comments that it would certainly be desirable to have a more robust database that would indicate that the drug is useful or is active in the patient populations being studied.  	
I think from the Phase I and Phase II studies and from 408, there clearly is activity, although it isn't clear in my mind that this meets the definition of having two studies with adequate data and adequate follow‑up to provide us enough guidance as to how to use it.
So, I don't think that the data about 120 mg, although promising, meet my definition for proving activity yet, and considering the comments that have been made about the toxicity, I think there is a lot to be learned there.
So, clearly if we need a better database on 120 mg, I think indicating that 60 mg is effective is premature based on what we have seen so far.
DR. HAMMER:  Thank you.  Dr. Hamilton?
DR. HAMILTON:  Perhaps an initial editorial comment will explain my position, which is that efficacy has not been satisfactorily established for the 120 mg dose, nor has the 60 mg dose been confirmed as comparable.
The editorial comment includes the following:  I am always incredibly impressed with personal testimonies and impassioned appeals for the licensure of drugs.  I have no doubt that in those instances those are heartfelt beliefs in every case, and I have also no doubt that there was a lot of substance to the comments.  However, we need to revisit what I think the charge of the committee is, which is to critically assess, by means of a systematic evaluation of systematically and scientifically conducted clinical trials.  I think that is so important because I think what we are being asked to do is, on the basis of limited and arguably unrepresentative data, to decide whether drugs have some effects and in a very limited and confined arena.
Though everyone does not necessarily share this view, it is my opinion that we are evolving more and more into the need to address not the short‑term implications of drug therapy but the longer‑term consequences of drug therapy in a disease that is now chronic.  Fortunately, we have 13 or 14 drugs that have been approved.  Fortunately, there has been a dramatic decline in mortality and morbidity.  But now it is a different scenario and we are talking about people taking drugs for year and year and years, and that is great, but I think we need to adopt new strategies to assess the value of those drugs.  And, that may be bad news to industry but I think that is where we are going, and short‑term clinical trials I just don't think are stepping up to the plate there.
So, in summary then, as I said at the outset, though there is some evidence for modest antiretroviral effect in a single trial, 408, there is not a confirmatory trial at that dose.  By that definition alone, it would not, in my opinion, meet the criteria for efficacy.
The comparison with 60 mg, it seems to me, is confounded by a variety of circumstances, including the complexity of the studies, the possibility of drug interactions, the short term of the trial, and the large number of missing data making pooling of the data suspect.  For those reasons, I would not accept efficacy of 120 mg, nor would accept 60 mg as comparable.
DR. HAMMER:  Thank you.  Dr. Yogev?
DR. YOGEV:  Early my career was as schizophrenic as I am with this specific drug.  Listening to the personal testimony, one cannot avoid compiling how many drugs those patients were taking and you find out it was six, eight, ten drugs, and in the studies which were presented to us there were not that many drugs.  So, I think that the 120 mg does have some marginal effect ‑‑ if one can block the other schizophrenic portion of me ‑‑ when you are out of desperation trying to use this, it is easier to take a drug that may has some marginal effect, I think that would be a place where I would say, yes, the 120 marginal effect might be there.  But I was not at all convinced that there is any comparability with the 60 mg.
So, I would say that under the public request, and I think when you do a critical review you have to be also somewhat human and not just look to science, this margin would be enough for me in a very rare patient.  And, there were 9000‑plus going into it, so there were some physicians along the line looking for something that we don't have today.  So, if someone can limit it somehow that if you take six drugs or above you can take this marginal, and it is your choice with the addition with all the toxicity that is there, I might say that this marginal might be sufficient for patients experienced, which many of my colleagues and I interpret as taking AZT for more than six weeks ‑‑ that is dangerous and I don't think the data are there.  So, 120 very marginal, adding toxicity, and the need in a small number of patients probably has a place for this drug, but I am not sure that 60 at all is the right answer.
DR. HAMMER:  Thank you.  Dr. Mathews?
DR. MATHEWS:  Before answering the first question, I think implicit in any discussion of accelerated approval is, is there a population in need of an agent with this drug's characteristics.  I think very definitely there is a need.  I think that the volume of the expanded access program clearly indicates that physicians and patients are scrambling like wild to find agents with some activity that can be components of salvage regimens for people with very limited treatment options.
So, having said that, I want to say that I don't think that the CPCRA study can be properly evaluated for efficacy, and a number of comments have been made as to its negative effect, but I don't think that is a fair appraisal of the results and the agency itself has not had access to the full data set, from what we have been told.  The ACTG 359 study, I think, is quite problematic in terms of the unanticipated results, the possible drug interactions that weren't anticipated in the company's previous drug interaction studies.  So, I think that is worrisome but, once again, that data set has not been fully evaluated.
Based on the Phase I/II studies and the 408 study, there is little doubt in my mind that the drug has modest activity, of the same order of magnitude of agents that were previously approved in related drug classes.  So, I would say, yes, there is activity and it is of a modest nature, which other people have said.
Now, with regard to the equivalence issue with the 60 mg dose, you know, I looked with some attention at both the FDA's analysis and the sponsor's analysis of the equivalence trial, and I must say understanding the statistical complexities of equivalence designs is not easy.  However, the point estimates of the drug effect were clearly equivalent or better for the 60 mg dose, and the issue of the statistical interaction between dose and concomitant regimen I think is debatable, and I couldn't come to a conclusion either way from either the sponsor's or the agency's discussion.
So, I am reasonably confident that the 60 mg dose is equivalent to the 120 mg dose.  On the other hand, the sponsor's proposed dosing guidelines and toxicity management program uses a 30 mg dose, for which I could see no data at all to support efficacy, and I would have major problems with that as being part of a recommended management strategy if the drug is licensed.
Now, with regard to the toxicity ‑‑ oh, we are just talking about question one right now?
DR. HAMMER:  Right now.  We will come back to questions two and three but let's stick with question one.
DR. MATHEWS:  Okay.  I think both limited efficacy and equivalence have been demonstrated.
DR. HAMMER:  Thank you.  Dr. Stanley?
DR. STANLEY:  Thank you.  Given the advantages of this drug, I wish that I could say that it is ready to be approved but, unfortunately, I think the answer to question one is no also.
Basically, they are asking us to make a decision on efficacy based on one study, 408, and the effect in that study was minimal.  I think it was there so I am ready to be convinced, but I need to see at least another study, as is required by the FDA for accelerated approval anyway.  We don't have two studies on true advanced patients that need salvage therapy.  Study 417 has patients that are PI naive and 411 had completely naive patients.  So, I think the company needs to decide, as I think Roger said, how they want to use this drug and then study those patients and provide us with some good clinical data that will support the efficacy of this drug in the population that they want to target it at.
So, additional data that would be necessary to characterize the efficacy of the 60 mg dose, as others have said, I think we need a placebo‑controlled trial using the 60 mg and the 30 mg dose,  I think 417 is seriously flawed by not having an arm where there was no adefovir used.
DR. HAMMER:  Thank you.  Dr. Bertino?
DR. BERTINO:  Thank you.  First, I would like to thank Dr. Hamilton for his very thoughtful comment.  He said a lot of the things that were going through my mind.
I think that in terms of my response to the question, I don't believe there is data to suggest that the 120 mg dose is effective.  I think that one of the things that many of us probably were surprised about when looking at 417 was, as Dr. Stanley said ‑‑ where was the placebo arm?
So, I would suggest that if the 60 mg dose should be studied again, we probably need a placebo arm, so 120, 60 and placebo perhaps, and look at patients that have received multiple therapies in the past.
DR. HAMMER:  Thank you.  Most of what has been stated I concur with.  My own personal view with regard to the 120 mg efficacy dose, or at least what I would say is antiretroviral activity, that it hasn't been demonstrated ‑‑ I would agree with Drs. Mathews and Wong that I believe it has if one looks at the 402 and 403 Phase I/II studies, and in the 408 study there is a consistency in the antiretroviral effect, and there are problematic issues in interpreting the 039 study.  Everyone agrees that if it is there, it is modest.
I also think the issues of minimal, at best, modest CD4 count rise also raise issues as far as what the ultimate role and efficacy of this drug is.  But my personal comment on efficacy of the 120 mg dose is that, yes, it has been demonstrated.  I think there is consistency there.  Otherwise, one has to try explain, in two of the studies and the larger study, the 408 study, one has to explain why there is that consistency there.
I would just take a step back though and say that one of the problems ‑‑ it has been a very difficult day I think for everyone here and on the committee because each study that has come up is subject to issues of interpretation, either in the design stage or the analysis stage, so trying to paint a consistent picture is difficult, and also with a drug that is of this level of antiretroviral activity it doesn't take much to undercut it because we are not dealing with a drug that has an intrinsic 0.5 log reduction.
That being said, I think efficacy at the 120 mg dose, to me at least, is there.  On the issue of has comparability been shown between 60 mg and 120 mg, we are really left with a difficult data set to interpret.  On the one hand, there is indication to me from the monotherapy 60 mg trial, the 420 trial, that there is activity there, and it looks across study to be about the same in the 0.3, at the most 0.4 log range, that is a study, because of its small numbers, that the agency has said must be taken in a supportive fashion, but at least it is one of the cleanest studies.  The direct comparison of 60 versus 120 in the 417 study ‑‑ I have little to add to what has been stated.  Basically, you either can believe it or you ask yourself where is the placebo control that helps differentiate the data because the background therapies make the comparison very difficult to state.
So, I am left really with a conundrum.  I tend to agree with Dr. Mathews that there probably is activity to the 60 mg dose.  It probably does cross the threshold of just biologic and assay variability so I would tend to come down mildly in favor of the fact that it is there but can I say it has been conclusively demonstrated?  The answer is no because it is based on the 417 study which, because of the design, the discontinuations, the potential of complicating drug interactions leaves us wanting additional data in that regard.  So, that is my personal response to question one.
I would like to turn to questions two and three.  I think these can be taken together since they both relate to the toxicity issues.  I will read both questions and I would ask each committee member to deal with both of them, and then we will move on to the voting question, question four.
Question two states, had the safety profiled of adefovir 60 mg been adequately characterized?  In particular, please comment on the adequacy of the available data to provide labeling information regarding nephrotoxicity and its incidence and reversibility.
The third question, to be taken with it in tandem, please discuss the adequacy and feasibility of the sponsor's proposal for renal toxicity management.
I will again start on my right.  Mr. Schouten?
MR. SCHOUTEN:  I think that patients and physicians are managing this drug.  Expanded access program is exposing a lot of people to this drug and its known toxicities, but I would encourage people not to be too paternalistic and say patients shouldn't be subjected to this risk.  I am very concerned about a drug that requires someone to come in for monthly laboratory testing for both the patient and the provider.  So I see it from both sides.  And, I don't think you can say if you don't come in for your lab next month you don't get your drug.  I think there are too many contingencies there, and I now there aren't going to be patients coming in for the drug.
I would like to see ‑‑ I know we had a lot of stuff to cover today ‑‑ some of the issues of rechallenging.  We heard some testimony about early supplementation but I think it does have a well‑defined safety profile.  It is concerning but I think it is easily managed and I don't think that that would preclude licensing the drug.  I mean, it is a manageable toxicity profile.
In terms of the sponsor's proposal for management, I would add there is an inconsistency.  In one place they mention phosphate of 1.5 and in other places 2.0 for contraindication.  I think what they mean is 2.0 in terms of on study, on the drug.
Then, the other issue is that I am concerned about recommending a dose decrease to 30 mg because of the efficacy, and would prefer to see discontinuation while that toxicity is resolving and not 30 mg.  Thank you.
DR. HAMMER:  Thank you.  Dr. Kimmel?
DR. KIMMEL:  I did not think from the data that I saw that the safety of 60 mg has been adequately characterized.  I was impressed by the very small number of patients who have been followed to 48 weeks, especially since late manifestation of nephrotoxicity is when you see these issues.  I think there was not enough time or patients to really evaluate the toxicity profile.
I was also impressed that the management plan for looking at renal toxicity ‑‑ there is very little data to say whether it is a good plan or not.  We saw very little data about what the effect of monthly management is in terms of outcomes, and I felt that we just really don't have enough information to make the decision about that plan.  I am a little concerned about stopping the drug and restarting the drug with very variable intervals.
DR. HAMMER:  Thank you.  Dr. Kopp?
DR. KOPP:  I also have some very significant concerns about the adequacy of the safety data.  I will say I found this a very difficult decision, and I certainly understand the position of community physician and patient who together wish to make the decision whether or not to use it.  On the other hand, I think it is our obligation as a committee to make sure that full and accurate information as to toxicity at various doses is available.
Maybe I could digress for just a couple of minutes or seconds on a couple of issues that have been raised.  First of all, how useful is serum creatinine to measure renal function?  I think everybody is aware that the most precise measures are inulin clearance, which is clearly not clinically practical.  It may not be readily appreciated that creatinine clearance is often used in the hospital setting is not terribly accurate and, actually, the Cock‑Croft‑Gault estimation of glomerular filtration is substantially better.
Having said that, if we use Cock‑Croft‑Gault that takes into account serum creatinine, patient age and weight, and imagine a 40‑year old patient, a male weighing 72 kg, if he has a baseline creatinine of 1, his creatinine clearance is estimated at 100 mL/minute using that Cock‑Croft‑Gault.
If we imagine now that he develops toxicity such that his serum creatinine rises to 0.5, if you work that out his estimated GFR has fallen to 67.  This is actually a geometric progression, not quite the logarithmic progression, but it is important to realize, and this is the point Dr. Feinberg was making earlier this morning, that relatively modest changes in creatinine represent significant decrements in glomerular filtration.  I know that the sponsor is acutely aware of this and certainly has set their limit relatively low.
I will point out for that same man that if his creatinine serum rose from 1 to 1.4, his clearance would still have dropped from 100 to 71.  So, significant decrements in creatinine clearance can still come about from relatively modest changes in creatinine.
The second link point to this is that there is a certain amount of renal functional reserve that I think we all realized.  That is, you can donate one kidney and the remain kidney hypertrophies and there is no change in glomerular filtration.  At some point, as you pass 50‑70 percent of renal mass reduction, that ability to compensate, that is, that renal functional reserve has disappeared, and further insult, toxic insult or something else, has tremendous consequences.
In addition, there is a further point where glomerular filtration has fallen probably below 50 where, in some patients, an insidious process of progression renal insufficiency leading to end‑stage renal disease goes forward.
So, the question is how do we understand the various changes in serum creatinine, not knowing in many cases patient weight and age to be able to estimate creatinine GFR?
I guess, as I look at the data, I see that about half a percent of patients getting this drug develop acute renal failure requiring hemodialysis, and about 5 percent of patients, and here the number is a little bit hard to be sure of ‑‑ perhaps as high as 8 percent, perhaps somewhat lower than 5 percent but I will use 5 percent for now are going to be left with a fixed renal deficit in excess of 0.5 of serum creatinine.  That is a fall in our hypothetical patient from 100 to 70.  What does that mean for that patient?  I don't think that patient is at risk for progression to end‑stage renal disease, and I think that is the good news.  But I think we have to recognize that by having given up a certain amount of renal functional reserve that patient is at greater risk should they live long enough and need additional therapies, should they need cidofovir, should they need contrast as one of these patients here did receive, of developing acute renal failure.  That is a certain definable risk.  It is not an inalterable problem but it is something that needs to be weighed against the benefit.
Another related point is what do we say about the patient whose creatinine goes up and then comes back down?  Can we say that that patient is entirely back to normal?  Unfortunately, we can't say that that patient is or is not back to normal because of this issue of renal functional reserve being very hard to measure.  So, I don't want to push this point too hard but I think in the back of our minds we have to worry a little bit about a drug for which 50 percent, perhaps, of the population treated a year experiences significant rises in their creatinine even though most of them, 80 percent, 90 percent or 95 percent return back to normal.
So, in terms of the available safety data, what I would like to see would be, insofar as possible, complete follow‑up of patients ideally after 48 weeks, which I see as the plan, 48 weeks of treatment and then 48 weeks of follow‑up in the two proposed studies.  I think that would give us a much stronger sense of do the final 5 percent get back to baseline, and they may or may not.  As far as 30 mg that has been raised, clearly we need to know a lot more about the safety profile of that drug.
Now, in terms of the packaging information, we are being told that these patients are at increased risk for renal failure if they have an elevated creatinine of 1.5 or more and should be excluded.  I would raise the issue for the FDA to consider and the committee to consider whether we should be using Cock‑Croft‑Gault there as well.  Again to give you an example, if we had a 40‑year old woman, weighing 60 kg, whose baseline creatinine is 1.4, she has glomerular filtration of 51 mL/minute.  I would argue that is such a minimal level of renal function that that might not be a good patient to receive this medication.
In terms of the management plan, once renal dysfunction has appeared, I actually it was quite well done and quite well thought out.  I thought the supplements seemed quite reasonable.  I actually don't have a major problem with monthly monitoring.  I realize that some patients do double their serum creatinine or drop their serum phosphate.  I am not clear that there is a major risk to the patient.  I am a little bit more concerned about a severe acidosis between monthly monitoring.  In fact, we have no data about acidosis in study 417.  But I am quite concerned about this issue of continuing a nephrotoxin, even at a low dose of 30 mg a day, in somebody who has established nephrotoxicity that is not returning to baseline, a patient who has a 0.2 or 0.3 increment.  It is interesting that many of these patients were able to be treated through the episode, and I don't understand that but I think my own initial take is that I would not want to consider exposing a patient to a nephrotoxin, the same nephrotoxin that has caused damage, and certainly not until information on efficacy is there.  I think I will stop at that point.
DR. HAMMER:  Thank you very much for those comments.  Dr. Verter?
DR. VERTER:  I pretty much agree for question two with the comments of the previous three speakers, and I don't have any sense of the package insert.
DR. HAMMER:  Thank you.  Dr. Wong?
DR. WONG:  I have nothing really to add.
DR. HAMMER:  Dr. Lipsky?
DR. LIPSKY:  On the issue of toxicity, I am a little concerned that, again, it is a one dose fits all.  I think there are differences in exposure.  We have a drug that is primarily eliminated by the kidney, and if one would think to amino‑glycosides, is this the way you would handle amino‑glycosides?  This isn't amino‑glycosides but it is another drug that accumulates in the proximal renal tubule, etc.
When you look at the curves of the time to problems with nephrotoxicity in the two doses, the inflection points or the changes are about the same, and one wonders if the exposure in the lower dose group in some of the patients is not comparable to the exposure in some of the patients in the higher dose group.  Perhaps therapeutic monitoring could help in avoiding toxicity with this agent and understanding if there is a relationship between concentration dose and the subsequent development of toxicity.
The other issue of reinstituting the drug, well, if it is an accumulation problem are you just going to postpone the inevitable, realizing that there is a risk/benefit and the inevitable of not having the drug could be worse than kidney damage.
DR. HAMMER:  Thank you.  Dr. Masur?
DR. MASUR:  I concur with the previous speakers, but I think Dr. Lipsky's point is an excellent point.  It appears that there is so little known about the pathogenesis of the renal disease that exploring more a pharmacokinetic or pharmacodynamic analysis for toxicity might be very productive.
DR. HAMMER:  Dr. Hamilton?
DR. HAMILTON:  I too concur with my associates and their concerns about the renal toxicity, but would add that as a clinician taking care of patients and even as an investigator, frankly, it is not this level of toxicity that is of concern to me in this case; it is the efficacy.  Heaven knows, we have learned to live with substantial toxicity when there were other issues more pressing at that time.  Unfortunately, we don't have that efficacy at this moment.  I will defer at that point.
DR. HAMMER:  Thank you.  Dr. Yogev?
DR. YOGEV:  I don't think we have enough on toxicity.  If you look at the curve and how more patients develop a creatinine problem, it doesn't level off even at 48 weeks.  So, we need a much longer period of time to see that accumulating.
Interestingly enough, most of the toxicity ‑‑ 60‑plus percent of the patients developed toxicity between week 20‑28 and one wonders should you add a little bit more closer monitoring at that specific period of time which, for some reason, is unique in the two studies that were presented.  So, I think I need to see more.  Many of the patients are going to use the amino‑glycosides, the amphotericin B, and other drugs that are nephrotoxicity.  Is there a synergistic effect, no effect?  That is another safety issue which was not addressed and one would like to see.
DR. HAMMER:  Thank you.  Dr. Mathews?
DR. MATHEWS:  Well, I agree with most of the people that spoke before about lack of long‑term safety data, meaning beyond 48 weeks.  On the other hand, I view this drug as sort of a bridge agent for people that need something in the short run that may not have the option of waiting for two years until the next generation comes along.  The fact of the matter is that at least half of the people exposed to this drug at the doses currently used aren't going to be taking it for more than a year, based on the toxicity and other reasons for dropping out.  So, the short‑term toxicity seems to be reasonably well characterized.  You know, when you view it from a pragmatic point of view, who is need of the drug and how long might they need to be in need of it, I don't have as big a problem with it.  If I put a patient on this, which I have many times, I would not expect that they are going to stay on it for much more than a year, at best, anyway.
With regard to their monitoring and toxicity management program, while it is well designed, I think there are a number of unanswered issues.  For example, they talk about a 7‑day window between use of adefovir and other nephrotoxic agents, but anybody who practices medicine realizes you may not have the luxury of a 7‑day window.  If somebody on adefovir comes into the hospital with sepsis and has to be put on an amino‑glycoside or amphotericin, there is no window.  I don't know what the risk is of the drug in that setting.  There are other agents that can affect renal function ‑‑ nonsteroidal anti‑inflammatory drugs, ACE inhibitors.  We haven't heard any discussion about those kinds of things.  So, I think more would need to be done with the toxicity management to clarify very practical clinical issues.
DR. HAMMER:  Thank you.  Dr. Stanley?
DR. STANLEY:  Yes, regarding the safety profile, I too would like more long‑term data on the nephrotoxicity, but also I keep going to the graph of study 417 and the continual dropouts of patients even from the 60 mg dose, and I just wonder what the nature of that is.  Are there other toxicities or side effects that were just not adequately assessed?  So, I think we still have a lot to learn about the safety profile of the 60 mg dose.
As far as the proposal for management, I do ask how did we come up with dose reduction instead of cessation of drug?  Again, as someone said earlier, I have seen no data to support that recommendation.  Monthly monitoring may allow some people to fall through the cracks, as the FDA's analysis pointed out, but I don't see much of a better alternative to monthly monitoring.
I would point out that that is going to be problematic for some of our patients who are perhaps ADAP or Medicaid patients who, to maximize their medication usage, have to rely on getting multiple months at once.  So, I think it is going to pose just some logistical problems for certain patients that need to be considered, but I don't see a better alternative at this point.
DR. HAMMER:  Thank you.  Dr. Bertino?
DR. BERTINO:  I would concur with many members of the committee that I would like to see more data on the 60 mg dose from a safety standpoint.  I am actually not even going to comment about nephrotoxicity but talk about some other things.  Carnitine supplementation, for example, is recommended and I am kind of sitting here, thinking, well, why?  Is there something that has been shown in terms of carnitine levels drops so that we need to supplement carnitine, etc?  Does that affect efficacy of the drug?  We don't really have any of that information at hand.
It appears that the decision to either reduce the dose or stop the drug ‑‑ I am not quite sure from the 60 mg to 30 mg dosage reduction that we saw data today that supported that.  So, I don't think that I could support that in the labeling either.
In terms of the sponsor's proposal for renal toxicity management, there certainly is a precedent for this kind of monthly monitoring and that is with the drug clozapine, where patients are monitored very regularly ‑‑ in fact, I think it is more than monthly, for white blood cell count, and then once the white count is obtained it is fed back to the pharmacy and the drug is dispensed.  We are king of facing a different situation here, however, because if a patient doesn't get their antiretroviral agent, or if they decide they are not going to get any of their antiretroviral agents for whatever reason, because they don't want to go in for monitoring or whatever, that I think is probably at least as problematic, maybe more problematic than, you know, missing your clozapine for a few days.
So, I don't have a better way to suggest doing it.  I think it is pretty ambitious of the sponsor to suggest this type of management.  I think there are a lot of other questions having to do with financial considerations that I know the FDA doesn't consider but I think a lot of us at this table are thinking about in terms of the monitoring and getting multiple months worth of drugs, and things like that.  So, I think it is an interesting proposal.  It will be interesting how it will work in practice, however,.
DR. HAMMER:  Thank you.  A couple of comments first with respect to question two, the safety profile of 60 mg of adefovir being adequately characterized, I would like to just dissect this quickly.  First, I think the description of it, yes, has been adequately characterized, and I think the time of onset is very clearly evident from the time graphs that we have seen with the inflection points between weeks 24 and 28.  I think what is not clearly characterized yet is its full incidence.  Of course, that depends on your definitions and your thresholds and, as has been already stated, where those curves will ultimately end up and study to study differences make it uncertain.  But that is less of a concern to me because with ongoing data collection, one would find out about that I think.
I think the one open question still, because of the lack of length of follow‑up, is the reversibility.  So, I personally have no problems with the description of it for physicians and patients with the clear time to onset, and I think we know the ballpark incidence but we may not know the final incidence per se, but the reversibility and the totality of that reversibility over time is still a question.  By itself, however, this does not dissuade from the drug's use.  I think it has been well stated by my colleagues about the fact that we have dealt with toxicity‑efficacy ratios before in other drugs, and when the efficacy aspects of it are there we can handle toxicities.
I think we should also ‑‑ at least some of us ‑‑ be internally consistent if in other venues we are stating that HIV disease should be managed by specialists in concert with well‑informed patients.  Then I think that toxicity such as this that has been fairly well characterized, even if its basic mechanism is not fully understood, can be handled by educated physicians.  It is just another statement that, in fact, this disease should be managed by people who know what they are doing in concert with excellent patient education.
As far as the adequacy and feasibility of the sponsor's proposal for renal toxicity management, the sponsor has made a very commendable effort in trying to detail this to get at what the best predictors are of full‑blown PRTD syndromes, and teasing that out as far as creatinine elevations and phosphate declines, and the monthly monitoring I think, in a practical sense ‑‑ one really can't do better than that and one has to realize that these are just guidelines for management, and there will be variability in their practice and there is nothing that can be stated in a guideline that will be 100 percent adhered to by 100 of physicians and 100 percent of patients.  So, I think the general guidelines are very well thought out.  My one reservation has been stated before, and that is that we have no data on the efficacy of the 30 mg, and my personal reaction would be, if one starts seeing nephrotoxicity to remove the nephrotoxin until there is data to suggest that 30 mg is efficacious.
Let's move on to this fourth question for the committee.  I will read the question itself for the record:  Do the provided data establish that adefovir 60 mg is safe and effective for the treatment of HIV infection?  I will defer A or B because it depends on what we say.  I would ask the committee members to comment on this but to reserve the vote.  They can state whatever they wish but we will take a formal vote after everyone has a chance to make a comment, and then, after the vote, we will deal with A or B as put forward to us by the agency.  So, I would put question four to Dr. Bertino.
DR. BERTINO:  No on efficacy.  I think we know the safety profile somewhat but I think we would like to know more.
DR. HAMMER:  Dr. Stanley?
DR. STANLEY:  No.
DR. HAMMER:  Dr. Mathews?
DR. MATHEWS:  Yes.
DR. HAMMER:  Dr. Yogev?
DR. YOGEV:  No.
DR. HAMMER:  Dr. Hamilton?
DR. HAMILTON:  No.
DR. HAMMER:  I think we are taking the vote.  Dr. Masur?
DR. MASUR:  No.
DR. LIPSKY:  No.
DR. HAMMER:  Do you want to make comments?
DR. WONG:  I will make a comment.  Had this come at 120 mg I would have voted yes but at 60 mg no.
DR. HAMMER:  Dr. Verter?
DR. VERTER:  No.
DR. HAMMER:  Dr. Kopp?
DR. KOPP:  No.
DR. HAMMER:  Dr. Kimmel?
DR. KIMMEL:  I am not supposed to vote.
DR. HAMMER:  Okay.  Mr. Schouten?
MR. SCHOUTEN:  I will make a comment first.  There clearly is a niche where some people are benefiting from this drug and I think that patients are being penalized because of the poor design of the trial, 417, in my opinion.  So, I am torn about what the FDA should do, and we have a situation where a drug is probably kind of a gap filler for a small group of patients who have no other options, and it works against a class of virus so there is evidence that it works against a class of virus that is resistant to AZT and 3TC.
So, I think if there is some way that this drug could be licensed with the caveat that it be used with AZT, with 3TC in people with documented 215 or AZT mutations and the 184 mutation, I think in that setting it is going to benefit people.  But if you are asking about whether or not there is proven efficacy that this drug works based on the data presented at 60 mg in the trials we are looking at, then it doesn't.
DR. HAMMER:  I will just make a few comments.  First, from the perspective of this committee, my view is that this committee has tried its hardest actually to improve access for drugs, and to look for ways to facilitate getting the sponsor and the agency together to get drugs out in the arena because I think everybody here realizes the need for additional therapies and that we are not where we want to be.
I also think that the sponsor deserves a lot of credit for trying to develop a drug for a treatment experienced population, particularly, obviously, with a lot of drug resistance, and for trying to exploit something that is at least intriguing to us, and that is the resistance mutation interactions, and for promoting an early expanded access program.
We haven't talked about it too much in this discussion but, in fact, the virology here ‑‑ if one accepts, as some of us do, the activity of 120 mg and accepts some of the in vitro data vis‑a‑vis hyper‑susceptibility with the 184 mutation and the 408 virology substudy, is one area that is of particular interest.  One wishes that that number were greater.  One wishes that there had been a trial that actually randomized patients with the 184 at baseline to various interventions to try to prove this.  One would also liked to have seen some similar data at the 60 mg dose per se in comparison to the 408 substudy.
I also have to mention that coming into this the virology issues with adefovir and activity against isolates with the 184 mutation and the niche that that holds, that the agency's presentation in that regard casts some doubt on one aspect of that which creates overall some doubt about full interpretation.  So, again, it is an area that is intriguing.  I wish that the fact were clear‑cut in that regard, but additional data are necessary.
I would echo what Dr. Wong just mentioned, although the toxicity make it incumbent upon the sponsor to reduce the dose from 120 mg to 60 mg, the vote on question four would have been substantially easier for me personally at 120 mg than it is at 60 mg.
With that said, I think we should go ahead and vote.  I will read the question again and list the voting members.  Do the provided data establish that adefovir 60 mg is safe and effective for the treatment of HIV infection?
The voting members are Drs. Masur, Lipsky, Hamilton, Pomerantz, Wong, Yogev, Mathews, Stanely, Feinberg, El‑Sadr, Verter, Bertino, Kopp and me.
So, if you are voting yes on question four, please raise your hand.
[One hand raised]
One vote yes.  Those voting no on question four, please raise your hand.
[Show of hands]
I would state for the record that Drs. Feinberg, El‑Sadr and Pomerantz left their written votes as no.  So, the final vote is one yes and thirteen no.
We will then go on to a discussion of 4A.  If not ‑‑ and that is the consensus of the committee ‑‑ what additional data should be provided prior to reconsideration of this application for approval?
Rather than going around point by point, person by person, I will open this up for those who want to comment.  Dr. Bertino?
DR. BERTINO:  Well, I think it will be very important to have drug interaction information in patients with HIV disease, particularly in this case I am curious about things like saquinavir, using multiple doses of both antiretrovirals, indinavir and whatever other antiretroviral agents, and also adjunctive agents that are used for OIs, things like that.
I also think that more data in terms of pharmacokinetics of these agents in HIV patients is important.  I think that we saw some data looking at sex and at ethnicity earlier, and it was nice to see that data.  But it is becoming pretty clear that HIV patients are not the same as normal volunteers, and one of the speculations is that it is because of cytokine production.  So, there may be a need, if you are going to do drug interaction studies to even stratify by viral load, if you want to use that as a surrogate, or actually measure cytokines, which is being done in some centers now because pharmacokinetics and drug interactions may change over time as viral load drops.  Pharmacokinetics in children ‑‑ I was kind of left with what exactly ‑‑ under the age of two what kind of pharmacokinetic data was available.
I wonder if the drug shouldn't be dosed on a milligram/kilogram basis.  I know that may be considered the death knell for a drug but, as Dr. Lipsky pointed out, we may be seeing a dose‑response effect and the reason why the 120 mg and 60 mg curves bump up at a fairly similar point for nephrotoxicity may be due to exposure.  So, should we look at dosing the drug on a milligram/kilogram basis?
Then, finally, how should toxicity be handled, nephrotoxicity?  Should you reduce the dose?  Should you stop the drug?  Should you supplement?  Can you treat through it, etc.?
DR. STANLEY:  As we have already said many times, we need a placebo‑controlled study of 60 mg as well as the 30 mg.  I think it needs to be done in the appropriate populations that this drug is going to be targeted for.
I would also ask for more evaluation of the potential drug interactions.  I think it is very suspicious ‑‑ the saquinavir and delavirdine results with 120.  Perhaps we would avoid that with the 60 mg but I think we need to see more studies on drug interactions.
Finally, in addition to what has already been mentioned, we need to look at the effect of the 60 mg and 30 mg doses on the resistant viruses.  Do they have the same apparently positive results as the 120 mg dose does?  So, I think we need some good virologic studies at those lower doses.
I think that the two proposed 415 and 458 are good studies, and we need the data from those studies.  That would help tremendously I think.
DR. HAMMER:  Dr. Mathews, did you have a comment?
DR. MATHEWS:  You know, it is not so obvious to me how, in the target population of treatment advanced patients, you can cleanly do a placebo‑controlled study that isn't going to have the same problems that, for example, the 417 study did, where you are going to be comparing it to other drugs that are also active, and not still have the same problems of teasing out confounding by putative drug interactions.  So, if any of you have ideas on exactly how this would work ‑‑ I am just at a loss to see how that would work.
Secondly, I think increasingly these kinds of studies are going to have to have baseline susceptibility known in advance, and not this business of saving the samples and running them later.  I mean, this is not how we practice, particularly for the nucleoside analogs, this drug and others like it.  I think these things have to be known up front, and perhaps that is a topic for the discussion tomorrow and the next day.
DR. HAMMER:  Comments?  Dr. Yogev?
DR. YOGEV:  Very quick, I think the company should better define what experienced patients we are talking about, and really find the right niche and not such a vague experienced population because of the toxicity, and I would love to see them also doing some work on pregnant women, especially with a drug which is taken once day which, hopefully, will also be cheaper.  Thinking about the international implication of that, maybe they should look into concentrations of the drug in breast milk also as part of that.
DR. HAMMER:  Other comments or suggestions?  Dr. Masur?
DR. MASUR:  I am glad Chris brought up the issue of looking at efficacy because I think it is no small feat to look at efficacy in this kind of population with a single drug.  But I think, as Joe and others said, looking at toxicity is something which can certainly be better defined.  I guess I would be more comfortable with this drug if it was clear what predicted or correlated with toxicity and how reversible it was if there were less data missing, and it would appear that that data will be forthcoming.
DR. HAMMER:  I would just mention a couple of things.  I agree completely that the study design issues here are hugely challenging and teasing out the activity of a single drug is easy to say in the context of this committee and hard to do in practice.  But there are a couple of things that one could think about in relation to this drug.  One is that when it is added as a fourth drug to a three‑drug regimen, while we didn't see data that that made a difference, one could look at early slopes of decline of RNA if frequently monitored and at least get a handle on whether there is a greater potency to the regimen compared to a very acceptable standard of care regimen since depth and rate of decline are predictive of durability.  So, one could have an inference there.
I think Dr. Feinberg made the point, since this drug gets selectively stopped often ‑‑ in other toxicity areas, because of threats of resistance, we usually stop everything.  This is a drug where often it is stopped in isolation and where that is the case, in a more formal analysis of what is truly happening to viral rebound, if it is there, when this drug is stopped, would be an indirect measure but also a helpful measure.
I also think that a prospective randomized trial based on resistance at baseline would have been terrific to see here because, again, the virology could drive the decision‑making around this drug.  The point, to me, is not just that it has a niche but it has a niche for a particular reason because of the in vitro data and the 408 virology substudy that suggest that it is active against viruses carrying the 184.  One could define a trial based on plus/minus 184 at baseline, then randomized to whether patients need 3TC or something to maintain the 184 in the presence of this.  Then with or without an adefovir‑containing regimen, again seeing whether you are defining something where adefovir gives you an extra margin of efficacy.  So, I think the niche, which is an overused word today, that this drug has allows you to define a study that is virologically based that allows you to look at efficacy.
I think the tortured views that the committee has expressed today are, I think, based on the fact that a lot of us feel there is something clearly here.  It may be that with other generation drugs it will be much more clearly there.  But one would have liked and wanted to have seen the data to really believe it.  I think that one could design a study that is not too large that defines that, and that might have been more convincing to a majority of the committee.  But I think that some of those designs that are virologically based can help us tease out the efficacy, and the safety issues have been so well described by others that I won't comment any further on that.
DR. WONG:  I guess just to reiterate, I think that the safety issues, the pharmacology, the pharmacokinetics, all of those things ‑‑ of course, we need my information but in my mind the problem was in efficacy of the 60 mg dose.  So, if the sponsor could come back demonstrating that the 60 mg dose is efficacious, that would settle it for me.
DR. HAMMER:  I concur with those comments.  I would also just add that the assay now seems to be available and looked at in primates, a handle on adefovir diphosphate levels at different doses in peripheral blood mononuclear cells would be very interesting to see whether, in fact, there is a dose response or not a dose response with at least relationship to intracellular diphosphate levels and the RNA responses.
MR. SCHOUTEN:  I guess my comments are going to relate to the drug‑drug‑drug interactions and the complexity of assessing that.  I don't have any easy solution for that but with a drug that has apparently a fairly flat dose‑response curve and an intracellular activation is blood PK data adequate to reassure us that there is not an adverse interaction, and that is a challenge.  Particularly for a drug whose purported indication would be for deep salvage, that is even more of a challenge.
DR. LIPSKY:  I think I heard that the demand for the expanded use was 400 a month, and you would think, or it should be obvious that that is a desire for efficacy and that one should be able to design a study based on that need and that desire to more formally answer that question.
DR. HAMMER:  Any other comments?  Dr. Kimmel?
DR. KIMMEL:  I think that the data on using the drug after nephrotoxicity is established is very important, and I think renal and virologic parameters should be investigated, and that might give a lot of comfort to members of the committee.
DR. HAMMER:  There is one last question which I think we probably have addressed in the ranging comments that we have had throughout the afternoon, but for the record I will read it:  What additional recommendations do you have for further investigation of adefovir for HIV?
Does anyone have a comment on that?  I think one comment that was made earlier is in the co‑infected populations.  I think that should be restated for the record.  Another very important population is HBV‑HIV co‑infected individuals.
Seeing no hands raised, I would ask Dr. Jolson whether there are other issues or clarifications you would like the committee to discuss?
DR. JOLSON:  Maybe I could just make a quick comment because I think that a meeting like this is difficult for everybody involved, and I think it has been a difficult application for the committee to consider.  It has also been a difficult application for our team as well to consider.  And, I think that the comments that the patients made at the open public hearing ‑‑ it is hard not to take that to heart, as well as the size of the expanded access program which certainly makes it clear to us that there is a sizeable population out there in need of more options.
Hopefully, the message that I am hearing is that there is something constructive out of this.  It sounds like the major issue, as I understand it, is really the standard of efficacy being met in terms of definitively establishing the 60 mg dose and its activity, and that with that type of data, as well as with some of the additional ancillary issues considered, the committee would then feel it appropriate to reconsider the application.
DR. HAMMER:  If I could speak for the committee, and please feel free to interrupt if you disagree, although I think there was split opinion on question one, I think the consensus of the committee is that there truly is something here with this drug; that the desire of this committee was to actually believe that there were efficacy data there and to see the data in a fashion that one could feel absolutely comfortable with.
I do think the sense of the committee is that this should not be a closed issue, that further studies and investigation should be performed, and that we applaud the studies that were started because we think that some of those will give us additional answers, and that whatever additional information can come forward clearly to establish the 60 mg dose as efficacious is the key issue here because that is where the indication is, and the bulk of the information is at 120 but we need efficacy data at 60.
Although much was discussed about what we still don't know about nephrotoxicity, it relates to data collection that is in process or will come about, and in management of it and in patient and physician education.  I would at least personally say I don't see that as the show‑stopper.  I see the issue here coming in with clear‑cut demonstration of 60 mg efficacy data that the agency and the sponsor can agree on, such that if it comes before this committee again we have a clearer focus that there is something there.  Some of us tried to see it but it was not fully clear to us.
So, I think what you are taking away is that, in fact, we would encourage more information and reconsideration of this agent, specifically with convincing information about the 60 mg dose, and however quickly one can get there is what we would like to see because I think it is obvious that this committee shares the thoughts that were expressed at the open public hearing that we are not where we want to be and that options should be out there for patients and physicians, and that is the position this committee has taken before.
We have an obligation to look at the data and critically review it.  Also, under the issues of accelerated approval, there are issues of critically reviewing the information and we are dealing with this individual agent but also, in our minds, we are looking at the history of where we have come from and where we are going in drug approvals for this disease, and critical data analysis is clearly part of that.
So, we would love to see a study that is unequivocal, or at least marginally equivocal, that both the sponsor and the agency can agree shows activity at the 60 mg dose.
Anyone disagree with that lengthy response?  On that note then, I would like to thank the sponsor, Gilead Sciences.  I would like to thank the guests and consultants on the committee and the members of the committee and the agency, and particularly the FDA presentations today which were clear, and for the audience participation.  Thank you.  The meeting is adjourned.
[Whereupon, at 5:55 p.m., the proceedings were adjourned, to resume at 8:30 a.m., Tuesday, November 2, 1999]
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